Scientists Extend Life Span Of Worms by Altering Genes




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Scientists Extend Life Span Of Worms by Altering Genes

By Marilyn Chase, The Wall Street Journal
October 24, 2003

Worms often are seen as symbols of death and decay, rather than longevity. But not in a biochemistry lab by this city's bay shore, where scientists are altering an important gene to make mutant worms that far outlive their normal cousins.

Friday, Cynthia Kenyon and colleagues at the University of California at San Francisco will report that they extended the lifespan of the worm, C. elegans, to six times its normal length, or 120 days. It's the longest life extension ever achieved in any animal, she says, and it has implications for human health.

"In human terms, these animals would correspond to healthy, active 500-year-olds," Dr. Kenyon and her co-authors Nuno Arantes-Oliveira and Jennifer Berman write in Friday's issue of Science.

Of course, the team isn't making human Methuselahs. But their work sheds light on the genes that govern lifespan in all animals, and holds hope for understanding many diseases related to aging.

Dr. Kenyon first began tinkering with the daf-2 gene to lengthen the lifespan of worms a decade ago. The human counterpart of daf-2 includes a whole cascade of genes, beginning with the gene for insulin, the hormone that turns sugar into energy.

These worms remained spry despite living six times as long as normal worms, after researchers changed a gene and a few cells.

This crucial network of genes is known collectively as "the insulin gene pathway." Scores of genes in this pathway are believed to influence basic functions like development and aging, metabolism and fat storage, and diseases of aging such as cancer, diabetes and neurodegenerative diseases.

Dr. Kenyon's team reports in Friday's Science that they achieved the sixfold life extension by turning down, or making less active, the daf-2 gene using a technique called RNA interference. RNA, or ribonucleic acid, is a strand of genetic material that determines protein production, the basic function of all genes. Dr. Kenyon and her colleagues made a complementary strand of genetic material that sticks to the worm's strand, and tricks the worm into destroying it. Turning the gene off throws the worm into a state of suspended animation. Turning it down extends life.

For medical researchers, the lure of the longevity studies is its link with a host of age-related disease genes that now beset an aging population.

"The insulin pathway is one of the most exciting pathways for human cancer research," says Laurence Lasky, formerly a researcher Genentech Inc., now a general partner of Latterell Venture Partners in San Francisco . Discoveries by Kenyon and other researchers like Gary Ruvkun at Harvard, are "applicable to both oncology and diabetes."

"I'm enthusiastic about targeting this gene pathway," says Charles Sawyers, professor at the Jonsson Comprehensive Cancer Center of the University of California at Los Angeles . Dr. Sawyers, an investigator funded by the Howard Hughes Medical Institute in Chevy Chase , Md. , is targeting a gene in the insulin pathway called PTEN that leads to aggressive prostate cancer and glioblastoma, a brain tumor.

"I can assure you that big pharma, small pharma, biotech and the cancer world are all over this [gene] pathway," he adds.

Dr. Kenyon, 49 years old, is a professor of biochemistry at UCSF and a member of the National Academy of Sciences. Her work is supported by the federally funded National Institute on Aging. She directs UCSF's Hillblom Center for the Biology of Aging, a centerpiece of its new $800 million Mission Bay campus, and the first phase of a $2 billion expansion.

Her fascination with C. elegans and its possible link to aging stemmed from her postdoctoral work on developmental genes in the Cambridge University lab of Nobel laureate Sydney Brenner. Colleagues warned her that aging research wasn't heading anywhere she recalls. "People think aging just happens. But I question everything."

In the current study, she also pushed longevity to extremes by removing sex cells that transmit hormone signals -- a move that made the worms sterile. But she found such measures aren't necessary to extend life: Previously, she doubled or trebled their lifespans without harming fertility.

Dr. Kenyon herself has co-founded a company Elixir Pharmaceuticals Inc. The closely held Cambridge , Mass. , concern has licensed her discoveries and is trying to apply them to drug development.

Despite the fountain-of-youth image conjured by the company's name, CEO Edward Cannon says Elixir's goal isn't rejuvenation, but treatment for diseases of aging -- not just cancer and diabetes -- but also such degenerative conditions as Parkinson's, Alzheimer's, Huntington's and Lou Gehrig's diseases. However, he cautions any products are seven to 10 years away. "We're a long way from having a product on the drugstore shelf," he says. "This is not a business for the faint of heart."

Regulating the insulin pathway -- a crucial control center for growth and metabolism -- may prove harder and riskier in humans, says Dr. Lasky.

"The big concern with this pathway is are you going to have toxicity?" says UCLA's Dr. Sawyers. Turning down genes too much might risk diabetes; turning them up too much risks cancer.

Still, Dr. Kenyon radiates optimism as she shows a computer movie of her worms. A normal aged worm lies inert, feebly wagging its head. "See," she says. "In the nursing home." She points to the mutant worm, wriggling about as frisky as a hatchling. "See," she says. "Looking good."