Cynthia Kenyon (UCSF): A Genetic Control Circuit for Aging

Uploaded by ibiomagazine on 08.01.2011

So I'm going to be talking about how we came to study
genes for aging, or to ask whether there were genes for aging,
that is genes that affect aging. We started this work in the early 1990s, and at that time
people didn't think that aging was subject to any kind of control
by the genes. They thought you just wear our like an old car wears out.
There are several reasons why I thought maybe this would be wrong,
that this idea was simplistic.
One is, that if you just look around in biology, nothing just happens.
It seems like everything is regulated, everything seems to be
subject to control by the genes
and when you look at different species of animals,
you see that they can have really different lifespans.
So the reason they have different lifespans is obviously because they have different genes.
So that tells you right off the bat that genes have a lot to do with the lifespan of an animal
I had been working in the field of developmental biology,
and during the time, during the early 1980s and 1990s it had become really clear
that basic fundamental mechanisms of life are conserved evolutionarily.
I lived through this realization in the field of developmental biology
when genes that pattern the body of worms, which is what we worked on
were the same as genes that patterned the body of fruit flies and mice,
which was amazing because these animals look so different,
but there was a lot of commonality there.
The same thing was happening in other fields,
like the cell cycle is driven by the same kinds of genes in different kinds of animals.
So it seemed that something so fundamental as aging, which seems to be evolvable
in other words, there are different animals that have very different lifespans,
so evolution can definitely change the rate of aging.
So anyway, it seemed to me that there might be genes
that controlled aging, so to find those genes, if an animal has them, you can just
treat an animal with something that causes mutations and look for long lived mutants.
We didn't study this in humans, instead we studied it in our little worms,
C. elegans, which is really nice for this kind of study because it is small, and simple,
and it has a very rapid lifespan of just a few weeks.
Actually, at the time we started our experiments,
it was already known that there was a gene that affected the lifespan of C. elegans
and if you change this gene, the animals could live about 50 percent longer than normal
but there was a lot of mystery surrounding this gene, because these mutants for one thing
were not very fertile, and so evolutionary biologists thought that
it was possible that the reason they live long was that
they didn't have to channel all of their resources into reproduction,
and so they would have more to live longer.
But to me it seemed like maybe it wasn't such a simple trade-off,
maybe there really were genes that controlled aging.
And I should say one more thing, which is I was really fascinated by several things
that had been known for a long time, one was Progeria. There were human mutants
that aged much more quickly than normal, so that was really interesting to me
and the other thing was that there was a phenomenon
called the Hayflick limit, where you put cells in culture,
they would just divide several times or a few number of times, and then they would stop dividing
and it had been reported that if you took the cells from a young person or animal,
they divided more times than from an old individual,
and so there was some kind of intrinsic clock for aging. So it was such a fascinating field
and it was discarded by molecular biologists, they just though there is nothing to study,
and so we thought we would give it a try. So I then decided,
okay well I'm going to look for genes that affect aging.
We already had a lab working on C. elegans,
they were studying development, but my lab members had no interest in aging,
they thought it was a real kind of a, what's the word, a swamp, is that the word?
Anyway, not very interesting. Most people had that idea because there was nothing to study.
Among molecular biologists, the field of aging had kind of bad reputation.
So I couldn't get anyone to work on the project, and the idea was to look for long lived mutants
So I kept trying and trying, and there were these students
called rotation students who come into UCSF, where I work, UCSF
and before they join a lab to get their Ph.D. they spend their time in each of three labs.
So I tried to interest these students and they weren't interested.
But then one student named Roman Tatiana thought finally
that it was a great idea, and he decided to look for long lived mutants.
So amazingly enough he set out to look for long lived mutants and he found one
He found that mutants that reduce the activity of a gene called daf-2 double the worm's lifespan.
Here you see in black, you see the lifespan of a normal worm
so by the end of 30 days, or about a month or so
all the worms are dead. But you see in red, the daf-2 mutant,
lives twice as long as normal, even more than twice as long.
The thing that was the most cool about this, was that the worms were, they didn't just go
into the nursing home and hang on, they were actually aging more slowly than normal
and I have a movie here to show you this.
