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I'd like to introduce you to the world's record holder for the oldest living person. It's
Jeanne Calment. She lived in France. She made it to the age of 122. Oldest person alive
today is 115, so she is going to keep the record for some time to go. She was really
remarkable. She started fencing at age 85. She rode her bicycle until age 100. She smoked
until age 116. And so, what that shows you is that smoking's good for you, as long as
you smoke for 100 years. We are studying some of these world's oldest people. I can talk
to you more about the world's oldest people in the break with sequence, "The World's Oldest
People," and the idea is that the world's oldest people are not fitness nuts. They actually
are a little bit less healthy in their behavior then I would say most of us are. They smoke.
They drink. She smoked until 116. They don't actually eat very well or exercise very well.
So, the idea is that it is good to diet and exercise and that will let you live 10 more
years (probably). But the real thing is to have the genes like Jeanne Calment. That's
30 years. And that's what we're trying to figure out in my lab at Stanford. It's one
of the things. So now let me switch from people to animals, and I'll tell you something about
our animal friends. Chimpanzee is 98% identical in DNA to us but it has only half our life
span. So, the 2% difference in our DNA gives us twice the life span. Turtle lives 140 years.
It's interesting because a turtle has more and more babies the older it gets, and it
becomes harder to kill the older it gets. So that way, it's actually living kind of
an interesting life where it gets stronger, the older it gets. Dogs and cats live somewhere
between 8-15 years. Mice live 2 years. Fruit flies live two months. So now let me tell
you about the last three: the whale, the clam, and the worm. Now, a whale is really interesting
because it's a very large mammal. Bowhead whale. The experiment was to go out and look
at the age of about 30 different bowhead whales, and they looked at all of these 30, and they
found a whale that they thought was 200 years old because it had a bone with about 200 rings
in it; they thought well this must have been alive for 200 years and you could say, like
I did, "'Well that's good, but I don't believe it,'" because who knows, maybe the rings aren't,
there are 2 rings per year for a whale. But they really proved that this whale lived 200
years because they found a harpoon in the whale that was thrown 203 years ago; so now
it was for sure that this whale lives 200 years. That's really interesting because look
it, this is a big mammal with a big liver and a big intestine that doesn't get colon
cancer or liver cancer for 200 years. So that animal has encoded in it, a really super duper
anti-cancer system. If we could figure out what the whale has that we don't have, we
could really cure cancer. The next one is the world's oldest animal; this is a quahog
clam, lives off the east coast in the north Atlantic. This clam, this specific clam was
named Ming. It's an Icelandic clam but is named Ming because it was born during the
Ming dynasty in China. These things live so long that you can not only study the biology
but you could study geophysics. You can watch global warming in the clam shell because it's
recorded in their rings. What I'm talking about is extreme difference in life span across
different animals. I told you about Ming, who can live 500 years. A whale is 200. We're
about 78 years as median life span. Dog. Mouse. Fly lives 2 months. Now, let me tell you about
the world's fastest aging animal. It's a worm called a nematode. It's one millimeter long
and we study it in my lab because it ages so fast, I can do experiments. This is what
a middle aged worm looks like...moving around. These things are harmless and live in the
soil, but they are great to study in the lab. This is an old worm at 18 days, and it barely
can move; it barely can eat. In 18 days, we can study what's happening over this time
period. So what we did, is we tried to figure out the clock. What is the clock that's running
so fast in just two weeks that allows a young worm to age into an old worm? When we got
that clock and we looked at it, we got a really surprising result. What we found is that these
regulatory proteins, called transcription factors, were part of the reason for the clock
running so fast in the worm. The first regulatory one is called ELT-3. It's a transcription
factor. Transcription factor normally controls expression of genes. This transcription factor
was disappearing and going down as the worm was getting older, and that was turning down
many, many, many downstream genes. This transcription factor ELT-3 is going down because 2 upstream
transcription factors are repressing it and they are going up. So, ELT-5, ELT-6, are climbing.
They repress ELT-3, so it goes down. Then, all of the downstream genes of ELT-3 are going
down. This was causing physiological aging in this worm, and it resulted in old worm.
Let me show you again. So, the green worm on the left is the young worm and it's green
because the ELT-3 transcription factor is on. It looks like the red blob. It's binding
to the genes and it's causing those genes to turn on. On the right is an old worm with
less green. So, the ELT transcription factor is on less. It's only one red blob. It's only
turning on one out of the many, many genes that it is normally turning on. So, in the
lab, I could test this. We could take the old worm and put back the red blob, turn on
the transcription factor and try to turn on the genes and see what would happen to the
worm, and the aging of the worm. This is what we got. So there's a 40 day old worm. So that's
a 40 day old worm. Now it looks pretty good. It's moving much better than a normal 18 day
old worm. By turning the genes back on, we could slow down aging. Now, this has kind
of interesting implications for how you think about aging. So, the old model for aging,
that's still true for part, and explains part of aging, is the accumulated damage model,
and that's sort of like, we age like a rusted car. So, imagine you have a 15 year old car,
it doesn't move very fast, and you want to know why and how did it age. Part of the answer
is because the piston is worn out and the nuts and bolts are all rusted, and there's
the equivalent of that going on in us which is called molecular damage, and that there
is oxidative reactive oxygen species that is damaging proteins and cells. But beyond
that, we found something really interesting. We found that there's a regulatory change
and that my 15 year old car and my 2 week old worm was not moving so fast because the
gas pedal or the transcription factor was no longer pressed down very much. So this
transcription factor, that is normally supposed to turn on the genes, was not turning on.
That's like the gas pedal just not being pressed down very far. In the lab, it was really easy
to turn back on the transcription factor and turn back on the genes. Now this has two interesting
implications for thinking about aging. One is that there is a master regulator. So I
don't have to go and fix all of the proteins and all of the cells from molecular damage,
which is very difficult to do. I could turn on one transcription factor and it would start
a downstream cascade that could cause many, many, many positive changes in the cell. The
other is that there's nothing irreversible about it. You could just turn it on, and take
an old animal, and turn back on the genes that it had when it's young, and then rejuvenate.
So it allows for the possibility of rejuvenation in aging. We're working on this type of new
thinking of aging where we are working on human skin and human kidneys right now. We're
getting some interesting possible results. These are my students in the post docs. Thank
you very much!