Basic Research: Cynthia Kenyon

By Jeff Minton, Steven Kotler|Thursday, November 25, 2004


molecular biologist, University of California at San Francisco

She loved playing the French horn and wanted to be a musician, but she discovered that her true talents lay in science.

On avoiding the wrong path in life:

“I think my big lesson was that it’s not enough just wanting to do something. I love the thrill of playing something and having it sound beautiful, but I just wasn’t very good at it. I finally realized that, and once I gave it up, I felt like I could fly, everything else just came so easily. . . . With science it’s very important not to go down the wrong path, but the wrong path in science is a path you go down where everything you learn is already known. So you need to steer around the obvious.”


STEPHEN P. QUAKE, professor of applied physics and physics, Caltech

FLOYD ROMESBERG, assistant professor of chemistry, Scripps Research Institute

HANS R. SCHÖLER, director, Center for Animal Transgenesis and Germ Cell Research, University of Pennsylvania

J. CRAIG VENTER, chairman, the Institute for Genomic Research

Once upon a time the study of aging was a scientific career killer right up there with cold fusion. Everybody had pretty much agreed that decrepitude was the result of entropy—a seemingly inevitable increase of biological disorder. Then Cynthia Kenyon came along. She suspected that aging was more programmed than disordered. “Think about the human girl,” she says. “She goes through puberty at age 12, and then four or five decades later, she goes through menopause. So there’s a timed process.” If key genes regulated aging, Kenyon thought she might find them first in one of the most tried-and-true models of biology: a tiny worm called Caenorhabditis elegans. In 1993 Kenyon discovered mutant C. elegans that lived twice their normal life span of 20 days. She found the cause of their longevity: a gene called daf-2 had been turned down. She also discovered that another gene, called daf-16, promotes youthful vitality. Stimulated by this work, other researchers found that similar genes in fruit flies and mice control aging. These days Kenyon, a molecular biologist at the University of California at San Francisco, is investigating how to postpone aging in humans. And why not? Looking good at 200 would be a pretty neat trick.

You were studying development in C. elegans. Why those? 

K: C. elegans is a tiny nematode worm, about one millimeter long. They have only about 1,000 cells, but they have all the cell types found in humans: nerve cells, muscle cells, pretty much all the neurotransmitters we have. They’re also hermaphrodites. If you put one on a plate and come back three days later, you’ll have about 300 more new ones and one old one. And if you wait three more days, you’ll have about a hundred thousand. But the other thing is that worms get old. That one old worm—well, you can see it. It moves around a lot less; it’s wrinkled. You just look at it and know it belongs in a nursing home.

Why do you believe extending longevity is possible through mutations of individual genes, as opposed to the old theory of uncontrollable deterioration?

K: Well, with worms you can just change genes at random and see if you can find a mutant that does what you want it to do. There was already a mutant worm that was reported to live 50 percent longer. It had been isolated by Michael Class 10 years earlier and been studied by Tom Johnson’s lab [at the University of Colorado at Boulder]. They thought maybe the mutant lived long because it didn’t eat well or didn’t reproduce well, but I thought there’s a real set of dedicated genes for aging and that was the reason why. So we looked for these mutants and, in 1993, we found the daf-2 gene. It was a gene that controlled aging. Scientists didn’t think there were going to be genes that controlled the aging process.

What is daf-2’s function?

K: Daf-2 encodes a hormone receptor. It’s a protein that allows tissues to respond to hormones. We found the mutations that lower the activity of the receptor, that make the tissues less responsive to the hormone. Our result told us that the normal function of these hormones was to speed up aging. Daf-2 was the grim reaper gene inside the worms. The same kinds of hormones are found in all animals. In people, it’s insulin, which is used in food utilization, and a hormone called IGF-1, insulin-like growth factor. We also found that in order for these worms to live so long, you need another gene—the daf-16 gene. This isn’t the grim reaper gene, it’s the fountain of youth gene. It promotes youthfulness. These long-lived worms don’t look chronologically old. It’s like you’re looking at someone who is 90 and you think they’re 45. They’re youthful; they move around.

What’s the purpose of having a gene to limit an organism’s life span?

K: There are lots of different strategies that an animal can use to survive. What a worm does is try to convert food into worms as soon as possible. In three days a single worm produces 300 progeny. So why put your resources into developing if you can make a brand-new worm in no time at all? On the other hand, humans control natural resources. We do this in a way that involves intelligence and social interactions. So our strategy for success is better served by a longer life span. By the time a male is 25 he could already have had children who are out of the nest. But how many 25-year-olds are running companies or countries? Very few. Generally, older people in their fifties, sixties, and seventies are running most countries and are CEOs of corporations. Which isn’t to say there aren’t entrepreneurs, but if the young were better in every respect, there’d be no reason for the old. Our life span reflects our particular life strategy.

What is your most important finding?

K: That aging is regulated by hormones, that it’s plastic. That it’s run by the endocrine system and that the endocrine system evolved early. That there’s a universal hormonal control for aging.

If aging is plastic and not a given, what are the consequences for disease?

K: It means that by postponing aging we can postpone age-related diseases. It also means that by studying aging, we may discover new molecules that play a role in disease. It’s another way of coming at the problem of disease. Age is the biggest risk factor for many diseases. You’re 100 times more likely to get a tumor at age 65 than age 35. It makes a huge difference. It gives a whole new meaning to preventive medicine.

You cofounded a company called Elixir. What are you working on?

K: We’re trying to develop drugs that can mimic some of the effects that we see in these long-lived animals. The hope is that if we can increase youthfulness, we can postpone age-related diseases.

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