送交者: dashing 于 2005-6-01, 13:22:32:
Cynthia Kenyon wants to live to be 150 years old, if she's young and engaged in life. "Who wouldn't?" she asks in a breathless whisper, telling me that humans might be able to live a very long time, if not forever.
Kenyon's long, angular face is framed by straight blond hair parted in the middle. She talks excitedly, waving long, graceful fingers as her words spill out almost too fast to follow about how her lab at the University of California at San Francisco has increased the life span of tiny worms called Caenorhabditis elegans up to six times their normal life span by suppressing a single gene. This regulator gene, she tells me, in combination with other genes, appears to control an entire symphony of genes that direct aging not only in worms, but in similar genetic pathways in flies, mice and, possibly, humans.
This is the equivalent of people living for 400 years, she says, adding that there is more good news coming from her millimeter-long lab animal of choice. Our worms stay young for most of these extended life spans, she says.
"You mean this is a Fountain of Youth gene?"
She nods, delighted that I have made this connection. Kenyon talks with the slightly exaggerated facial expressions of someone telling and receiving juicy gossip -- expressions of "Oh my gosh!" and "No way!" Her voice is soft and light, and she frequently says "cool" and "neat." Yet her enthusiasm is infectious. "Life's too short to not be around nice people," she says, this woman who is delving into the mechanisms of how to make life considerably less short.
As we talk -- and she talks very quickly, as if she won't have time to say everything she wants even if she lives for 400 -- she offers me peanuts. I take a couple of nuts as Kenyon instantly shifts the topic -- she does that often -- and explains to me that she has totally changed her diet, eliminating most sugars, including those found in processed flour. Hence the peanuts. An experiment with her tiny worms is responsible, she says; that experiment proved that sugar switches on a genetic sequence that increases the amount of insulin produced by an organism, which in turn causes the body to demand more sugar. This not only adds flab to the waistline, if worms had a waistline, but also increases damage to cells in the body, speeding up the slow degradation of cells that contributes to aging. "It was a revelation," Kenyon says. She also drinks red wine and green tea, which her lab and others have shown help repair cells and contribute to an increased life span.
Kenyon's talk about immortality and a diet based on the molecular biology of a millimeter-long nematode make one wonder whether she had spent too much time at organic Zen retreats in California's Big Sur. But Kenyon is serious. Her title alone tells you this: the Herbert Boyer Distinguished Professor of Biochemistry and Biophysics at UCSF. She trained at the Massachusetts Institute of Technology and at the Laboratory of Molecular Biology (LMB) in the United Kingdom. Kenyon trained directly under the legendary Sydney Brenner, the "father" of C. elegans research. In the '60s, Brenner had chosen this tiny creature to use as a model to figure out how genes work in a simple organism. With fewer than 1,000 types of cells and a minimal number of genes for an organism with a simple nervous system and other key organs, C. elegans has the added advantage that it is translucent -- its heart, neurons and other innards can be clearly seen through a microscope.
For two decades, Brenner toiled over this little roundworm, which gave him great insight into the workings of other organisms, such as humans. Brenner also trained hundreds of young scientists at the LMB, including Kenyon, to help unfold the secrets of its genetic mysteries. In 2002, Brenner won the Nobel Prize for his work with the worms; along with two former students, John Sulston and Robert Horvitz. Nobel watchers see Kenyon as a contender for the big prize if her research holds up in higher mammals. Kenyon's work also has attracted commercial investors. In 1999, Kenyon cofounded a company with her fellow longevity expert, Lawrence Gaurante of Harvard, and Cindy Bayley, a founder of Iceland-based DeCode Genetics. Appropriately named Elixir, the Boston company has raised $36.5 million to see whether they can turn her research and that of others into a true Fountain of Youth in a pill. Some say such a pill is decades away, or impossible, and Kenyon herself admits that none of this may work with humans. But she is hopeful.
I met Kenyon in 2003, when she had extended the life span of worms by only twofold. At that time, she had just moved her lab from the main UCSF campus to the university's new silver-skinned lab complex at Mission Bay, a stretch of land in south San Francisco being revitalized beside the bay, where a sprawling navy shipyard and warehouses used to be. In her office is a copy of "Alice in Wonderland" and James Watson's classic textbook "The Molecular Biology of the Gene," along with other textbooks and journals about worms. Hanging on the wall is a framed one-page article about Kenyon from Glamour, a question-and-answer column called "Women Right Now."
"Might there be a way to put off physically aging for an extra few decades?" asked the columnist Judith Newman.
