The genetically altered nematodes are more than two weeks old — way past middle age for this type of worm — but they are sleek and robust. They slither swiftly and constantly, and although scientists have yet to get into the heads of these lint-sized animals, they appear to be happy and enjoying life.

The leap from worm to human is perhaps too huge — for now - but imagine a drug or therapy that triggers or curbs the genes linked to aging and resets the internal clock that signals our time is up. People living routinely to some ripe old age of, say, 110 — or even more — and looking and feeling half those years, is not out of the question, says Kenyon.

"We're not just talking about extending life span, but also extending the good years; what we call the 'health span,'" she says.

It's something Kenyon ponders every day in her UCSF laboratory. And this is not some huckster dreaming up some "fountain of youth" potion. Kenyon is part of an elite core of researchers, an internationally recognized pioneer who has helped thrust the science of aging to the research forefront. Their studies in the smallest of animals, including worms and fruit flies, are unveiling the genetic underpinnings of aging and making a compelling case that it may be possible to reset the clock in humans.

It was in 1992 when Kenyon made a startling discovery in the roundworm called C. elegans — a favorite model for developmental biologists and geneticists because its simple structure and entire threeweek life is easily scrutinized under the microscope: disabling a single gene, called daf-2, doubled the life of the worm.

Watching the mutant worms, says Kenyon, was like "witnessing a miracle." Not only did they live longer, but these worms also had good muscle tone, squirmed, sought food and stayed youthful. In comparison, normal or wild worms of the same two-week age were flabby and tattered. They barely moved, and Kenyon described them as in a "nursing home state."

These worms — the mutants and the wild — offered a clear picture: the rate of aging is not "fixed in stone" and it can be slowed. Until then, the belief, even among many scientists, was that there was nothing one could do about aging, except for eating healthfully, exercising and maintaining other good habits. Eventually, cells whither in the body's critical tissues, and, like cars, we wear out to a point beyond repair.

If the aging process is indeed under genetic control in humans, worms can perhaps show the way. A path leading to therapies to postpone the bad things that occur with old age is a long and circuitous one, but discoveries by Kenyon and others in the past ten years hint of a puzzle that can be solved.

The daf-2 gene is now known to be part of a hormonal pathway; daf-2, for example, encodes a receptor for insulin and IGG-1, an insulin-like growth factor. Taking their cue from the worm, scientists have asked whether these same genes control the aging of higher organisms, flies and mice, and found that they have. This means that this regulatory system arose early in evolution, before the separation of vertebrates and invertebrates. "Chances are, it's present in humans as well," says Kenyon. Thus by studying these primitive worms, Kenyon may possibly have discovered a fountain of youth for all organisms.

Since the discovery of daf-2 mutant worms in 1992, Kenyon's lab has found:

Another gene, daf-16, acts in concert with daf-2, and its activity is necessary to extend life in the mutant daf-2 worms. This gene affects aging by switching other genes on or off. At least some of these genes, in turn, appear to encode proteins that prevent or repair damage to other proteins and molecules in the cell.
The interplay of these genes and others triggers a cascade of cellular responses, including secondary signals that control the longevity of individual tissues in the worm.
The daf-2 gene affects reproduction as well as aging. Many evolutionary biologists predicted that one could not lengthen a life span without inhibiting reproduction. But life span in the worms can be extended without harming reproduction or producing any obvious side effects if daf-2 is disabled only in adulthood.
Cells in the reproductive system, and also sensory neurons in the brain influence life span, probably by affecting hormone signaling. By manipulating genes and cells, they can extend life span and youthfulness in worms by up to six times.

Kenyon does not yet predict that science in the next decade will be able to stretch the human life span like of that of the mutant worm. Just a doubling of the human life expectancy would take us to a hardly imaginable 170 years. But Kenyon says that many of the fundamental biological processes that occur even in the simplest of organisms, including the worm, are conserved through time and can apply in complex animals, including humans.

That argument and the findings in her lab have energized those in the field of aging and won Kenyon much acclaim and support. In 1997, she earned the Herbert Boyer Distinguished Professorship at UCSF and an award from the Ellison Medical Foundation in the following year. She was awarded the King Faisal International Prize for Medicine, granted by a Saudi Arabian foundation for excellence in medical research. Her prize included a 240-carat, 200-gram gold medal and a $200,000 cash award for her research.

A sign of her credibility and the scientific acceptance of her work — her selection as a speaker at a Spring 2003 conference at Cambridge, England, celebrating "DNA: 50 years of the Double Helix." James D. Watson, codiscoverer of the DNA structure, was there, and Kenyon was among a distinguished group of eight internationally renowned scientists, including Nobel laureate and former UCSF professor Harold Varmus.

At the beginning of her daf-2 discoveries in worms, Kenyon could hardly attract postdoctoral fellows to do the experiments in her laboratory. Aging was just not an attractive field for eager young investigators. Today, they clamor for a chance to join her team.

"When I first saw the daf-2 mutant worms, I became a believer. This is not just fantasy," says Arjumand Ghazi, a postdoctoral fellow from India who joined the lab this year.

"Cynthia is definitely a pioneer," says Ghazi, one of seven women scientists (of the total of 14) in the Kenyon lab. "Her enthusiasm and passion are infectious and she encourages us to be creative and independent in pursuing experiments."

Ghazi's previous expertise was studying muscle development in flies, but she has happily shifted to probing C. elegans. "I have grandparents and parents who are getting up there in age," she says. "I can relate to this research and see myself still working in this field in 20 years."

Indications are that the field of aging will blossom even more, and under Kenyon's guidance. In November 2002, UCSF received $8 million to establish the Larry L. Hillblom Center for the Biology of Aging at its new Mission Bay campus. Some two dozen researchers — experts in everything from cell biology to protein folding — have joined the center to probe the potential of preventive and therapeutic treatments for age-related diseases.

Lessons from the diminutive worm already have had a big impact. This year, says Kenyon, her lab will start experiments in mice to check whether some new worm life span genes discovered in her laboratory control aging in mice as well. As with the insulin and IGF-1 pathway genes, it's a step up the ladder to higher animals and closer to proving the genetic effect in humans.

Will drugs slow that aging — and prolong youthfulness — and eventually target longevity genes? Kenyon and others obviously believe so. In 2000, she and MIT scientist Lenny Guerente founded Elixir Pharmaceuticals, which will develop therapies targeting the steps along the daf-2 pathway. UCSF this year completed a license agreement with the Massachusettsbased company to provide access to aging-related genetics discoveries by Kenyon.

"It's really amazing when you can take a worm and change its life span by sixfold," she says. "We have worms that are the equivalent in human years to 450 and appear to act and look like they're 60. "It just makes you wonder how far you can go."

Source: Andy Evangelista

Last updated January 28, 2005

Cynthia Kenyon

Cynthia Kenyon (center) with postdocs in her lab at Genentech Hall. Photo by Robert Foothorap.