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Welcome to part two of my lecture series. When we finished the first lecture
what we were talking about was whether there might be environmental factors
that could change the level of hormones present in the worm
that would then change the activity of the insulin/IGF-1 system
which would then lead to a longer lifespan.
And we discussed the possibility, or the likelihood
that the response to caloric restriction,
that is, eating less than you want to eat, is actually
mediated at least in part, in some animals through this insulin/IGF-1 pathway.
Now what I'm going to do is to tell you something
else that's really interesting that we discovered
which is that in C. elegans, sensory perception
regulates the insulin/IGF-1 pathway.
In other words, something that the worm
is either smelling or tasting is affecting its lifespan.
So, let me introduce you first to the sensory apparatus of the worm.
This is the beautiful face of C. elegans.
You can see its lips here. It has six lips. Here.
And what you see is...see right here? There's a little nostril.
There's another one right over here.
This is the nose of the worm and this is where the sensory neurons are.
So here you can see the sensory neurons.
Here are the endings. So here's the outside, here.
And this is the inside. The worm is now standing up.
So its head is up and its tail is down.
And you see these sensory neurons here. These are the endings.
So these little neurons allow the worms to smell
and taste things that are in the environment.
And worms move towards things they like, like sugar,
and away from things they don't like, like garlic.
But what we discovered in our lab was that mutations
that prevent the worm from smelling or tasting
as well as it normally would extend the lifespan of the animal.
So what you see here in this slide are lifespan curves
of nine different mutants. Each mutant is
defective in one gene that encodes a protein
that's required for sensory perception.
And what you can see is all the mutants are long-lived in red. You see them all?
They're long-lived. So one thing you should know is that
these worms are not calorically restricted.
They're eating as much food as they want.
They eat a lot of food, as much food as normal worms eat.
And if you calorically restrict a worm it has delayed reproduction,
but these worms don't have delayed reproduction.
So they're not calorically restricted, yet they're living longer.
So, we also found that we could change genes that...
all these lifespan curves that I'm showing you here
are from the lifespans of worms with defective genes
that are needed for the structures of these neurons.
But we also found that we could make mutations
or knock-down genes whose protein products are actually
specific chemosensory receptors, proteins that are situated
right here at the very tip of these neurons
with one face open to the outside world and the other end inside the neuron.
And knocking down those kinds of proteins also could increase lifespan.
OK, so this is our model. I'm not going to go into all the details about it.
The model is that there's in the environment
that worms are smelling or tasting that's affecting their lifespan.
And we think that at least part of the way this works
is by regulating the activity of the insulin/IGF-1 pathway.
Now, why do we think that? First of all, I told you earlier
that if you inhibit the activity of the DAF-2 hormone receptor
or this pathway in various different places, worms live long,
and that they have to have DAF-16, the transcription factor,
in order to live long.
And we found that DAF-16 was also required in order
for these sensory mutants to live long.
In fact, if you make a mutation that only affects
a protein right here, in the tip of the worms nose,
DAF-16 protein accumulates in all the nuclei
of all the cells in the animal. It's amazing.
Also, if we take a daf-2 mutant that already lives long,
and we make changes in these sensory genes, the worms don't live any longer.
OK, so this is our model. The model is that
the cell bodies of these sensory neurons,
which are shown here, contain the hormone.
And they do. We know...C. elegans has about 30 or 35 genes
that encode insulin and IGF-1 like proteins
and many of them are expressed in these neurons.
So, the idea is that there's something in the environment
that is regulating the activity or the release of these hormones.
So, for example, the idea is that when the worms
are in their normal environment
these hormones are being released rapidly
and so they bind to the receptor and speed up aging.
But when we make a mutation that knocks down the activity
of this pathway by screwing up these sensory neurons,
then there's less hormone so the activity of the receptor
is down so the worms live longer.
So that's our model.
So now we've been asking...it's clever I should say.
It's clever. I forgot to say this.
What the worms seem to be doing, possibly,
is responding in advance to a changing environment.
You can imagine, caloric restriction extends lifespan
but in order for that to happen you have to actually be hungry.
But if you just have to smell or taste the difference
you may be able to get a head start on a response to a poor environment.
OK, so the question is: Which neurons influence lifespan?
There's two possible models you can imagine.
One is that one neuron or one pair of neurons, one in each nostril
affects lifespan and that's it.
