Experiments that hint of longer lives Cynthia Kenyon
have you ever wanted to stay young a
little longer and put off aging this is
a dream of the ages but scientists have
for a long time thought this was just
never going to be possible they thought
you know you just wear out something you
can do about it kind of like an old shoe
but if you look at nature you see that
different kinds of animals can have
really different lifespans now these
animals are different from one another
because they have different genes so
that suggests that somewhere in this
gene somewhere in the DNA our genes for
aging genes that allow them to have
different lifespans so if there are
genes like that then you can imagine
that if you could change one of the
genes in an experiment an aging gene
maybe you could slow down aging and
extend lifespan and if you could do that
then you could find the genes for aging
and if they exist and you can find them
then maybe one could eventually do
something about it so we set out to look
for genes that control aging and we
didn’t study any of these animals
instead we studied a little tiny
roundworm called C elegans which is just
about the size of a comma in a sentence
and we were really optimistic that we
could find something because there had
been a report of a long-lived mutant so
we started to change jeans at random
looking for long-lived animals and we
were very lucky to find that mutations
that damaged one single gene called daph
to double the lifespan of the little
worm so you can see in black after a
month they’re very short-lived that’s
why we like to study them for studies of
Aging in black after a month the normal
worms are all dead but at that time most
of the mutant worms are still alive and
it isn’t until twice as long that
they’re all dead and now I want to show
you what they actually look like in this
movie here so the first thing you’re
going to see is the normal worm when
it’s about a college student age a young
adult it’s quite a cute little fellow
next you’re going to see the long live
mutant when its young so this animal is
going to live twice as long is it
miserable it doesn’t seem to be it’s
very active you can’t tell the
difference really and they can be
completely fertile have the same number
of progeny
the normal worms do now get out your
handkerchiefs here you’re going to see
in just two weeks the normal worms are
old you can see the little head moving
down at the bottom there but everything
else is just lying there the animals
clearly in the nursing home and if you
look at the tissues of the animal
they’re starting to deteriorate you know
even if you’ve never seen one of these
little C elegans probably most of you
haven’t seen one you can tell they’re
old isn’t that interesting so there’s
something about aging that’s kind of
universal and now here is the Deaf two
mutants one gene is changed out of
20,000 and look at it it’s the same age
but it’s it’s not in the nursing home
it’s going skiing so its aging actually
this is what’s really cool its aging
more slowly it takes us worm two days to
age as much as the normal worm ages in
one day and when I tell people about
this they tend to think of maybe a 90 or
80 or 90 year old person who looks
really good for being 90 or 80 but it’s
really more like this suppose here let’s
say you’re a 30 year old guy or 30 in
your 30s and you’re you’re a bachelor
and you’re dating people and you meet
someone that you really like you get to
know her and you’re in a restaurant and
you say well how old are you she says
I’m 60 that’s what it’s like and you
would never know you would never know
until she told you
okay so so what is the death to gene
well as you know genes which are part of
the DNA there are instructions to make a
protein that does something and the Deaf
to gene encodes a hormone receptor so
what you see in the picture there is a
cell with the hormone receptor in red
punching through the edge of the cell so
part of it it’s like a baseball glove
part of its on the outside and it’s
catching the hormone as it comes by in
green and the other part is on the
inside where it sends signals into the
cell okay so what is the def 2 receptor
telling the inside of the cell I just
told you that if you make a mutation in
the deaf to gene said that you get a
receptor that doesn’t work as well the
animal lives longer so that means that
the normal function of this hormone
receptor is to speed up aging that’s
what that arrow means it speeds up aging
it makes it go faster so it’s like the
animal has the Grim Reaper inside of
itself speeding up aging okay so this is
a really all together really really
interesting it says that on aging is
subject to control by the genes and
specifically by hormones so what kind of
hormones are these are lots of hormones
there’s testosterone adrenaline you know
about a lot of them these hormones are
similar to hormones that we have in our
bodies the deaf to hormone receptor is
very similar to the receptor for hormone
insulin and igf-1 now you’ve all heard
of at least insulin insulin is a hormone
that promotes the uptake of nutrients
into your tissues after you eat a meal
and the hormone igf-1 promotes growth so
these functions were known for these
hormones for a long time but our studies
suggested that maybe they have a third
function that nobody knew about maybe
they also affect aging and it’s looking
like that’s the case so after we found
made our discoveries with little C
elegans people who worked on other kinds
