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