The other possibility is that all of those neurons in the nostrils are affecting lifespan.
Each one...there's 12 in each so each one would have
about one twelfth of the total amount of effect.
So we decided to see which was the case or if maybe there was
a third possibility by changing...
we decided to do this by killing individual neurons with a laser.
And so what we found was really interesting.
We found that killing one gustatory neuron or taste neuron
extends the lifespan of the animal. So let me show you how we did this.
This is a picture here of part...it's really the worm's throat here.
The nose is out here in this region.
And this is where the cell bodies are.
So we can take a laser and point it at one particular cell and kill that cell.
And we can do that in lots of animals and then see if the animals live longer.
And we found that if we kill this one particular cell,
they live long as you can see here in green.
And then what we found was the following.
That if we killed a different gustatory neuron
called J, which is located right there, called J,
as well as the first one (we killed both), they don't live any longer.
OK, isn't that interesting? So here we have one neuron that promotes longevity
and one neuron that inhibits longevity.
OK, so here's another way of just telling you what I already told you.
If we kill this one taste neuron, we have a long lifespan.
If we kill that same taste neuron plus J,
we live a normal life. We have a normal lifespan.
OK, now there are also neurons that mediate the response to smell.
So we can...to smells, they're olfactory neurons. So we can kill those neurons also.
So if you kill one of these smell neurons, in many cases, the worms live longer.
And actually, if you kill a taste neuron and a smell neuron,
both in the same animal, then they live even longer.
OK, so now what happens if we take an animal and we kill a smell neuron
plus J, plus this neuron?
Smell neuron plus J. Do we have a normal lifespan,
the way we did when we killed the taste neuron plus J?
Or do we have a long lifespan? The answer is we have a long lifespan.
OK, so killing J can affect the lifespan of an animal that lacks
the taste neuron but not an animal that lacks the smell neuron.
So, in other word, J is talking to this neuron but not this neuron.
You see? So they're having little, private conversations with each other.
So this is really interesting. We also find that if we kill
certain other neurons, nothing happens.
So it looks as though neither one of our two models is correct.
It's not just one neuron matters,
but it's also not the case that all the neurons have the same function.
It looks as though there's a lot of sensory discrimination
going on in the brain of this worm that's affecting its lifespan.
So, these and other findings I don't have time to
tell you about suggest that the lifespan of C. elegans is
influenced by its perception of both soluble compounds
that it tastes and volatile compounds that it smells in the environment.
So, of course, we always ask the question:
If smell and taste affects the lifespan of worms,
is this true in other organisms as well? And very recently it was shown that...
well, I'm going to get to humans in a minute.
Very recently it was shown that the fruit fly Drosophila
that its lifespan is also regulated by sensory perception.
In other words, if you change the ability of the fly to smell, it can live longer.
So what about humans? We don't know.
And it's kind of a scary thought that something that you smell or taste
could affect your lifespan. But, I'll just leave you with one thought,
which is that if you eat some food,
your insulin levels rise. But, if you also smell the food
that you're eating, they rise even more.
Alright, what about reproduction and aging?
It's a fascinating question of great interest to evolutionary biologists
and to everyone.
What is the link between longevity and reproduction?
I already sort of mentioned in lecture number one
that there's not a necessary decrease
in reproduction in order for daf-2 mutants to live long
And, in fact, there are a lot of long lived mutants now
that have even more progeny than normal.
So there doesn't have to be a direct trade off
between the length of life that you have
and the number of offspring that you can have, which is good.
However, I should tell you that if you lower the activity
of the daf-2 receptor a fair amount,
then you get a long-lived worm that does have fewer progeny.
OK, so the same gene, the daf-2 gene, controls reproduction and aging both.
But you can uncouple them from one another.
In other words, if you just lower the level of the gene a little bit,
you live long and you reproduce perfectly well. If you lower it a little bit more,
you still live long, but now you have problems reproducing.
So now we've talked actually about three things this gene does:
it controls reproduction; it controls growth, and it controls aging.
Now what I want to tell you is something really interesting
about the reproductive system and aging.
It turns out that the reproductive system
actually controls the aging of the worm.
So to tell you that first I have to introduce you to it.
So what you see here is the reproductive system of the worm
when it's just hatched from an egg.
It has four cells in it. These two blue cells here give rise to the germ line.