of animals started asking if we make the
same deaf to mutation the hormone
receptor mutation in other animals will
they live longer and that is the case
then flies if you change this hormone
pathway and flies they live longer and
also in Mice and mice are mammals like
us so it’s an ancient pathway because it
must have arisen a long time ago in
evolution so the touch that still works
in all these animals and they also the
common precursor
also gave rise to people so maybe it’s
working in people the same way and there
are hints of this so for example there’s
one study that was done in a population
of Ashkenazi Jews in New York City and
just like any population most of the
people you know will live to about 70 or
80 but some lived to be 90 or 100 and
what they found was that there were
people who lived to 90 or 100 were more
likely to have deaf to mutations that
has changes in the gene that encodes the
receptor for igf-1 and these changes
made the gene act may the gene not act
as well as the normal gene would have
acted they damage the gene okay so those
are hints suggesting that humans are
susceptible to the effects of these
hormones for aging so the next question
of course is is there any effect on
age-related disease as you age you’re
much more likely to get cancer elsa
murmurs disease heart disease all sorts
of diseases it turns out that these long
live mutants are more resistant to all
these diseases they hardly get cancer
and when they do it’s not as severe so
it’s really interesting and it makes
sense in a way that they’re they’re
still young so why would they be getting
diseases of aging until they’re old so
it suggests that if we could you know
have a therapeutic or a pill to take to
replicate some of these effects in
humans maybe we would have a way of
combating lots of different age-related
diseases all at once so how can a
hormone ultimately affect the rate of
aging how could that work well it turns
out that in the deaf to mutants a whole
lot of genes are switched on in the DNA
that encode proteins that protect the
cells and the tissues and to repair
damage and the way that they are
switched on is by a gene regulator
protein called Fox oh so when adapt to
mutant you see that I have the X drawn
here to the receptor the receptor isn’t
working as well under those conditions
the Fox out protein in Blue has gone
into the nucleus that little compartment
there in the middle of the cell and it’s
sitting down at a gene binding to it
where you see one gene there lots of
genes actually that by now Fox oh and
it’s just sitting on one of them so Fox
though turns on a lot of jeans and the
genes that turns on includes antioxidant
jeans jeans I call caregiver genes whose
protein products
actually help other proteins to function
well to fold correctly and function
correctly and it can also escort them to
the garbage cans of the cell and recycle
them if they’re damaged DNA repair genes
are more active in these animals and the
immune system is more active and many of
these different genes we’ve shown
actually contribute to the long lifespan
of the deaf to mutant so it’s really
interesting these animals have within
them the latent capacity to live much
longer than they normally do they have
the ability to protect themselves for
many kinds of damage which we think
makes them live longer so what about the
normal worm well when the deaf to
receptor is active then it’s triggers a
series of events that prevent foxo from
getting into the nucleus where the DNA
is so it can’t return the jeans on
that’s how it works that’s why we don’t
see the long life spin until we have the
deaf to mutant but what good is this for
the worm well we think that the insulin
and igf-1 hormones are hormones that are
particularly active under favorable
conditions and the good times when food
is plentiful and there’s not a lot of
stress in the environment then they
promote the uptake of nutrients you can
store the food use it for energy grow
etc but always think is that under
conditions of stress the levels of these
hormones drop for example having limited
food supply and that we think is
registered by the animal as a danger
signal a signal that things are not okay
and that it should roll out its
protective capacity so it activates Fox
oh so goes to the DNA and that
triggers the expression of these genes
that improve the ability of the cell to
protect itself and repair itself and
that’s why we think the animals live
longer so you can think of foxo as being
like a building superintendent so maybe
he’s a little bit lazy but he’s there
he’s taking care of the building but
it’s deteriorating and then suddenly he
learned that there’s going to be a
hurricane so he doesn’t actually do
anything himself he gets on the on the
telephone just like Fox Oh gets on the
DNA and he calls up you know the roofer
the window person the painter the floor
person they all come and they fortify
the house and then the hurricane comes
through and the house is in much better
condition than
would normally have been in and not only
that it can also just last longer even
if there isn’t a hurricane so that’s
that’s the concept here for how we think
this life extension ability exists now
the really cool thing about växjö is
that there are different forms of it we
all have foxo genes but we don’t all
have the same so exactly the same
form of the Fox Oh gene just like we all
have eyes but we still of us have blue
eyes and some of us have brown eyes and
there are certain forms of the Fox
