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If you were a nematode in Siegfried Hekimi's genetics lab, you would be one of the most remarkable creatures in the world. It wouldn't be your looks that made you special, of course. As a tiny transparent worm measuring a millimeter from tip to tail, you would be nearly invisible to the naked eye. Nor would it be the way you spent your time. Moving little and eating less, you would pass all your days inside a Petri dish, resting atop a bed of nutrient.

No, what would make you unique as you lived your unexceptional life would be how long you got to live it. Nematodes in Hekimi's laboratory at Montreal's McGill University have been known to survive for 50 days. Nematodes outside the lab survive for barely nine. A human being this long-lived would be 420 years old.

Across the continent, at the University of California at Irvine, evolutionary biologist Michael Rose has created a community of fruit flies almost 1 million strong. The fleck-size insects spend their time doing what fruit flies do: they eat, they breed, they fly. But they do it for a lot longer. Fruit flies in Rose's colony may survive for up to 140 days. In the absence of predators, fruit flies in the wild get just 70. A person with this kind of longevity would easily exceed 150 years.

For researchers studying aging--as well as for the rest of the human population, getting inexorably older and feeling none too happy about it--the rules have always been simple: organisms are born, they live a more or less prescribed number of years and they die. If you watch your weight, eat right and get plenty of exercise, you can perhaps negotiate the terms a bit, squeezing out a bit more time here and there. But tripling life-spans? Quadrupling life-spans? Eliminating the very idea of life-spans? Not an option.

Or so it seemed. But now the rules are quietly being broken. Hekimi and Rose are only two members of a growing community of scientists who have decided that the old way of thinking about senescence needs to be challenged. In laboratories around the world, investigators are beginning to suspect, to their growing surprise and excitement, that what works in flies and worms may work for people too. From species to species, genus to genus, the cellular mechanisms responsible for aging appear to be the same. Armed with that knowledge, a new breed of longevity specialists is beginning to tease out answers to two of the great mysteries of life: Why do we age? And even more important, What can we do about it?

The clues are tantalizing. In some research centers, investigators are studying an area at the tip of chromosomes that appears to shorten, fuselike, as we grow older. Extinguish the chemical fire that consumes the fuse, and you might be able to bring aging to a halt. Elsewhere, scientists are studying how the waste produced when a cell consumes food can contaminate its innards, a process that can lead to the body-wide breakdowns we associate with aging. Clean up the cells, and you should be able to buck up the entire organism. Still elsewhere, geneticists are beginning to map the very genes that direct us to get old in the first place. After mapping genes, the next logical step is manipulating them, and once you start reweaving the DNA that codes for life itself, anything is theoretically possible.

Most promising of all is the possibility that scientists may someday not only lengthen life-spans but improve them as well. Researchers are starting to talk about the likelihood of people living well into their second centuries with the smooth skin, firm muscles, clear vision, high energy and vigorous sexual capabilities they once could enjoy only in youth.

For human beings, the sea change in aging has been a long time in coming. In the past decade or two, there has been an explosion in new therapies designed to slow the senescence process--from melatonin to antioxidants to hormone-replacement therapy to the intriguing hormonal precursor DHEA.

Popular as some of these treatments are, what they promise is modest: a few years added here and there, and an increased likelihood that those years will be healthy ones. What the new wave of researchers is looking for is life extension that's not so much incremental as exponential. Not just a year here or there, but a doubling or tripling of human life expectancy.

History shows it's possible. In 1900 the life expectancy for a person born in the U.S. was 47 years. At mid-century, it was little better. After 1950, however, things started to stir. In a single year, subtle improvements in medical care caused the 47-year figure to jump 2%. The next year it jumped another 2%; then another. For four decades, that pattern has roughly continued, a compounding of existential interest that, according to U.S. figures, has pushed the average life expectancy to nearly 76, with many Americans living well beyond. Less conservative demographers are more optimistic still, believing a child born in America today can realistically look forward to living 100 years. Last week the sunnier scenarios got a boost when the National Cancer Institute reported that between 1990 and 1995, U.S. death rates from cancer fell more than 3%, the first sustained decline since 1900 (see box).

But what if the medical breakthroughs were more dramatic? If living to the century mark involves little more than riding the demographic wave, how much further than 100 is it possible to go? Is 150 reasonable? 200? What about 300? And if not, why not? The body, after all, is just a machine--albeit a wet, cranky, willful one--and, as with all machines, it should be possible to extend the warranty. "There is no evidence we know of that human life expectancy is anywhere close to its ultimate limit," says James Vaupel, a Duke University demographer and the soon-to-be director of the Max Planck Institute for Demographic Research in Germany, "if there is an ultimate limit."