And these two green cells, here, give rise to the somatic reproductive tissues
like the uterus and the ovary and so forth.
Well, what we found several years ago was that removing the germ line,
again with a laser, extends lifespan.
So here in black you see a normal worm and in blue you see the lifespan
of a worm that doesn't have any germ cells
and they live a lot longer.
It's amazing, 60% longer. So you might think,
"Alright, are they living long because they're sterile?"
But, that's not the case and the reason we know that is because
if you take a laser and you kill all four cells,
they don't live long and now they have a normal lifespan.
So they're still sterile but they don't live long.
So what this means then is that both the germ cells
and the somatic cells are affecting lifespan.
So we have a new signaling pathway here:
from the reproductive system to the rest of the animal.
The germ cells somehow, these two blue cells,
are making something that is inhibiting longevity because
when we kill the germ cells the worms are living longer.
Whereas the green cells are making something that is promoting longevity
because when you kill those then you shorten the lifespan.
OK. So, we have sort of equal and opposite effects here.
So, the germs cells are kind of in charge. It's really interesting.
The germ cells are giving rise to the next generation.
They become the next generation,
but they're also controlling the aging of the body of the animal.
So they're in charge of everything.
So you might say, "Well, why is that?"
Is that so that an animal that lacks germ cells can live long,
which seems kind of odd?
But, so we thought, "Well, why might this have evolved,
a system like this?"
And our favorite idea is the following.
The idea is that maybe having the germ cells control
the aging of the body allows the animal to coordinate
the process of aging with reproduction.
OK. It's obviously important that an animal reproduce when it's in its prime.
So, let's just see what would happen, according to this model,
if something happened to the germ cells.
So, suppose the development of the germ cells were delayed somehow.
Well, then of course the animal would also reproduce later.
Its production of progeny would be delayed.
So you might worry. You might think, "Uh oh, I hope the
worm isn't going to be too old to have progeny."
But it wouldn't because you would also be slowing down the aging of the body.
So, that would keep the animal in its prime when it's ready to produce progeny.
So, you see how potentially this system could allow the animal to coordinate
two really important things it has to do; its rate of aging with its reproduction.
OK, so how does germ line removal extend lifespan?
Well, that same transcription factor DAF-16/FOXO
is required because in animals lacking that gene
if you kill the germ cells the worms don't live long.
They still have normal lifespan.
So DAF-16 is involved. And I'm not going
to go into all the details because I don't have time.
But what I'll just tell you is removing the germs cells activates
another kind of hormone pathway, a steroid hormone pathway.
And these hormone pathways activate DAF-16 which extends lifespan.
And this is work from two labs; from the Antebi lab
who's discovered a sterol hormone called dafachronic acid
that acts in this pathway and Etienne Baulieu's lab
in collaboration with our lab whose work implicates
a different steroid hormone, pregnenolone, in this pathway.
OK, so what happens now if we take a worm and we change the daf-2 gene
and the reproductive signaling system both in the same animal?
What we get is something quite amazing.
We get an animal that lives six times as long as normal.
So, normal worms in this experiment have a lifespan of 20 days on average.
These worms lived 126 days. And what's really spectacular
is that they stay young and healthy for a really long time.
So this is a movie of these worms when they were 144 days old.
And you can see that they're moving.
If you think back to the slide...the movie that I showed you
at the beginning of the first lecture series.
Remember that worms that were 13 days old, that were just lying there,
in the nursing home. These animals are ten times as old,
and they're still moving around.
So, it's absolutely remarkable that you could do this,
that you could make a few very small changes
and produce a six-fold extension of lifespan is just amazing.
And it really makes you...this would be like people that live to 500.
So it really makes you wonder just what's possible.
I'm not saying that people could live to 500. I don't know. We don't know.
But, in human terms that's what it would be like and they're on the golf course.
OK, what about mammals?
Could the reproductive system affect lifespan in mammals?
It does. The lab of Gary Anderson and Jim Carey have shown,
those two labs have shown
that if you take a mouse and you remove
its own reproductive organs, the female mouse,
and you let it get old and then you introduce
the reproductive tissues from a young mouse into an old mouse
the old recipient mouse lives longer.
So, in other words, putting young reproductive tissues into
an older mouse extends the lifespan of the older mouse.
It's amazing because somehow the reproductive system is sending signals
to the rest of the body telling it not to age as fast.
