Kenyon’s Ageless Quest

The poster taped to the door of Cynthia Kenyon’s office at the University of California at San Francisco seems so ordinary that you would hardly suspect it advertises a revolution in human affairs. It announces a talk she was about to give on genes that influence the life span of a type of nematode, a tiny worm that lives in soil. The poster shows a cartoonish illustration of a wizened little worm hobbling along with the help of a cane, while half a dozen human infants, in diapers, splash in the spray of a fountain. Despite the whimsical drawing and the mischievous title of Kenyon’s lecture, “Genes from the Fountain of Youth,” she’s not kidding. Since the early 1990s, Kenyon, a molecular biologist, has produced a body of research about this simple organism that has broad implications. She and her collaborators have doubled, quadrupled, and in some instances sextupled the worm’s life span by manipulating several of its genes. And others have found that the same metabolic pathway, controlled by genes, appears to function in other organisms, including yeast, fruit flies and mice. The question is whether it also functions in people—and might be manipulated to extend human life.

Many scientists say no, but Kenyon is betting on yes. Four years ago, she co-founded a biotechnology company, Elixir Pharmaceuticals, in Cambridge, Massachusetts, to develop drugs and other products to treat age-related diseases and slow down the process of aging. Another company cofounder, Leonard Guarente, an MIT biologist and an old friend of Kenyon’s, has suggested that the company might, within a decade, develop a pill that could add 10 to 30 years to a person’s life. “We may not have a perfect drug in 10 years, but we’ll have something to build on,” says Kenyon, 50. “Potentially, we could have it sooner.”

Elixir is one of about a dozen small biotechnology companies jumping into the fountain-of-youth business. Only a decade or so ago, the pool was pretty empty, unless you counted the pseudoscientists and snake-oil salesmen who have historically hawked anti-aging nostrums. But genuine advances in genetics and the study of stem cells, unspecialized cells that can be coaxed to develop particular functions and thus might replace damaged tissues, have engendered new ways of thinking. “The thing about aging,” Kenyon says, “was that everybody thought, ‘Well, you know, the animal just breaks down, and what’s to study, really? It’s not going to be very interesting.’ But when I looked at it, I could see that different animals have different life spans.” Consider a mouse, a canary and a bat. “The mouse lives two years and the bat can live 50 years and the canary lives about 15 or so years. They’re all small animals. They’re warmblooded. And they’re not that different, really, in such a fundamental way from each other.”Afairly small number of genes, she argues, may control the creatures’ differing life spans.

To a lot of biologists, aging research has not always been a respectable calling. When Kenyon’s lab first began to work in the field, she insisted that her co-workers avoid even using the “a-word” in research reports and grant applications. “It was embarrassing to say we were working on aging,” she says. “The field had a reputation for going nowhere.” To be sure, life extension is still subject to wild exaggeration and implausible predictions, but the field has progressed tremendously, and Kenyon’s research has had a lot to do with that. “The field needed an injection of fantastic talent, people like Kenyon and Guarente,” says Gordon Lithgow, a molecular biologist at the Buck Institute for age research in Novato, California. “They’re great communicators, but they’re also just the tip of the iceberg. There’s some great science coming out of this area.”

The marriage of molecular genetics, our most precise and vaunted life science, with perhaps the oldest and most alluring human fantasy—eternal youth—is one of the most intriguing aspects of recent gerontological research. Given the moral embedded in the misfortune of Tithonus—the sad sack of Greek mythology whose wife mistakenly asked the gods for eternal life for him instead of eternal youth, causing him to wind up in an endless purgatory of decrepitude—the myth of a fountain of youth has been part of the record of human longing for at least two millennia.