In the same way that the modern era of genetics research began in 1953 when the DNA double helix was identified, the modern era of aging research is thought to have begun in 1961, when anatomist Leonard Hayflick made an equally significant discovery. Hayflick had been troubled by the question of where aging begins. Is it the cells themselves that falter, dragging the whole human organism down with them? Or could cells live on indefinitely were it not for some age-related deterioration in the higher tissues they make up?

To find out, Hayflick harvested cells from fetal tissue and transferred them to a Petri dish. Freed from the responsibility of doing anything to keep a larger organism alive, the cells did the only other thing they knew how to do: divide. Shortly after they were placed in culture, they doubled their number. Then they doubled the doubling. The cycle repeated itself about 100 times, until all at once it stopped. From then on, the cells did something a lot like aging. They consumed less food; their membranes deteriorated; and the culture as a whole languished. Hayflick repeated the experiment, but this time used cells from a 70-year-old, and found that the cellular aging began a lot earlier, after 20 or 30 doublings. Clearly, it seemed, the cells from the older human were older themselves.

"What we were seeing," says Hayflick, now a professor at the University of California, San Francisco, "was the concept of cellular aging: growing old in the microcosm of a Petri dish."

For gerontologists, this was monumental stuff. If human tissue behaved in the body the same way it did in the dish, they felt, it meant that somewhere in the nanoviscera of each cell there was an actuarial hourglass that gave it only so much time to live and no more. If the clock could be found--and, more important, reset--both the cells and the larger corpus that gave rise to them might be made immortal. Of course, hypothesizing the existence of such a cellular timekeeper was one thing; finding it and manipulating it were something else again. In the years since, senescence scientists have taken two approaches to achieving this goal.

The first idea researchers have explored is broadly thought of as the cellular-damage model of aging. For any complex system--whether it's made of inorganic metal or protoplasmic goo--the mere act of doing the work it was designed to do carries a price. No sooner does the hardware begin operating than its parts begin wearing out and its journey to the junkyard begins. Cells are not spared this fate, and one of the functions that takes the most out of them is the job of processing food.

Like all organisms, cells produce waste as they metabolize energy. One of the most troublesome by-products of this process is a species of oxygen molecule known as a free radical--essentially an ordinary molecule with an extra electron. This addition creates an electrical imbalance that the molecule seeks to rectify by careening about, trying to bond with other molecules or structures, including DNA. A lifetime of this can lead to a lot of damaged cells, which may lead to a range of disorders, including cancer and the more generalized symptoms of aging like wrinkles and arthritis.

In recent years, some nutritionists have advocated diets high in fruits and vegetables containing carotenoids--substances that act as antioxidants by sopping up free radicals and carrying them out of the body. But antioxidants have an uneven record. In some studies they seem to be associated with a dramatic reduction in cancer or other diseases; in others, some antioxidants, such as beta-carotene, actually seem to be associated with an increase. In either event, few contemporary aging researchers think self-medicating at a salad bar is the best way to extend the human life-span. Far more promising might be new research into another by-product of cellular metabolism: glycosylation--or what cooks call browning.

When foods like turkey, bread and caramel are heated, proteins bind with sugars, causing the surface to darken and, in some cases, turn soft and sticky. In the 1970s, biochemists hypothesized that the same reaction might occur in the bodies of people suffering from diabetes, as excess glucose combined with proteins in the course of metabolism. When sugars and proteins bond, they attract other proteins, which form a sticky, weblike network that could stiffen joints, block arteries and cloud clear tissues like the lens of the eye, leading to cataracts. Since diabetics suffer from all these ailments, the biochemists guessed they were right.

But joint pain, circulatory disease and poor vision sound an awful lot like the symptoms of aging. Was it possible that as the cells of nondiabetics metabolize sugars, the same glycosylation process might take place, only much slower?

The idea that the grand tragedy of aging and dying might be nothing more than a body-wide process of caramelization was humbling, but more research provided still more proof. Studies of the collagen sac between the brain and skull in diabetics and the elderly turned up brown pigment characteristic of advanced glycosylation. "The glycosylation process is like the free-radical process," says Dr. Robert Butler, head of the International Longevity Center at Mount Sinai Medical Center in New York City. "It's a natural phenomenon that keeps us alive but also helps lead to aging."

In the years since the caramel theory was first advanced, the gooey glycosylation residue has been given an appropriate acronym: AGES, for advanced glycosylation end products. If residue from AGES do indeed gum up the body's works, however, there may now be a way to get things unstuck. Investigators at the Picower Institute for Medical Research in New York are working on a drug that acts as an AGES solvent. Known as pimagedine, the medication dissolves the connections between the AGES protein and the proteins that cluster around it. In one study, 18 patients taking pimagedine showed reduced blood levels of lipoproteins, the substances that act as precursors of artery-clogging cholesterol. In another, rats taking pimagedine did not exhibit any signs of heart disease.