We don't know at all how this works or if it's
related to the system I've been telling you about.
But, it's pretty cool because it's the reproductive system.
OK, so now the last thing that I want to talk about in my lecture series here
is what links normal aging to age-related disease?
This is a really important question.
There are all sorts of diseases that you get at
a much higher frequency if you're old.
You're 100-times more likely to get a tumor at age,
say, 65 than you are at age 35, much more likely.
And the same with lots of other diseases like Alzheimer's disease,
cardiac malfunction, all sorts of things.
So, what is it? Why is it that an older individual is more susceptible.
Well, you can ask the question genetically.
You can say, "Here's a pathway, the DAF-16/DAF-2 pathway
that affects aging. So, does the same pathway affect age related disease?"
And the answer is yes. And it's quite remarkable just how pervasive this effect is.
So let's start here with worms.
You can cause worms to get Huntington's disease or Alzheimer's disease by
expressing the genes that cause those diseases
in the worm and it turns out that the long-lived daf-2 mutants
are resistant. They get the diseases but not until they're much older.
Worms, normal worms actually, develop a muscle condition
that's very similar to human sarcopenia
where the muscles start to deteriorate when they get old.
And the daf-2 mutants get that condition later.
In the case of flies they've done a very interesting experiment.
If you take an electrical shock and you
deliver it to the heart of a young fly at a certain strength, the fly is fine.
But if you give an old fly that same shock, its heart fails.
But if you take this long-lived insulin/IGF-1 receptor mutant fly
and you do the same thing to it,
you stress the heart, even when it's old,
even when it's on its deathbed, the heart's fine.
So, in this case the heart seems to be in better shape
than the rest of the animal.
So there's an affect on cardiac function.
In mice we know that cancer is delayed in these long-lived animals.
And there are unpublished reports now of a lot of
other diseases as well that are delayed.
OK, so it looks like these animals really are young in every sense of the word.
They look young and they're young in the sense that
they're not susceptible to age-related diseases.
OK, so I'm going to tell you a little bit now about one particular
age-related disease that we've been studying in our lab.
Oh, first before I do, I meant to tell you that this ushers in the possibility
of a brand new therapeutic strategy where we go after
lots of age-related diseases all at once by going after aging.
In other words, if we can slow down aging, then we can slow down
cancer, heart disease, protein aggregation diseases,
all the diseases of aging potentially.
So it's...we don't know if this would really work,
but it seems to be working for worms at least
and these other animals as well so the potential is huge.
And actually I founded a biotech company called
Elixir Pharmaceuticals that's trying to
develop compounds like that, to go after age related diseases
by going after aging itself, pathways that control aging.
OK, so now what I want to do is to tell you about
some work that we've been doing in our lab
on tumors that worms get. So, worms normally don't get tumors.
But you can cause them to get tumors with a mutation.
This is what...and these tumors affect the germ cells.
So, now what I want to do is introduce you to the
reproductive system of the normal adult worm.
I showed you before the reproductive system of the animal
at hatching when it only had four cells,
but now I'll show you what they look like when they're adults.
So what you can see is the reproductive system is huge,
here and it has these green cells, here, are the oocytes.
And these red cells here are the stem cells, the germ line stem cells that keep dividing in the adult
to replenish the germ cell population.
OK, so now mutations in a gene called GLD-1 which stands for germ line
defective number 1 cause germ line tumors.
And I'll show you what these look like.
What happens...so this is what the normal reproductive system looks like, again.
Here in green you see the oocytes.
But now look at this. In the mutant these oocytes
change their mind and they start to proliferate again.
They become very similar to these stem cells here.
And they divide and divide and divide and pretty soon
they fill up the whole ***
and they burst out of the *** and they fill
the whole entire animal up and then the animal dies.
So its lifespan is about half of what it would be normally.
OK, so we wanted to know: Do mutations
that extend lifespan delay the gld-1 tumor phenotype?
OK, do they delay the tumor?
OK, now there are lots of different longevity pathways in C. elegans.
And I'm just going to remind you of the ones I told you about
and tell you about a couple new ones.
First of all there's the insulin/IGF-1/FOXO signaling pathway
that I've been telling you about.
There's also caloric restriction, you can get worms...
you can calorically restrict worms by using a mutation
that prevents the animal from eating food very well.
That's an eat-2 mutant and those worms live longer.