If Tithonus gave that longing a cautionary quality, ancient cultures, notably the Egyptians and Chinese, gave it an aura of quackery, at least to modern eyes. More than 2,000 years ago, Chinese alchemists known as “thaumaturgists” devoted considerable energy to creating “drinkable gold” as a means of prolonging life. “The king of the state of Chu was presented with an ‘elixir of deathlessness’ by thaumaturgical technicians,” notes a Chinese text of around 400 b.c. (which did not, however, reveal if the potion worked). Gerald J. Gruman, a historian who has surveyed life extension, writes that “interest in the fountain of youth had reached an apex in the fourteenth and fifteenth centuries, and the discovery of America gave a new impetus to the tradition in the early years of the sixteenth century.”

It was Juan Ponce de León, of course, who put a more modern face on the myth and gave it an enduring ethos of futility. Legend has it that, around 1509, while serving as governor of what is now Puerto Rico, he first heard tales about a fountain or spring on Bimini, an island to the northwest, that rejuvenated anyone who drank from it. Intrigued perhaps more by reports of gold than rejuvenating waters, Ponce de León mounted an expedition in March 1513. He failed to find either Bimini or the “Fountain of Youth,” but within a month or so did discover Florida.

The search for youthful immortality took a notably pseudoscientific turn in 1889, when the respected French scientist Charles-Edouard Brown-Sequard claimed he could rejuvenate old men with an injection containing crushed dog testicles. Though the claim was mistaken, it incited scientific races in the early 20th century to isolate the male hormone testosterone and the female hormone estrogen, which have long been promoted by physicians and charlatans alike as anti-aging tonics.

On Kenyon’s office bookshelf, Lewis Carroll’s Alice’s Adventures in Wonderland and Edgar Allan Poe’s Tales of Mystery and Imagination sit alongside James D. Watson’s The Molecular Biology of the Gene, a combination that hints not only at the breadth of Kenyon’s interests but the way they straddle popular culture and hard-core science. Even her scientific papers are accessible. “The process of aging influences our poetry, our art, our lifestyle, and our happiness, yet we know surprisingly little about it,” she writes in the data-thick, jargon- strewn journal Cell.

Born in Chicago and raised in Georgia, New York, New Jersey and Connecticut, Kenyon attended the University of Georgia, where her father was a member of the geography faculty and her mother worked as an administrator in the physics department. Cynthia Kenyon traces her passion for genetics to the day her mother brought home Watson’s The Molecular Biology of the Gene, which taught her, she recalls, “about switching on and off genes in bacteria. I just thought it was fabulous.” After graduating as class valedictorian in 1976 with a degree in biochemistry, Kenyon moved on to MIT, where she got her PhD. She then spent five years at CambridgeUniversity in England, where she was tutored in the ways of one of the lowliest and yet most astonishingly instructive creatures to crawl out of the ground: the nematode.

At Cambridge, she trained as a developmental biologist under Sydney Brenner, who received a share of the 2002 Nobel Prize in Physiology or Medicine for work showing how genes dictate the development of organs and tell some cells when to die, as though they’d been preprogrammed to self-destruct at a particular time. Brenner had long championed the virtues of experiments with the nematode C. elegans. The translucent smooth worms, barely the size of the comma at the end of this phrase, are in constant motion; viewed under a microscope, they carve sinuous arabesques across the gel on which they’re grown in the lab. To scientists, the worm provides a remarkably revealing model of genetics in action. C. elegans has a three-day cycle from birth to laying eggs and lives a little more than two weeks. It possesses a relatively modest 19,000 genes, and has the added benefit that its body’s 959 cells are virtually transparent when viewed through a microscope—enabling scientists to literally peer into the worm’s parts as it develops, whether naturally or in response to an experiment. Soon Kenyon became part of an army of researchers who, through sophisticated experiments, could show genes being activated in distinct patterns. Those tests yielded important clues about which genes controlled specific steps in the worm’s growth, development and aging.