"We're at the early stages of development, but we have a theory and proof of concept," says Dr. Richard Bucala, a Picower researcher. "The biochemistry of glycosylation occurs in a lot of medical conditions, so it's not a great leap to aging."

An alternative to changing the way cells process nutrients is giving them less to process in the first place. Studies have shown that rats whose caloric intake is 30% lower than that of a control group tend to live 30% to 40% longer. In humans, that would translate to a spartan diet of just 1,400 calories a day in exchange for 30 extra years of life.

Just how this business of swapping food for time works is not entirely clear, but George Roth, molecular physiologist with the National Institute on Aging in Bethesda, Maryland, has some ideas. When animals are placed on caloric restriction, Roth explains, the first thing that happens is that their body temperature drops about 1[degree]C. Lower temperature means a less vigorous metabolism, which means less food is processed. "In order to compensate for the reduction in diet," Roth says, "the animals switch from a growth mode into what can be thought of as a survival mode. They get fewer calories, so they burn fewer.

Cold and hungry, of course, is no way to go through life, but the condition has its rewards. When metabolism slows down, all its attendant processes do too, including cell division. Since, as Hayflick discovered, the number of divisions is limited, animals that go through them slowly may be able to salt a few away for later in life.

Roth, who has already observed the life-extending effectiveness of caloric restriction in rodents, is conducting similar experiments with primates. Even if they succeed, however, trying to apply the treatment to humans could prove dicey. In a nation of consumers for whom caloric belt tightening can mean little more than a smaller serving of French fries with their bacon cheeseburgers, the belief that people would be willing to reduce what they eat by a full third is probably unrealistic.

Roth finds this frustrating. "I think caloric restriction could take us beyond a life-span of 80," he says, "maybe even 120. After all, you rarely see a fat centenarian." Given modern dietary habits, however, it may be more practical to find out what part of the metabolic system caloric restriction operates on and then imitate that effect pharmacologically. "Essentially," explains Roth, "we'd use a pill to trick a cell into thinking less food is coming in."

Even if Roth succeeds, however, the impact of his work may be limited. In the world of antiaging, caloric reduction is essentially maintenance work, little more than patching holes in a slowly sinking ship and hoping you can stay ahead of the water it's still taking on. What senescence researchers really want is a way to get down into the body's engine room--the genes themselves--and rebuild things from the boilers up. Remarkably, it appears there may be a way.

Although he made history when he discovered the limits on cell replication in the lab, Hayflick left a question unanswered: why the cells die. In the years following his work, biologists mapping human chromosomes looked for a gene that enforced cellular mortality, but found nothing. One thing that did catch their eyes, however, was a small area at the tip of chromosomes that had no discernible purpose. Dubbed a telomere, the sequence of nucleic acids did not appear to code for any traits. Instead it resembled nothing so much as the plastic cuff at the end of a shoelace that keeps the rest of the strand from unraveling.

But telomeres weren't completely inert. One thing they almost always appeared to do was grow shorter. Each time a cell divided, the daughter cells it produced had a little less telomere to play with. Finally, when the cell reached its Hayflick limit of 100 or so replications, the telomere was reduced to a mere nub. At that point, the cell quit replicating. Once it did, researchers theorized, the genes previously covered by the telomere became exposed and active, producing proteins that triggered the tissue deterioration associated with aging.

While most every cell in the human body exhibited telomere loss, a few didn't. Among those spared were sperm and cancer cells--just the cells characterized by their ability to divide not just 100 times, but thousands.

The next step for scientists was obvious: study the cells with little or no replication limit and find out what mechanism kept their telomeres--and their lives--so long. In 1984 molecular biologists Carol Greider and Elizabeth Blackburn, then with the University of California, Berkeley, did just that. Working with a single-cell pond organism, they discovered a telomere-preserving enzyme they dubbed telomerase. Five years later, Gregg Morin at Yale University confirmed their work, identifying the same substance in cancer cells. In the Petri dish, the agent of eternal life had been found.

"The moment telomerase was discovered," says Hayflick, "it was clear that for immortal cells at least, this was a way to circumvent the inevitability of aging and dying." Telomerase has now been found in the precursor cells that give rise to human eggs, in the stem cells that give rise to blood cells and in up to 95% of cancer cells.

