Cynthia Kenyon, PhD, director of the UCSF's Larry L. Hillblom Center for the Biology of Aging, smiles a lot these days. And with good reason. She has aging cornered and she knows it. In less than 20 years, her once-crazy idea — that genes regulate aging — has not only gone mainstream, but spawned a huge field of research with giant conclaves and dozens of journal articles published every year.
It wasn't always this way, of course. Like many young scientists with a novel idea, Kenyon encountered more skepticism than support in the early 1990s. Indeed, one fellow scientist, worried that she had gone "over the edge," warned that if she continued to insist that aging was subject to genetic regulation, she would soon fall off the Earth altogether. But her world turned out to be round, not flat. And now firmly anchored as, if not exactly the "queen of aging research," then certainly its ace, Kenyon commands no fewer than 386,000 entries on a standard Google search.
"It didn't matter that most people thought I was nuts," says Kenyon in breathless staccato. "I was dead set on studying this because I was convinced that there was something there." Why else, she explains, would mice live two years, rats three years, squirrels 25 and bats 50? "If there were genes that regulated the rate of aging, then you would expect that evolution could change life span by changing regulatory genes," she states with certitude.
The kernel of her revolutionary suspicion was that life span and aging were too important to be left to chance completely. Proving it — particularly in her animal model, the lowly roundworm known as C. elegans — required both pluck and luck. It also helped that she was at UCSF. "UCSF is a place where nonconformity is valued."
The story is now well-known. One of Kenyon's lab rotation students — Ramon Tabtiang — in one of his very first experiments, picked a needle out of the haystack that is the C. elegans genome. In short, he found a mutant gene, dubbed daf-2, that made worms live twice as long. C. elegans was — and is — a favorite model for developmental biologists and geneticists because its simple structure and entire three-week life are easily scrutinized under the microscope.
Watching the mutant worms, says Kenyon, was like "witnessing a miracle." Not only did these worms live longer, they retained good muscle tone, squirmed, sought food and stayed youthful. In comparison, normal, or wild, worms of the same two-week age were flabby, tattered and sedentary. They looked old. The message was clear. The rate of aging was not "fixed in stone," after all. It could be slowed.
In the years since, Kenyon and her team have made more eye-popping discoveries, including the role of a companion gene, called daf-16, that controls on or off signals in still other genes. Learning more about the insulin pathway in which these genes operate helped her to understand a cascade of signals and responses as they reverberate through individual tissues.
Better yet, by using this information to tweak here and there in the worm genome, Kenyon and her laboratory colleagues have been able to extend a worm's life up to six times the normal span, with no significant decline in vitality until late in life. They did this by altering cells in the reproductive system, which controls life span, as well as by changing daf-2. The six-times-longer-lived worms don't reproduce, unlike the daf-2 mutants, which live twice as long as normal and can be fully fertile.
Researchers have since confirmed that similar genes and pathways work in approximately the same way in both fruit flies and mice.
But what does that say about humans? Has Kenyon found the secret to immortality? From all the hype that sometimes surrounds her work, you might think so. Kenyon herself makes no such claim. She is enthusiastic, yes. She is persuasive, definitely. She is provocative, occasionally. But she is also careful. There is still much to learn about all the twists and turns in the genetic landscape that influences human life span.
That said, some truths have emerged, particularly about the role of the insulin pathway, which clearly plays a role in how fast an animal ages. Indeed, the many websites and publications promoting longevity often call insulin the "death hormone." Some adopt a more positive slogan: Eat less, live more. Still others tout the more scientific-sounding term "caloric restriction."
Call it what you will, the basic message is the same. By eating fewer carbohydrates, you can provoke a bit of a "there's-a-shortage-of-food" response inside your body. Kenyon suggests a possible explanation, supported by her studies: "When you don't have enough insulin, your body senses danger and mounts a response. Protective mechanisms are mobilized. Antioxidants are produced. Chaperone proteins that help other proteins fold correctly become resistant to infections. Your immune response is strengthened."
But how much restriction is good for us? And what does Kenyon herself do in her own life? In the next edition of Science Café, we tackle these and other questions, including whether aging is really a disease, and what happens if we all start living to be 120 years old.
- UCSF Department of Biochemistry and Biophysics
- Wormworld (Kenyon Lab)
- Calorie restriction
- Calorie restriction
- Longevity Meme Website
- The fast supper (calorie restriction diet)
- New York Magazine, October 30, 2006
- Old worms, new aging genes
- Science News, August 2, 2003
- Genes that act downstream of DAF-16 to influence the lifespan of C. elegans
- Nature, July 17, 2003
- Ageing: A message from the gonads
- Nature, May 27, 1999
- In Methuselah's mould
- PLoS Biology, January 2004
- One for the ages: A prescription that may extend life
- New York Times, October 31, 2006
- Aging Drugs: Hardest test is still ahead
- New York Times, November 7, 2006