She learned not only the exquisitely sensitive genetic choreography of developing organisms, but also that when it comes to genes, evolution keeps going back to the same well: the genes that control the development of nematodes and frogs and mice also tend to control human development (albeit in slightly more complicated ways). Similarly, Kenyon theorized that aging in nematodes and people might also be controlled by comparable genes. Moving to the University of California at San Francisco in 1986, and aware of the work of Tom Johnson, a University of Colorado biologist who had studied a nematode that lived longer than usual, Kenyon and her co-workers looked for genes that, when altered in particular worms, made those worms live longer than others. She found that changing one specific gene, called daf-2, dou- bled the animal’s life span and also prolonged its youthful activity. Another scientist, Gary Ruvkun of Harvard Medical School, discovered that the genes in question regulated a hormone-signaling system in the worm that is surprisingly similar to the way the human body signals the need for both the hormone insulin, which spurs the breakdown of sugar, and an insulin-like growth factor (IGF-1), which affects physical growth. Flouting the scientific tradition of understating one’s findings, Kenyon began to talk about the “fountain of youth gene,” an idea, as she recalls it, that people thought was “kind of cute.”

As Kenyon and co-workers delved into the problem, they learned more about the insulin-signaling pathway, showing that when certain worm hormones were suppressed, it activated a host of other genes that appeared to play a role in extending the animal’s life. So the question became: Did evolution favor this mechanism and pass it along to other organisms? “Is it in humans?” Kenyon asks. “We don’t know.” Still, she and other scientists have what they believe are promising leads—thus the work at Elixir and other biotech firms to identify human versions of the same life-extending genes found in simpler creatures.

One of Kenyon’s buddies from her Cambridge, Massachusetts, days was Guarente, a meticulous and somewhat reticent molecular biologist. He has studied important but esoteric aspects of gene regulation for 20 years. In the mid- 1990s, his research group discovered a family of specialized genes that influence the life span of yeast cells. Called silencing genes, their job is to make proteins that smother, or silence, other genes, usually in response to changing environmental conditions. When the MIT biologists genetically engineered yeast to have an extra copy of one such gene, called sir-2, the yeast cells lived longer. As important as the function of the sir-2 gene—it directs the making of an enzyme—is that the gene is activated when food intake and metabolism are reduced. In short, the silencing gene linked the high-tech molecular manipulations of life extension in yeast to a low-tech life-extension strategy that had been known for decades in rats: a starvation diet.

In a classic set of experiments in the 1930s by Clive McCay at CornellUniversity, rats fed just enough food to fulfill the animals’ nutritional needs but not enough to maintain their usual weight lived about 20 to 40 percent longer than rats raised on a normal amount of food; some lived twice as long. More than half a century later, caloric restriction remains the only proven strategy of life extension other than gene engineering. It has been demonstrated to work not only in rodents but also in yeast, fruit flies, spiders and fish, and, in continuing studies sponsored by the National Institute on Aging, it appears to have a similar effect in monkeys.

The link between diet and longevity has intrigued fanatics as well as researchers. Aprofessor emeritus of pathology at UCLA and a member of the 1991-1993 Biosphere 2 experiment, Roy Walford, 79, has undertaken a much-publicized experiment on himself—for years he has eaten a nutrientrich diet of just 1,600 calories a day in the hopes of extending his life. (His research is now complicated by his own amyotrophic lateral sclerosis, or Lou Gehrig’s disease.) Likewise, according to the Wall Street Journal, hundreds of Walford disciples are restricting themselves to as few as 1,500 calories a day in hopes of living longer.

Guarente, following up on his group’s discovery of a lifeextending sir-2 gene in yeast, a single-celled organism, has more recently shown that the more complex nematodes possess an analogous gene that can also prolong life. In fact, the researchers showed that endowing nematodes with an extra copy of that gene prompted the worms to live nearly 50 percent longer than usual. In any event, human beings possess versions of both the daf-2 and sir-2 genes, which is what tantalizes researchers, biotech investors—and consumers.

