Jan. 17 issue - Though death is still as inevitable as taxes, future generations may age more slowly and live significantly longer. Here are five scientists in the vanguard of research, offering new insights into the biochemistry of aging—and opening the door for life-lengthening drugs. Their approaches vary, but they share the belief that the human life span is not fixed.

Enhanced: TARGETED GENES ARE MORE ACTIVE IN FIGHTING AGING

The "guess your age" booth at a carnival isn't often exactly right. But it's not usually as off-base as Cynthia Kenyon's colleagues. A few years ago Kenyon, a molecular geneticist, had one of her grad students cart a tray of worms around her lab, asking people how old they thought the worms were. Most said about 5 days. What they didn't know was that Kenyon had tinkered with the worms' genes. The squirmy creatures had the perfect health of 5-day-olds, but they were 144 days old—six times their normal life span.

Over the last decade, Kenyon's continuing work has shown that "you can make huge changes in life span so easily"—in worms, at least—by changing hormone levels and enhancing the effects of fewer than 100 genes. Some of the target genes produce antioxidants; some make natural microbicides; some are involved in transporting fats throughout the body, and some, called chaperones, "keep the cell components in good working order," says Kenyon. What they all have in common is their effect on aging. The more active the genes, in general, the longer an organism is likely to live.

When Kenyon's work with worm genes was first published in 1993, skeptics predicted it wouldn't translate well to humans. One hundred forty-four days might be ancient for a worm, but a far more complex human being can already expect to live about 200 times longer than that. Scientists still don't know exactly why the life spans are so different, much less what a change in a worm's life span might mean for a person's. Nonetheless, much of the cellular machinery in worms closely resembles that in higher mammals. That finding has opened the door for a neutraceutical company, Elixir, which is trying to develop a drug that would yield the same kind of results as Kenyon's genetic tampering. "I'm not saying that with a few changes humans could be immortal," she says. "But it'd be like looking at an 80-year-old and thinking he was 40." Who could object to that?

Stressed: CHRONIC TENSION MAKES CELLS DETERIORATE FASTER

If you've ever blamed stress for new wrinkles or gray hairs, you may have been right. "As a society, we have a deeply held belief that life stress causes premature aging, but there's actually been very little empirical evidence to show this," says Elisa Epel, assist-ant professor of psychiatry at the University of California, San Francisco.

Until now. In a UCSF-led study published this past fall in Proceedings of the National Academy of Sciences, Epel and her colleagues found that chronic stress—or even the perception of stress—significantly shortened the length of telomeres, the tips of chromosomes within cells that can be used as a measure of the cells' aging process. The shorter the telomere, the shorter the cell's life span and the faster the body's deterioration. As more cells die, the effects of aging kick in: muscles weaken, skin wrinkles and eyesight and hearing worsen.

Epel and her colleagues studied 39 women between the ages of 20 and 50 with children suffering from serious chronic conditions, like cerebral palsy, and compared them with 19 mothers in the same age group with healthy children. The longer a woman had been caring for a sick child, the shorter her telomeres—and the greater her oxidative stress (a process that releases DNA-damaging free radicals).

But what startled researchers more was that the most profound differences were tied to the women's perceptions of how much emotional strain they were under, regardless of whether their children were healthy or sick. When compared with the women with the lowest perceived stress levels, women in both groups who described themselves as having the highest stress levels had telomeres equivalent to someone 10 years older.

While Epel acknowledges that more studies need to be done to confirm her findings, she says the results could have positive implications. "Now that we think we can see intracellular damage from stress, people might weigh the importance of positive mental health more heavily," she says, adding that there is "absolutely" hope that the DNA damage is reversible. "Lifestyle changes—and learning to cope well with stress—could potentially improve your quality of life, your mood and your longevity."