You can also get worms to live long by perturbing
the mitochondria in various ways.
If you make mutations that inhibit respiration, worms live long.
And one of these mutations is one that's been studied
in the Hekimi lab called isp-1.
And another mutation that affects the production of ubiquinone
also studied in the Hekimi lab is called clk-1.
And these mutants also live long.
And this pathway seems to be different from either caloric
restriction or the insulin/IGF-1 pathway.
OK, so the question is: What happens to these tumors in these mutants?
All these pathways are conserved so it seems like
a reasonable question to ask because
what we learn in worms may have relevance for higher organisms.
And as I already told you, both caloric restriction and insulin/IGF-1 signaling
are known to extend lifespan and delay tumors in mice.
OK, so we wanted to see what we could learn from the worm.
So there were several possible outcomes. I should tell you right away that
there are mutations in mice that have been described that affect proteins like
p53 and other proteins that have a kind of bad effect on the animal.
They suppress the formation of tumors, but they speed up aging.
So there's a trade off there. You benefit by not having a tumor, but
you don't really benefit because you're dead anyway
because you die of premature aging.
So one possibility would be that any or all of these pathways
could actually cause the tumor...if the worms would live long
without the tumor, but they might speed up aging.
That's one possible outcome. The next possible outcome is that
there's no affect on the tumor.
In which case, the animals would still die from the tumor at a normal time.
And the third possibility is that these mutations would cause
the animals to get the tumors later in life.
So the animals would live longer.
And what we found is that all of the longevity mutations
extended the lifespans of the tumor mutants;
the caloric restriction mutations, the daf-2 mutations,
and also the mitochondrial mutations.
The daf-2 mutants were amazing.
They were completely immune to the lifespan shortening effects of the tumors.
This is normal worm here in gold.
That's its lifespan. They're all dead in this experiment by about 25 days.
And this is what happens if you just introduce the tumor
mutation into a normal worm.
You cut the lifespan in half.
And now out here you see the wonderful long daf-2 lifespan in red
and you see that it doesn't really shorten much at all,
if any. It's not statistically significantly different
if you introduce the gld-1 mutation.
In other words, in a daf-2 mutant the gld-1 mutation no longer kills the animal.
The tumor doesn't kill the animal. So, why not?
Here's what the animals look like. Let me just introduce you to this.
This is a little line drawing of the head of a worm.
Here's the pharynx, here. And this is the intestine here.
And what you see here in this drawing or this photograph are the nuclei
of cells that are stained with DAPI, which is a stain for DNA.
And now, look at this. This is the gld-1 tumor mutant.
And what you see is that the animal is just jam packed full of germ cells.
And that's why it dies very soon, very early.
But this is what the tumor looks like in the daf-2 mutant. It's much smaller.
There still...it doesn't look normal. You don't have the oocytes back,
but there are 50% fewer germ cells here.
And so it doesn't...it's no longer toxic or lethal to the animal.
OK, so how exactly do these longevity mutations inhibit the tumor?
What are they doing?
Well, first of all let's talk about what the gld-1 mutation does.
It does two things...it causes a tumor.
It does two things; it speeds up or it promotes cell division
and it prevents apoptosis. Apoptosis is programmed cell death.
So, in the gld-1 mutant...normally in a normal germ line some cells just die.
But in the gld-1 mutant they no longer die.
OK, so if you have fewer dead cells and you have more cell divisions,
you're going to get a tumor.
And that's what happens.
OK, so what do the daf-2 mutations do to delay the growth of the tumor?
Well, the first thing is they cause apoptosis to occur.
So here is the normal worm, called N2.
Here's the apoptosis that you see in the normal worm.
Here's the tumor mutant where it's gone.
And you see in the daf-2 mutant it comes back partly.
And here in this part you see these two little dots here
are little cells that are undergoing cell death.
They're stained with something that is specific for cells
that are undergoing apoptosis.
The daf-16 gene is required for this.
What about p53?
p53 is a famous tumor suppressor gene that's known
to play a role in apoptosis in mammals.
So is it required?
Yes, it is. Here what you see is a normal worm.
There's a certain amount of apoptosis.
Oh, I'm sorry, this is a worm treated with gld-1 RNAi so it has a tumor.
So the level is low. You have a little bit because the RNAi
is not quite as effective as the mutation.