"Maintaining youthful beauty longer -- wouldn't that be great!" answered Kenyon. "All I can tell you for sure is that my worms not only acted younger, they looked younger. So you can draw your own conclusions. One thing that's likely: How you look as you age is hereditary. Some of my family members, for example, look younger than their real age. And people have mistaken me for 30, even 25."
"How old are you really?" asked Newman.
Kenyon frequently appears in the media, combining a rare ability among scientists to communicate effectively with nonscientists with a truly fantastic story. Before she worked on aging, she told the writer Stephen Hall, author of "Merchants of Immortality," hardly anyone outside the scientific community paid attention to her work. But as soon as the aging work began, she was inundated. "Night and day, night and day," she told him. "The public is absolutely fascinated by aging.
"They don't want to get old. And you can see -- read Shakespeare. Read the sonnets. They're all about aging."
I'm still skeptical until I see the evidence in a video on Kenyon's computer monitor: A normal, three-day-old worm in the prime of life, a C. elegans, is wriggling in a gelatinous broth of nutritious bacteria. At 13 days in this worm's normal life span it is sluggish, its head barely stirring as death approaches. The next images show the mutant worm tweaked by Kenyon to suppress, or "knock down" the regulator gene called daf-2. At the ripe age of 25 days, the worm is still squirming away. "This video says more than 20 Nature articles," says Kenyon.
Her original research announcing the doubling of the worm's life was published in Nature in 1993. Until her discoveries, scientists were unaware of these genes' role in regulating the highly complex process of aging, which involves hundreds, possibly thousands, of individual factors in cells and organs. Her surprising findings launched Kenyon on a decadelong quest to try to extend life span further, which culminated in an even more startling event in 2004, when Kenyon announced that her team had tweaked their worms to live up to 125 days -- the same as humans living for four centuries. Put another way, if this elongation of life works for us, Sir Isaac Newton and Cardinal Richelieu might still be alive.
To prove the youthfulness of her long-lived worms, Kenyon has developed a number of tests, including an analysis of worm tissues and cells that measures youthful traits. The 125-day worms did not show any of the telltale signs of decrepitude and frailty until the very end of their extended life. They remained vigorous, wiggling happily in their gel, as shown in Kenyon's videos. In human terms, this would mean a person would remain young for decades, growing old very slowly. It also suggests a radical new method for treating maladies of aging such as Alzheimer's, Huntington's and some cancers, which might be put off or eliminated if youth is extended. "Age is the single largest risk factor for an enormous number of diseases," says Kenyon. "So if you can essentially postpone aging, then you can have beneficial effects on a whole wide range of disease."
Other researchers have conducted versions of Kenyon's age-bending experiments to increase the life spans of flies and yeast -- and, far more significantly for humans, of mice. Conducted by Martin Holzenberger of the French Biomedical Research Agency and independently by Ron Kahn at the Harvard Medical School, the mouse tests genetically coaxed mice to live 33 percent longer than normal. These experiments are still very early, says Kenyon; she expects mouse years to be extended considerably longer as the researchers improve their techniques. The mice research is crucial because these mammals are genetically much closer to humans than are squirmy worms. The work on mice and other creatures also supports Kenyon's contention that old assumptions about life spans being fixed for each organism might be wrong. She believes that life span may be regulated by relatively simple genetic mechanisms that can be turned up (or down) by evolution almost as a volume knob is on an iPod.
Kenyon's research suggests that the daf-2 gene controls possibly 100 or so other genes that impact important mechanisms in the worm for maintaining longevity. "You can think of daf-2 as the orchestra conductor, leading the flutes, and the violins, and the cellos, each doing a little bit. So they play in concert," she says. "But what's neat is what they do.
"Some of the genes function as antioxidants -- they stop the damage done to worm cells by free radicals." Free radicals are chemical by-products of cell metabolism, mostly created by the burning of oxygen, that wreak havoc on a cell's mitochondria, DNA, proteins and enzymes by stealing electrons. Deprived of electrons, molecules then start snatching them from each other in a vicious chain reaction. Cells counterattack with free-radical-scavenging enzymes called chaperones and other damage-repair mechanisms. Over time, free radicals and other environmental toxins -- such as ultraviolet light, heat and radiation -- can overwhelm the cell's defenses, allowing the toxins to tear up DNA, rearrange and delete genes, and initiate either runaway cell growth (cancer) or cell death. Free radicals contribute to human illnesses from emphysema and some cancers to Parkinson's disease and vascular disorders. The daf-2 in worms and similar genes in humans seem to be involved in repressing the synthesis of free-radical scavenging enzymes.
Other genes in the daf-2 "orchestra" include those that help repair damaged proteins and those that fend off bacteria that can cause infections. "Still others affect metabolism," Kenyon says. "They affect fat transport and food utilization [by the cells] and things like that."