Restricted: A TOUGH LIMIT ON CALORIE INTAKE MAY SLOW AGING

Leonard Guarente didn't come up with the trick of calorie restriction, or strictly limiting nutrients to achieve longer life. And the idea sounded crazy back in 1986, when Guarente first proposed to study the biology of aging via calorie restriction. Aging was seen as too complex a topic for molecular biologists, and the effect of calorie restriction on aging, though detailed in scientific literature since the 1930s, was even more poorly understood. Guarente's colleagues called him "bonkers," but he didn't care: "I wanted to work on something risky," he says. "Besides, I had just gotten tenure, and at that point they couldn't get rid of me."

They certainly wouldn't want to now. Guarente is not the least bit bonkers—and, unbeknown to his colleagues at the time, he wasn't even the only scientist thinking about the molecular biology of calorie restriction. In the last decade, researchers have made great strides in understanding why a sudden drop in calorie intake can kick up the activity of a gene called SIR2 and prolong life in simple organisms.

At the head of the class are Guarente and a Harvard researcher named David Sinclair, both of whom are focusing on sirtuins, the family of proteins produced by SIR2 or its mammalian analogue, SIRT1. Guarente's lab has unraveled many of the basic molecular processes behind SIR2. For instance, a natural chemical called NADH can inhibit sirtuins' effects; Guarente's lab has determined that yeast with lower NADH levels lives longer. Sinclair's work has a slightly different focus—resveratrol, the chemical he has connected to calorie restriction's effects. (It's better known as the major reason red wine is touted as healthful.) Sinclair's work at Harvard has shown that heavy doses of resveratrol can prolong life span in yeast by 70 percent. Still another scientist, Marc Tatar, has garnered similar results in fruit flies.

The fact that calorie restriction works isn't all that surprising from an evolutionary point of view. In fact, calorie restriction is an extremely effective strategy for survival during lean times, when it's an imperative, not a choice. "Let's imagine I had a gene that could allow me to suspend reproduction and slow down aging during a famine," says Guarente. "When the famine ends, I'll still be around to reproduce." As a result, he adds, "every animal we know can do this."

Including humans, of course. But since few people particularly want to limit their calories drastically (least of all Americans), Guarente is searching for a pill that will have the same effect. Elixir, the same company building on Kenyon's work, is also using Guarente's—which means, someday, humans may reap the benefits of calorie restriction without even having to say the word diet. Sinclair has a competing company called Sirtris. He expects to get his drugs into clinics in just five years. Until then, he'll be drinking one glass of red wine a day—and toasting to what he hopes will be a huge success.

Supplemented: TWO CHEMICALS MADE OLD RATS NEW

Five years ago Bruce Ames called his son, a computer executive in New York, with some exciting news. "I told him, 'We're changing old rats to new rats!' " recalls Ames, a senior scientist at Children's Hospital Oakland Research Institute in California. His son was not impressed. "Let me know when you change old people to young rats," he said. Such human-to-animal transformations are still confined to the minds of sarcastic sons and science-fiction writers, but researchers are getting closer to replicating Ames's rat results in humans.

In studies published in Proceedings of the National Academy of Sciences in 2002, Ames and his colleagues fed older rats two chemicals normally found in the body's cells (and also sold as nutritional supplements): acetyl-L-carnitine and alphalipoic acid. Not only did the rats perform better on problem-solving and memory tests, but they moved around with more ease and energy.

Researchers determined that the combination of chemicals had improved the function of mitochondria, organelles that serve as a cell's main energy source. Ames formed a company called Juvenon to license the combination of cell-rejuvenating supplements (also sold separately at several health stores). The company plans to begin human trials soon to evaluate the cognitive effects of the dual supplements. In the meantime, Ames, who chairs Juvenon's scientific advisory board but gets no proceeds from the company, is overseeing lab research on human cells in tissue culture. In one study, Berkeley researchers found that lipoic acid protected the cell from oxidation when iron or hydrogen peroxide was added.

Now he hopes to replicate those results in human subjects. Other studies have already linked unhealthy mitochondria to Alzheimer's, Parkinson's, type 2 diabetes and other degenerative diseases, so reversing or repairing decay in mitochondria could help to stave off the age-related diseases. "I'm hoping we can add a few years to people's lives," says Ames, who's 76. "I think we can."