It goes way up in a daf-2 mutant, and then it goes back down again if you take away p53.
Ok, now I have to tell you something interesting about this.
In C. elegans, p53 plays only a minor role
in germ cell death under normal conditions.
But, what we really see the effect of p53 is when you
take a worm and you shine...you expose it to gamma rays
or other agents that produce damage in DNA.
Then you get a lot of cell death, and that cell death
in the germ line requires p53.
OK, so I told you that cell death...sorry, I told you that
daf...sorry that p53 is required
for the increase in cell death that you get in a daf-2 mutant.
So we wondered, "Is it possible that a daf-2 mutant
is sort of similar to an animal that's been subjected to genic toxic stress.
So, in other words, are daf-2 mutations maybe inducing a response to stress?
And we think that's probably the case.
Part of the reason we think that is we found that DAF-16,
the transcription factor, is required for gamma rays
to trigger germ cell death in normal worms.
Both p53 and DAF-16 are needed for this extra cell death in the daf-2 mutant
and in a normal worm that you treat with gamma rays.
So, we also tested another, different kind of a tumor.
This tumor has a different name, it's called glp-1
and this is a tumor in which what happens is that the germ line stem cells
just keep dividing. The oocytes are still oocytes.
This is affecting a different population of cells.
In this case, what happens is that normally there's a receptor
on the surface of the stem cells that
receives a signal from the environment, from nearby cells, telling them to divide.
And what happens is that when the germ cells move away
from the source of the signal they stop dividing.
But in this mutant, the receptor for this signal
is just on all the time even if there's no signal.
So these cells just divide and divide and divide, and they make a tumor.
So what happens in this tumor?
We found that daf-2 mutants or mutations
also extend the lifespan of this tumor mutant,
but they don't trigger germ line cell death so they're doing it a different way,
specifically by cell proliferation. I'll get to that in a minute.
But, keep this in mind because I'll come back to this later.
So what about cell division? We found that daf-2 mutations reduce mitosis,
cell division, in both tumor mutants, in both gld-1 and glp-1.
So here you see dividing cells in the normal animal,
lots of dividing cells in the tumor mutant
and many fewer dividing cells in the...when you put
daf-2 mutations into the tumor mutant.
The cool thing is that daf-2 mutations don't just willy-nilly block cell division.
They only block cell division within the tumor.
Here's what happens. So here's the tumor, with lots of cell division.
And here's when you put a daf-2 mutation into the tumor,
into the animal containing the tumors.
Cell division goes down, but look what happens if you put a daf-2 mutation
into a normal worm.
We still get the same amount of germ cell proliferation, no effect.
So that's really neat. Somehow it knows which cells are the tumor cells.
I mean it doesn't really know consciously but you know,
teleologically, you could say that.
So I just want to stop for a second and pause here
and say that this...we see effects both on cell death and on cell proliferation.
And there's some similarities here between the worms
and vertebrates, and I'll point them out now.
One is, in humans it's known that mutations
that activate insulin and IGF-1 signaling cause cancer.
So we've shown the opposite in the worms.
We've shown that if you turn down insulin/IGF-1 signaling,
lower than it would be normally, you actually sort of cure cancer.
I mean you don't die from it anyway. I shouldn't say cancer either.
These are tumors. And I should make this clear.
These tumors they...a tumor is a group of cells that
is proliferating too much. It's over proliferating.
And that's what happens. That's why they're called tumors.
But the cells don't undergo the late stages of human cancer
like angiogenesis where they attract blood vessels
and they don't actually actively metastasize.
So they're a good model possibly for the early events of human tumors
but not the later ones. I should have made that point clear before.
But anyway, the cool thing is that what we've shown is that if you
inhibit this pathway you can actually do the opposite of what you would do
of what would be happening in a human that has a mutation that
increases the level of signal.
The second thing is, I told you before that
in the long-lived mice that have defects in this pathway
it's known that cancer levels are down and
what our findings suggest is that maybe DAF-16 and p53
are involved in this. Maybe that's the pathway.
Nothing is known about the pathway in the mice,
but maybe that's the pathway and maybe that's
affecting cell death as well as mitosis.
What about the other mutants?
Well, caloric restriction and mitochondrial mutations
also inhibit the tumor growth. Here's a picture, again,
a diagram of the head of the worm.