though gene that have been found to be
more frequently present in people who
live to be 90 or 100 and that’s the case
all over the world as you can see from
these stars in each one of these stars
represents a population where scientists
have asked okay are there differences in
the type of foxo genes among people who
live really long time and there are we
don’t know the details of how this works
but we do know then that foxo genes can
impact the lifespan of people and that
means that maybe if we tweak it a little
bit we can we can increase the health
and longevity of people so this is
really exciting to me a fox 0 is a
protein that we found in these little
round worms to affect lifespan and here
it affects lifespan in people so we’ve
been trying in our lab now to develop
drugs that will activate this human this
fox so cell using human cells now in
order to try to come up with drugs that
will delay aging and age-related
diseases and I’m really optimistic that
this is going to work there are now lots
of different proteins that are known to
affect aging and for at least one of
them there is a drug there’s one called
tour which is another nutrient sensor
like the insulin pathway and mutations
that damage the tour gene just like the
Deaf two mutations extend lifespan and
worms and flies and mice but in this
case there’s already a drug called
rapamycin that binds to the tour protein
and inhibits its activity and you can
take rapamycin and give it to a mouse
even when it’s pretty old like age 64 a
human we’ve got old for a mouse if you
give the mouse rapamycin it will live
longer now I don’t want your all to go
out taking rapamycin it is a drug for
people but the reason is that it’s it
suppresses the immune system so people
take it to prevent organ transplants
from being rejected so
this may not be the perfect drug for
staying young longer but still here in
the Year 2011 there’s a drug that you
can give to mice at a pretty old age
that will extend their lifespan which
comes out of this science that’s been
done in all these different animals so
I’m really optimistic and I think that
it won’t be too long I hope before this
age-old dream begins to come true thank
you
Thank You Cynthia um let me get this
straight although you’re looking for a
drug that could solve Aging in in sort
of old men like me what you could do now
pretty well in the lab if you are
allowed Ithaca Lee is start a human life
from scratch with altered genes that
would make it live for a lot longer ah
so should you said the kinds of drugs I
was talking about would not change the
genes they would just bind to the
protein itself and make it change its
activity so if you stop taking the drug
the protein would go back to normal you
could change the genes in principle
there isn’t the technology for a human
to do that but I don’t think that’s a
good idea and the reason is that these
these hormones like the insulin and the
igf-1 hormones and a tour pathway
they’re essential if you knock them out
completely then you’re very sick so it
might be that you would just have to
fine-tune it very carefully to get the
benefits without getting any any
problems and I think that’s much better
that kind of control it would be much
better right right drug and also there
are other ways of activating so
that don’t even involve insulin or igf-1
that might even be safer right so
there’s I wasn’t suggesting that I was
going to go and do it but Tim well um
what about there’s a phenomenon which
you have written about and spoken about
which is negligible senescence there are
some creatures on this planet already
that don’t really do aging just move to
one side for us if you would and there
are there are some animals that don’t
seem to age for assembly are some
turtles called our tortoises called
Blandings turtles and they they grow to
be odd this size and they’ve been tagged
and they’ve been found to be 70 years
old and when you look at these 70 year
old Turtles you can’t tell the
difference just by looking between those
turtles and 20 year old Turtles and the
70 years old ones actually they’re
better at scouting out the good nesting
places and they also have more progeny
every year so and there are other
examples of these kinds of animals that
like turns you know certain kinds of
birds are like this and nobody knows if
they really can live forever or what
keeps them from aging it’s not clear if
you
get um if you look at birds which live a
long time that cells from the birds tend
to be more resistant to a lot of
different environmental stresses like
high temperature or hydrogen peroxide
things like that and our long live
mutants are too they are more resistant
to these kinds of stresses so it could
be that the pathways that I’ve been
talking about which are set to run
really quickly in the worm or has it
have a different normal set point in in
something like a bird so that a bird can
live a lot longer and maybe they are set
really even differently in animals with
no senescence at all but we don’t know
but what you’re talking about here is
not extending human lifespan by
preventing death so much as extending
human youths palace that’s right it’s
more like say if you were a dog you
notice that you’re getting old and you
look at your human and you think why
isn’t this human getting old they’re not
getting old and in the dog’s life span
it’s more like that but now where the
human looking at looking out and
imagining a different human all right
thank you very much indeed since again