Old Worms, New Aging Genes: Biologists Look into DNA for the Secrets of Long Life

Article excerpt

For more than a decade, Cynthia Kenyon has watched microscopic worms of the species Caenorhabditis elegans live far longer than they should. She has seen mutant strains of this worm, which is normally dead and gone after a mere 2 or 3 weeks, last well into their second month. It's as if a person lived to be 200 years old. Kenyon's long-lived worms are a result of mutations in individual genes. That's a radical notion to many scientists who have long thought of aging as an uncontrollable process of deterioration that isn't regulated by single genes.

"There have to be genes that affect life span," counters Kenyon of the University of California, San Francisco. Noting the dramatic differences in life span among various animals--a mouse may last for 2 years while a bat can live for half a century--Kenyon has become convinced that longevity has evolved in animals many times. She argues that her long-lived nematodes can reveal some of the fundamental molecular biology that controls longevity in more-complex organisms, even people.

In 1993, Kenyon and her colleagues jump-started the field of aging genetics when they reported on a mutant strain of C. elegans that lives twice as long as normal. It showed the largest proportional lifespan extension of any animal known at the time. Researchers eventually determined that this long-lived nematode strain arose from a defect in a hormone-triggered cascade of molecular signals that resembles one in people that is prompted by the hormone insulin. Mutations affecting a similar hormone-driven cascade in fruit flies can lengthen the lives of these insects as well.

Over the past few months, Kenyon's team and several other groups of worm researchers have documented an unexpectedly large number of genes controlled by this hormonal system, including genes involved in stress responses and antimicrobial actions. This aging pathway appears to be at work in mammals, also. Two research teams have shown that altering how mice respond to insulin or a related hormone can extend the animals' lives, raising the prospect that manipulating these hormones in people could slow aging or enable them to age with better health.

"There's a possibility in humans that a similar aging pathway is at work," says Catherine Wolkow of the National Institute of Aging in Bethesda, Md.

WRINKLED WORMS Some scientists challenge Kenyon's work by claiming that her long-lived nematodes aren't actually aging slowly. Perhaps, these critics say, the genetically altered worms become old and frail at the normal pace but simply have had a major cause of death eliminated. Settling that controversy requires a routine way of measuring the aging process.

In her initial work with C. elegans, Kenyon gauged the increasing age of a worm by its decreasing mobility. More recently, she and her colleagues trained high-powered microscopes on aging nematodes and documented many changes in various tissues. Among other signs of deterioration, cell boundaries become less distinct, and the insides of cells go from smooth to curdled and become filled with cavities. In complementary work, Monica Driscoll of Rutgers University in Piscataway, N.J., and her coworkers found that worm muscle fibers lose their organized appearance as worms age (SN: 10/26/02, p. 260).

Like elderly people, who have wrinkles and other signs of age, "old worms have a particular look to them," Kenyon says.

Now that biologists have an idea of what happens to a worm as it grows old, they may be able to make better sense of all the genes they've identified over the past decade that affect aging. Indeed, the number of these longevity genes continues to grow. At a recent annual international meeting of C. elegans researchers, Kenyon's group reported unearthing more than 30 previously unrecognized genes that, when mutated, extend the nematode life span.

At the moment, the best-characterized genetic pathway of worm aging is the one Kenyon's group described in 1993. …