And here's the DAPI staining and this is the animal packed full of germ cells
and you can see that it's a lot better
if you, in this case, introduce a mutation that causes caloric restriction and
you get the same effect if you introduce
a mutation that affects the mitochondria.
They don't affect apoptosis (cell death),
but they do reduce the number of mitotic germ cells.
And amazingly none of them affect mitosis
in the normal germ line, none of them.
The daf-2 mutation I told you before and these
mitochondrial mutations and the eat-2 mutation,
none of them affect normal mitosis, just...they all
can tell the difference between normal mitosis and the tumor.
And so how do they do that? Why should this be?
Well, we have an idea and I think a clue comes from the stem cell tumor,
the glp-1 mutant that I told you about.
Now, in that tumor, daf-2 mutations inhibit cell divisions and those tumors,
the glp-1 tumors, are thought to consist of lots of normal germ line stem cells.
In other words, those tumors, if you recall, are different from...
are caused because the receptor for
a growth factor is...thinks it's on all the time.
It's mutant so it's constitutively active.
And that's why the cells are dividing.
But that receptor is normally active in those cells at a normal time.
So basically, I think what we've done in that mutant
is just to make many more copies of normal cells.
The cells aren't, probably, any different
from a normal cell, but they're just more of them.
And yet, when there's a lot of them,
you need DAF-2 for cell division and these other genes for cell division.
Whereas when there's just a few of them you don't.
So the model then is a tumor is a large metabolic load.
In other words, having all these cells
dividing and dividing may require a lot of energy, a lot of nutrients.
And perhaps these longevity pathways, which as I told you
shift the physiology of an animal from
one that favors growth to one that favors maintenance,
maybe they just can't support the tumor.
They can...it's not a problem for them to support
the small little group of germ line cells that are dividing normally.
But when you put a real big metabolic load on they just can't stand it.
And that's why I think the tumor cells are probably affected.
At least that's the model.
OK, so to summarize: daf-2 mutations do two things:
they induce a stress response that triggers apoptosis
in a p53 dependent fashion,
and they also reduce mitosis within the tumor,
and the other mutations specifically reduce mitosis.
This raises an interesting question of whether these clk-1 mutations
are going to turn out to affect tumors in mammals and stay tuned.
So, a few thoughts about this:
first of all, we see a really strong correlation in these worms between
the rates of normal aging and tumor growth
and a variety of different longevity mutants.
In nature it's generally the older individuals that are susceptible to cancer.
And it's not...the animals aren't...it's not the number of days they've been alive.
So, for example, people get high rates of cancer
after many decades, 60, 70 so forth, at high rates.
Whereas a dog gets cancer at the same high rate when it's 10 years old
and a mouse when it's just a year and a half.
But all these animal have in common the fact that they're elderly.
OK, so there's this correlation that you see in all animals
between being elderly and being susceptible to cancer.
And so it's really interesting that all these mutations
that increase lifespan also delay tumors,
and it suggests to me that maybe single gene mutations
in the genes that I've been telling you about or
the downstream genes they control link these two processes during evolution.
In other words, you have an animal with a short lifespan
and there's a mutation that
increases the lifespan. Maybe that same mutation
also makes it more tumor resistant.
So that if you keep doing this, you know,
through evolution pretty soon you get a human
that has a really long lifespan and stays really resistant to cancer for a long time.
OK, alright so I'm going to end now my lecture series.
And I just want to tell you about the people who did the experiments
I talked about in part two of my series.
I started off by talking about sensory perception.
Javier Apfeld is the one who discovered that sensory mutants
extend the lifespan of worms.
Joy Alcedo did the experiments of killing individual neurons and showing
that there's a really an elaborate sensory processing going on here
in the brain of the worm.
Honor Hsin showed that killing the germ cells extends lifespan.
And Kui, Natasha, Jen have worked on the reproductive system.
And also I mentioned that in collaboration with Florence Broue,
who was a graduate student in Etienne Baulieu's lab
and our lab...this collaboration resulted in the knowledge that steroid hormones
can influence the lifespan of C. elegans via this pathway.
And I also mentioned that Adam Antebi's lab working independently showed
that dafachronic acid, a sterol hormone, was part of this pathway.
Nuno Arantes-Oliveira produced these worms
that lived 6-times as long as normal, these amazing worms.
And Julie Pinkston did all the work on the tumors that I talked about.
OK, thank you very much.