Kenyon explains that the daf-2 gene allows cells to respond to worm hormones that are similar to the human hormone insulin, which is best known for regulating how the body processes food, and insulin-like growth factor 1 (IGF-1), another hormone that influences growth. In humans and in mice there are three genes whose functions resemble those of a worm's daf-2 gene. One of them allows cells to respond to insulin, another allows cells to respond to IGF-1 and the third has an unknown function.
I ask how one gene -- or perhaps three genes in a human -- can control so much. "Maybe because that way you can make big changes in life span all at once," she says. "I believe this was a part of early evolution. It turns out that the daf-2 circuitry also allows the animal to withstand environmental stress." She explains that in worms, daf-2 is naturally suppressed in larvae during times when food is scarce and other stresses are present, and that suppression puts the worm in a dauer state, a kind of suspended animation that greatly slows aging and development until the stress has passed. Kenyon discovered that suppressing this gene after the worm has reached adulthood triggers life extension, but not in the dauer state. "This mechanism probably evolved to cope with these stresses," she says, "but once it existed it could also drive extensions of life span during evolution. This could happen by mutations that change the regulatory genes, like daf-2. Now the conductor makes the whole orchestra play forte instead of pianissimo. You see? Having everything under one system made this relatively easy to do.
"The first organism, which gave rise to all life, probably had a very short life span," she says. "But once this machinery was in place, organisms evolved to use the regulators to make big changes in life span, which also gave them advantages. For instance, humans live a thousand times longer than worms. Some creatures, such as the Galapagos giant tortoise and some species of lobsters, live to over 150 years old. It's possible that the tortoise might live considerably longer if not for predators."
And what about humans?
"It's possible that we could change a human gene and double our life span. I don't know if that's true, but we can't rule that out. I think that the difference between the life spans of different species may boil down to the activity of master regulator genes, like the daf-2 receptor. We also discovered that downstream from daf-2, the hormone receptor, is another important gene, a master transcription factor called daf-16, which binds to the many downstream genes and turns them on and off. So I bet it will be changes in those genes. And also fine tuning of the downstream genes, the chaperones, antioxidants and the rest. I doubt that humans have special genes for longevity that the worms don't have."
But these organisms are quite different from humans, I say.
"That's why it's so exciting that these experiments are working in mice, in mammals. In mice, two different research groups have shown that the homologues [similar genes in two or more species descended from a common ancestor] of daf-2 control mouse life span. Normal mice have two copies of the gene for the IGF-1 receptor, just as humans do, one copy they got from their mother and one from their father. So what one research group did was to knock out one copy. So now they have mice that have half as much receptor as normal, and they found that the mice live longer. The other group took mice and completely removed the receptor for insulin. Not IGF-1, but the insulin receptor, from the fat tissue, which is known to be an active hormone- producing tissue. They removed the insulin receptor from this tissue and extended life.
"If you trick the body into thinking it's young, and it's constantly replenishing everything, every cell," says Kenyon, "it's like building a ship where you could replace all of the parts and keep it going forever. The catch, the big catch, is that there might be things you couldn't do, you couldn't replace. Who knows?"
I ask her whether there are any side effects.
"Not for those mice, they were lucky mice. They lived longer, and they didn't get fat. That's great. That's the kind of thing we're trying to do."
I tell her this seems too easy. There must be a catch.
"We're so used to thinking that you can't get something for nothing. But why would that be true? Humans live a lot longer than dogs, and we don't suffer any penalty that I can see. We're superior in almost every way -- they can smell better. But really, they can't drive cars, they can't do half the things we can. I don't understand why you can't live longer and be really fit. Like our long-lived worms."
I ask Kenyon about the ultimate issue -- immortality.
"I think that it might be possible. I'll tell you why. You can think about the life span of a cell being the integral of two vectors in a sense, the force of destruction and the force of prevention, maintenance and repair. In most animals the force of destruction has still got the edge. But why not bump up the genes just a little bit, the maintenance genes. All you have to do is have the maintenance level a little higher. It doesn't have to be much higher. It just has to be a little higher, so that it counterbalances the force of destruction. And don't forget, the germ lineage is immortal. So it's possible at least in principle."
At 50, Kenyon looks 35. And if she is right about a treatment to slow aging, and it comes in time for her, she could be among the first generation of women to be perpetually young since Eve, the first woman, who told the hapless Adam what to do with the apple.
From the book "The Geneticist Who Played Hoops with My DNA" by David E. Duncan. Copyright © 2005 by David Ewing Duncan. Reprinted by permission of William Morrow & Co., an Imprint of HarperCollinsPublishers.