What this shows you first, is a normal worm, just to orient you.
So this is a young C. elegans adult, where it is about graduate student age
it's three days in worm time, and this is the long lived mutant when it is young,
and the reason I am showing you this is that the mutant looks healthy
and active, it looks great. And in fact these mutants can be completely fertile
so there is no reproductive trade-off involved here.
Here is a normal worm where it is old. You can see that its head is moving here
but otherwise it looks like it is about to die, and it is about to die.
And now next you are going to see the long lived mutant at the exact same age
and what you'll see is that the mutant
these are some more, a dead worm here and here is a worm in the nursing home
So now what you are going to see is at the same time, the long lived mutant looks much younger
than this, and I actually tell people about this, and they end up thinking
oh it's like being 90 but looking really good when you're 90
but like a 90 year-old who is healthy. But it isn't and here is a little analogy
it's like this, suppose you are single and maybe in your 40's,
and you are dating, and you find someone who you really like
and you go on a couple of dates, and then you go with them to a restaurant
and then you are sitting there with them and they ask well how old are you
and they say, oh, I'm 80, and you go oh-my-gosh because they look 40.
That's what it is like, it's like they took two days to age as much as you normally age in one day.
So it's something that, the reason I keep emphasizing this is that people
don't realize this is not something in our experience,
we never thought this kind of thing could happen, but it did.
We just change one gene and we double the lifespan.
So I have told you that was really hard to find anyone to work on this project
well Roman, the rotation student who just made this discovery
didn't join our lab, he went to another lab
and I still couldn't get anyone to work on the project
but there were all these experiments that we wanted to do with daf-2 mutants,
so we kept asking rotation students if they wanted to work on it, and they all did,
they liked to work on it, so one after another they would come to the lab
and they would do some more experiments on the daf-2 mutant,
and finally we wrote a paper, and Nature published the paper,
and except for me, every single person on the paper was a rotation student.
The amazing thing is that not one of those rotation students joined the lab.
They all went to other labs, and it was really a long time before anyone decided that aging was a
sure enough bet for a Ph.D. thesis that they would actually come to the lab and work on it.
So what is this gene, what is this daf-2 gene?
Well the Gary Ruvkun lab cloned the gene, and they found that daf-2 encodes a hormone receptor
So that means hormones control aging, and not only that,
it is similar to receptors that we knew about, number one, the human receptor for insulin,
which is a hormone that controls nutrient uptake,
and also it was similar to a hormone called IGF-1
which controls growth, and these hormones are similar to one another
that is, it was similar to the receptor for these hormones.
Okay, so what our findings had showed was that the worm's version of the same receptor
had a third function, it also controlled aging
and we now know what that happens is when you slightly damage the daf-2 gene,
the animals sees it as a signal for danger so it
rolls out a protective stress response, and that's what makes it live longer.
But anyway the big question then of course was is this just a worm thing,
or is this also the case for higher organisms. And I'll just say really quickly
that inhibiting this gene can extend the lifespan of flies, or mice, and there's a study of
Ashkenazi Jews carried out by Nir Barzilai, and he showed that
centenarians are more likely to have reduced function of the IGF-1 receptor gene
than are Ashkenazi Jews that die earlier. So at least in this population,
this mutation in the same gene have been linked to exceptional longevity.
We also found a gene called daf-16 is needed for the long lifespan,
and humans have this gene, and it's called FOX-O
and it turns out that FOX-O variants are associated with exceptional longevity
in populations all around the world. These little stars represent a population,
showing that variants in this longevity gene are present in people who live a long time.
So I think the bottom line here is that we started because we had an idea, I had an idea,
that aging would be regulated. We were really really lucky to find the daf-2 gene,
in fact my colleagues had said to me, one of them said, "You know, I knew people who started to
work on aging and they just fell off the edge of the earth
as if the earth was flat, they just fell of the edge of the earth",
but in this case we didn't fall off the edge of the earth, we found something really really interesting
that may be conserved in humans, and actually these mutants
are resistant to lots of diseases so there are all sorts of potential here for
improving human health, but that's the story. Thank you.