Around 1996, Kenyon began showing, to venture capitalists, a five-minute film dramatizing the difference between geezer and genetically rejuvenated nematodes. “I show them the movie, of worms that are normal that are about to die after two weeks, and the altered worms that are still moving,” Kenyon said. “They see it with their eyes, you know? . . . And that’s really all you have to do. It speaks for itself.” In December 2000, Kenyon and Guarente started Elixir with the ultimate hope of selling a product—ideally, a small molecule that could be packaged as a pill—that would extend life span and prolong youthfulness by affecting the sir-2 gene, among other parts of the insulin-signaling system. Last year, Elixir merged with Centagenetix, another Cambridge-based biotech firm, which has been scouring the chromosomes of centenarians and other very old people for genes that may have contributed to their long lives.

Even before the yeast and nematode research, scientists suspected that genes play a role in determining life span. More than 50 gene mutations affecting it have been identified in various animals. Agroup headed by Thomas Perls, of the Boston University School of Medicine and one of the cofounders of Centagenetix, has investigated many centenarians in New England and beyond, and this past November he reported that a gene on chromosome 4 appears related to life span. (People who lived to 100 were more likely to have a particular version of the gene that produces a protein that plays a role in processing fat.)

Such findings dovetail with Kenyon and Guarente’s approach. “When single genes are changed, animals that should be old stay young,” they wrote recently. “In humans, these mutants would be analogous to a ninety year old who looks and feels forty-five. On this basis we begin to think of aging as a disease that can be cured, or at least postponed.”

But skeptics say that extending life span through genetic manipulation is not inevitable. The distinguished gerontologist Leonard Hayflick, a pioneer in the study of aging cells, says he doubts that lives can be significantly prolonged by genetic tinkering and has famously stated that eradicating cancer, heart disease, diabetes and other principal causes of death would add, at most, about 15 years to average life expectancy. S. Jay Olshansky, a biodemographer at the University of Illinois at Chicago, applauds the work on nematode aging but questions its relevance to people. Human life span, he suggested at a recent scientific meeting, is not a simple matter of genetics: “There are no death or aging genes—period.” He bases his assertion on evolutionary reasoning, arguing that natural selection operates primarily on traits that affect an organism’s ability to reproduce; accordingly, one would not expect evolution to favor genes that extend an organism’s life much beyond its reproductive years. In fact, Olshansky has warned that trying to extend human life by manipulating genes could have “unintended and unwanted consequences,” such as an extremely old person who is physically fit but cognitively impaired.

Every month, however, it seems a new research report adds credence to the notion that the fundamental ravages of aging might at least be blunted by exploiting the biochemical pathways discovered by Kenyon and Guarente. This past August, HarvardMedicalSchool researcher David Sinclair and colleagues reported that several common organic molecules— including resveratrol, an ingredient in red wine—activate sir-like proteins in human cells and extend the life span of laboratory yeast. Those findings have bolstered the observation that people who drink moderate amounts of alcohol, including wine, appear to live longer than those who abstain. Sinclair, a former post-doctoral fellow in Guarente’s MIT lab, has said he plans to set up his own company to develop a drug that acts like resveratrol. Says Kenyon: “It’s kind of romantic that red wine contains something that could extend your longevity, don’t you think?”

Given the mere hint of such possibilities, she is struggling to balance the unforgiving demands of science against the expectations of a public understandably eager to live longer. Some scientists have gone so far as to talk of “practical immortality,” the idea that human life span can be extended perhaps hundreds of years. Kenyon recoils from the notion, but does not entirely retreat from its contemplation. “These worms aren’t immortal. They live twice as long. Or they live four times as long. In fact, we can now get ’em to live six times as long.” She pauses, then allows that it’s not theoretically impossible to make nematodes practically immortal, though, she says, “we haven’t.”

And therein may lie the difference between molecular biologists and philosophers: the latter often inflect their pronouncements with a palpable, if unspoken, “but.” The unspoken phrase for biologists is always “not yet.”