`Die Young At An Old Age'

The race is on to find longevity genes

In 1513, the explorer Juan Ponce de Leon arrived in Florida in search of the Fountain of Youth. Today, scientists are still looking for antidotes to aging--not in Florida but in the DNA of such humble organisms as yeast, worms, and fruit flies. There they have found at least a dozen longevity genes that can dramatically increase life span. Scientists hope to find corresponding genes in human beings that could be manipulated to help people live longer, healthier lives. "We want to have people die young--at an old age," says S. Michal Jazwinski of the Louisiana State University School of Medicine in New Orleans.

Although still at an early stage, research on longevity genes is moving quickly. The National Institute on Aging (NIA) has launched a program with a dozen or so laboratories to search for longevity genes. Three companies are also pursuing these alluring genes--betting they will help prevent diseases of aging and increase life span (table). Aging research is now changing from "a field where there's a lot of theory to one where there's a lot of fact," says Joseph P. Brown, CEO and founder of LifeSpan BioSciences Inc., a startup in Seattle.

Even so, many challenges remain. Human aging is an extremely complicated biological process. There is no single gene that switches on to cause white hair and wrinkles. Instead, cells in every tissue of the body gradually stop functioning at peak levels. Some of the decline is controlled by genes. But environmental stresses like a high-fat diet or sun exposure also play a role. Older cells become less able to repair damaged DNA, and they malfunction in other ways.

A big obstacle in aging research is that humans and many experimental animals take too long to get old. So researchers have turned to yeast, worms, and fruit flies, which share a surprising number of genes with humans but have life spans measured in weeks or months.

RESISTANCE TO STRESS. The work in simple organisms offers a "stripped-down version of aging," says Jazwinski. Here, scientists can peer into individual cells to see what is influencing aging. In yeast, for example, researchers have discovered a half-dozen genes that directly affect longevity. When the gene called LAG-1 is eliminated, yeast strains live up to 100% longer than average. Jazwinski cloned and patented LAG-1 two years ago. He has yet to determine its function, but he has found a counterpart in human cells. LSU licensed the LAG-1 gene to Jouvence Pharmaceuticals Inc. in San Diego, where Jazwinski is a scientific adviser.

Microscopic worms, specifically the nematode, have also proven to be a rich source of longevity genes. Nematode larvae can undergo a developmental "time out": a sort of hibernation when there is overcrowding or a shortage of food. During this state--which can last up to 60 days--the larva doesn't feed or age. When the genes that govern this hibernation are "tweaked" during the worm's adult life, it can live 100% longer. Some of these larval genes may increase longevity by conferring great resistance to stresses such as heat and chemicals--both of which can damage DNA and decrease life span.

Shutting off one such nematode gene, called AGE-1, causes an increased production of enzymes that mop up toxic byproducts of cell metabolism. This increases the nematode's life span by 70%.

Fruit flies, known to scientists as drosophila, also are providing clues to aging. Fifteen years ago, scientists bred populations of fruit flies that live twice as long as their normal brethren. James W. Curtsinger, a biology professor at the University of Minnesota, has screened some 1,200 drosophila genes looking for the so-called Methuselah genes responsible for the longer life. He has found one that seems to expand life span by one-third--and he has identified counterparts in other organisms.

REACTIVATION. Despite the spate of discoveries in simple organisms, it still takes a leap of faith to relate findings in fruit flies to humans. With that in mind, another cadre of researchers is hunting for aging genes in human cells. Their strategy is to compare old and young cells from various tissues, looking for genetic differences.

Geron Corp., in Menlo Park, Calif, is focusing on senescent human cells--those that have reached the end of their useful life span. Instead of dying, senescent cells "remain viable and have abnormal behavior," says Calvin B. Harley, Geron's chief scientific officer. Some genes active during embryo development are reactivated; other genes for repairing DNA or fending off genetic damage are turned off. Take skin cells. The stress of sun exposure makes them old and tired. Some, instead of dying, behave erratically--increasing production of enzymes that cause skin to thin. There's also a reduction in collagen and other structural components that maintain thickness and help wounds heal.

One focus of research at Geron is a search for drugs that could turn off errant genes in old cells. Heart disease and skin aging are Geron's first targets. LifeSpan BioSciences is searching for longevity genes in a bank of "several hundred thousand" tissue samples, says CEO Brown. Both groups watch for clues from the research on simple organisms. "The work is synergistic," says Dr. Anna McCormick, head of the longevity gene program at NIA.

In the end, many researchers believe humans are unlikely to exceed their maximum life span of about 120 years. Rather, the goal of this research is to increase individual longevity and to delay diseases associated with aging. "The dream we have is that someone retires at age 65 and looks forward to another 30 years of healthy life," says Brown. If yeast and worms are any guide, that dream may someday come true.

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