Cynthia Kenyon: I want to live forever - New Scientist

jbone at place.org jbone at place.org
Wed Oct 22 21:44:55 PDT 2003


 From >Htech, thx Gene / James Hughes.

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http://www.newscientist.com/opinion/opinterview.jsp;jsessionid=CMFHOCGJG
CEG?id=ns24171

I want to live forever
Photo: Timothy Archibald

Cynthia Kenyon thinks we can have it all: health, wealth, hordes of
children - and a long life. A very long life. She disagrees with
prevailing ideas that we can only live longer by paying a high price in
terms of reduced fertility or a sluggish metabolism. What made this
professor of biochemistry and biophysics at the University of
California, San Francisco, so sure? A little worm. James Kingsland was
keen to discover the secret

What makes you think we can cheat nature, increasing human lifespan
without having to pay some kind of price?

Longevity is evolvable. The common precursor to worms, flies, mice and
humans was a very simple, short-lived animal. And to get from a worm to
a human you have increased lifespan a thousandfold. This happened by
changes in genes, which tells you that every time there is a change in
DNA that increases lifespan, there doesn't have to be some horrible
trade-off - because it's been happening throughout evolution. This whole
idea that there is always a trade-off is nonsense.


But how can an ageing mechanism evolve if the relevant genes only kick
in when an animal is too old to reproduce?

I still don't have an evolutionary explanation that I'm completely
satisfied with. But take humans. We go downhill pretty much after we
have grandchildren. I think there are two reasons why we have the
lifespan we do. One, because with grandparents the parents have an
advantage - they can go off hunting or whatever they have to do. The
other is that the elders are the ones who have experienced conditions 30
or 40 years before. If something changes, if there's a drought or a new
kind of predator, they are the people who will know what to do. Tribes
with wise elders will have a huge advantage.


How would you go about developing an anti-ageing drug?

It's just a question of finding a drug that would mimic the changes that
we've made in worms, flies and mice. Basically we should have a hard
look at the insulin and insulin-like growth factor 1 (IGF-1) endocrine
systems. The receptors for both have been shown to control ageing in
mice: if you mutate either they live longer. I suspect the key will be
to target those systems. In fact, I have helped to found a company,
Elixir Pharmaceuticals, that is trying to do just that.


Isn't Elixir just looking for a cure for age-related diseases rather
than ageing per se?

We think it's all one and the same. Age is the biggest risk factor for
cancer, heart disease, protein-aggregation disease - many, many
diseases. We think these endocrine systems coordinate age-related
disease with ageing. At Elixir, we think that if we can perturb these
systems with drugs, they will work in a large range of age-related
diseases.


How would such a drug work?

We know what the best possible path towards this drug would be. It's
just a question of finding a molecule that mimics the changes that we
have made in worms and flies and mice.


Did you start out researching worms?


As a graduate student at the Massachusetts Institute of Technology I
worked on bacteria. We were studying the response they have to
DNA-damaging agents. That got me interested in development. You took an
E. coli cell and you treated it with a DNA-damaging agent and it turned
into a whole different animal. But Bob Horvitz, winner of the 2002 Nobel
prize in physiology and medicine, had his worm lab right next to mine.
In Caenorhabditis elegans you have only a thousand cells and people knew
where they all came from in the cell lineage, starting from the
fertilised egg. It was the most amazing thing I'd seen, almost like the
crystal structure of an animal. You could go in there and find a gene
that acts at this point in the lineage to make a muscle, for instance.
And I thought, wow, that's what I want to do. So in 1982 I went to work
with Sydney Brenner in the UK to study the developmental biology of C.
elegans.


You weren't studying ageing at that point?


Not at all. When I started out they didn't know that there would be
genes controlling something as complex as development, or that the genes
would be doing the same thing in worms and people. No one knew that. We
thought that we might get some vague principle that was conserved, but
not anything as faithful as it turned out to be. We found a gene that,
when you knocked it out, made the back of C. elegans look like the
front.


But the front of a worm looks pretty much like the back of a worm...


No, it doesn't - it has all these different structures. So we cloned the
gene and it turned out to be a Hox gene. Those genes were very famous by
that time because they had been found to give particular segments in
Drosophila their identities. At the time only segmented animals were
thought to need Hox genes, not nematode worms. It showed us there was a
depth, an ancient character, to these genes.


How did that lead you onto ageing?


Basically, we were learning that everything in biology is highly
conserved. Biologists studying ageing were convinced that it just
happened and there wouldn't be genes that controlled it - you just wore
out. I thought, I bet ageing is regulated too and the mechanism is
conserved. All animals age, but at different rates: maybe there's a
regulatory mechanism that controls the rate of ageing and it can be set
differently in different species, and that's why a bat lives for 50
years and a mouse lives 2 years. So we set out to find genes that
regulated ageing. And all our work on ageing has shown that it's
regulated.


So what was your first big surprise?


We found that mutations that lowered the activity of a single gene,
called daf-2, caused the worms to live more than twice as long as
normal. We showed that their long lives weren't caused by changes in
feeding or reproduction - two boring possibilities. But the best thing
was that the long-lived worms remained active and healthy long after
normal worms were decrepit or dead. They were like 90-year-old people
who looked like 45-year-olds.


What are genes like this doing?


The daf-2 gene encodes a hormone receptor similar to the human receptors
for insulin and IGF-1. So hormones control ageing. They speed it up.
Then there are many genes "downstream" of this receptor that do lots of
different things. Some of them code for proteins that protect animals
from all sorts of stresses, chaperones that help other proteins fold
correctly, and antioxidant proteins such as catalase and superoxide
dismutase. Then there are those that encode proteins that kill bacteria,
and metabolic genes. But you have a single hormone receptor, the
IGF-1/insulin receptor, and a transcription factor commanding between 50
and 100 genes that directly affect the ageing process. It's like an
orchestra conductor coordinating the flutes and the cellos and the
French horns. That's how you get these big effects on lifespan.


OK, but what makes you think the worm genes have the same effect in
humans?


People have shown that the system first found in worms controls
longevity in fruit flies and mice. That means it had to evolve early in
a common precursor of mice, flies and worms. In genetics everything else
that has been found to be true in mice, flies and worms has also been
found in humans - with variation, of course, but the basic system is the
same. We don't know for sure yet, but on rational scientific grounds the
chances are very high.


So when can we expect the big breakthrough - an anti-ageing drug?


It could come at any time. A compound in red wine, resveratrol, has just
been found to increase the activity of a longevity protein that affects
the insulin/IGF-1 system in worms. So we may already have a drug, though
it might not be that simple. But the fact that there's this compound
already in red wine, it really makes you optimistic, doesn't it?


It's only a matter of time?


Yes, it's all about time!


But for now, caloric restriction seems the one proven way to extend
lifespan. Is that why you've virtually given up carbohydrates?


That's not necessarily why I do it. I do it because it makes me feel
great and keeps me slender. And I don't feel really tired after a meal.
But I think if I wanted to eat in a way that extended lifespan this is
how I would do it. In fact, I stopped eating carbohydrates the day we
found that putting sugar on the worms' food shortened their lifespans.


How does it work?


I eat a diet that keeps my insulin levels low. So, for example, at
breakfast I have bacon and eggs with tomatoes and avocados. It's bit
like the Atkins diet. I don't actually know if I eat fewer calories, but
I feel great and I weigh what I did in high school. I certainly wouldn't
want to be hungry all the time, but I'm not, I'm never hungry. I tried
caloric restriction just for two days but I couldn't stand it, being
hungry all the time.


What don't you eat?


I don't eat sweets, bread, pasta, potatoes or rice. I actually do eat
lots of carbohydrates, just not starchy ones, the ones that turn into
sugar quickly in your body. I eat lots of vegetables and salads, and
lots of fish and nuts, cheese, eggs and meat. People are now studying
these low-carb diets like Atkins and the zone diet scientifically.


How do you know it's doing you any good?


My blood profile is off the scale. Apparently triglycerides are very
good indicators of your insulin and glucose levels. Anything below 200
[milligrams per decilitre] is good, and mine is 30! And my "good"
cholesterol (HDL) is 86 [mg/dl], which is fabulous.


Suppose we all lived to 150. Would we just be prolonging the misery of
unhealthy old age?


I think it would be fabulous to live to 150. Remember, if you're like
these worms, at 150 you would be just the same as a normal 75-year-old.
Of course you want to be in good health - providing you are in good
health and you love life, you want to live longer. These long-lived
worms stay young longer. That's the thing that's so hard for people to
grasp: it's not just being healthy longer. It's being young longer. The
worms have told us it's possible.


Who is going to pay the pensions of all these ancient people?


That's not a problem, because they should be working longer. If there's
a pill, it's not going to immediately double lifespan - though I
shouldn't say that. You would never have said, with a worm, that you
could change a single gene and that it would double lifespan. The fact
that it did just blew my mind. I'll never get used to that. So it's
possible. But the chances are it would be pretty gradual, so society
would have time to adjust. If you had 90-year-old people who were
biologically just like 40-year-olds there is just no way that society
would agree to give them a pension! And the chances are they wouldn't
want one anyway.


How would you like to live to 150 and still be around at the same time
as your great-great-grandchildren?


It would be fantastic - you'd get to know them. And when you look at the
progress of science over the past 50 years - what we couldn't do 50
years ago that we can do now, for example with DNA - what will it be
like 50 or 100 years from now? Wouldn't you love to see



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