Since telomerase keeps these tenacious cells going, is it reasonable to assume that the same enzyme could be used artificially to help mortal cells--and the body itself--exceed their programmed life-span? At Geron Corp., a San Francisco-based biomedical firm, biologist Calvin Harley is trying to find out. Harley, who collaborated with Greider on her later telomere work, is looking for the genes that direct telomerase production, believing he might be able to manipulate them so that the spigot for the enzyme can be turned on and off at will. "I think we are going to see fundamental medicines for aging," Harley says. "With a pill, with cell therapy, I think we may be able to treat aging in very specific areas."

Of course, telomerase therapy has obvious problems. Dosing tissues with precisely the enzyme that helps turn healthy cells cancerous strikes many skeptics as less than a life-extending brainstorm, and even advocates of telomerase therapy don't pretend that such treatments could yet be considered safe. Moreover, how easy it would be to manipulate the telomerase gene in the first place is an open question, since merely locating it among the 100,000 or so we carry in each cell can be a mind-numbing job.

But even as Harley begins his search, other genes implicated in aging have already been flushed out of hiding. At McGill University, Hekimi's long-lived nematodes have helped expose a few of them. Hekimi created his little uberworms by crossing and recrossing individuals that lived longer naturally, slowly extending the life-spans of later generations. He then searched the animals' chromosomes until he found the mutated gene responsible, a gene he dubbed Clock-1. "The Clock-1 gene is critical in setting life-span," Hekimi says. "More important, with cloning and genetic mapping, we were able to determine just which protein the gene created to get that job done."

After locating three other nematode clock genes, Hekimi went looking for similar ones in people. He found one whose amino acid schematic nearly mirrored Clock-1's. "The Clock-1 genes in the two species are so very similar," he says, "that it's possible the whole clock system works the same way. If we find all of the human clock genes, we can perhaps slow them down just a little, so we can extend life."

In California, Michael Rose, who created the aged fruit flies, has not yet found the genes responsible for his insects' longevity, but does believe genetic manipulation can be a key to prolonging life. Manipulating any senescence genes could be years--indeed, decades--away. But the alternative--subjecting human beings to the same selective mating processes applied to lab animals--is out of the moral question. "We're not going to be breeding humans the way we breed fruit flies," he says. "We have to find some less fascistic method of intervening in aging."

Meanwhile, more and more genes involved in the aging process are giving up their secrets. At the Veterans Affairs Medical Center in Seattle, a group led by molecular geneticist Gerard Schellenberg has identified the human gene responsible for the disorder known as Werner's syndrome. People suffering from Werner's start life normally, but by the time they reach their 20s begin a process of eerily accelerated aging, exhibiting such ailments as heart disease, osteoporosis and atherosclerosis. Typically they die by their late 40s.

Schellenberg's work is noteworthy not only because he found the gene behind such misery, but because he knows how it works. The genetic sequence he discovered codes for the enzyme helicase, which is responsible for unzipping the DNA double helix before it replicates. If this unzipping is disrupted, helicase can't tweeze out mutations that randomly occur and instead allows them to pass through to the next cellular generation. Accumulate enough glitches, and diseases of aging develop. "We know that DNA is being damaged at a high rate," he says. "Knowing that a helicase is responsible gets us closer to solving the mystery."

If the mystery indeed is solved, the benefits could be enormous. Schellenberg suspects that the same helicase deficit that accelerates senescence in Werner's sufferers might, in a more measured form, cause aging in others. To prove this, he will create a strain of mouse that carries a mutant helicase gene so that he can learn how the enzyme works, and more important, how it can be manipulated. Depending upon what Schellenberg learns from these mice, it might be possible to sidestep genetics and simply use helicase boosters to slow aging in both Werner's patients and healthy people.

Running parallel to Schellenberg's work is research being conducted at the New York State Institute for Basic Research into the more devastating Werner's-like disorder known as progeria. People suffering from progeria grow old precociously too, but at a much faster rate; they are claimed by the infirmities of age in their 20s or teens. W. Ted Brown, chairman of the Institute's Department of Human Genetics, believes that progeria, like Werner's, is triggered by a single mutated gene. That genetic miswiring, however, may stimulate activity in the countless other genes that play a role in aging. "Understanding all the genes," says Brown, "will help us understand aging in general."

The problem facing any scientist trying to find a genetic lever on the aging process is the sheer number of genes involved. Geneticist George Martin at the University of Washington in Seattle, who was involved in the discovery of the Werner's gene, believes that even if only a few master-clock genes directly guide aging in humans, up to 7,000 more might be peripherally involved. Re-engineering even one of these is an exquisitely complex process. Re-engineering all 7,000 would be impossible.

For the time being, therefore, many researchers are shifting their focus to goals that are more achievable. If the genes responsible for regulating senescence can't yet be manipulated, they wonder, is it possible to directly treat parts of the body they affect? Jerry Shay, a biologist specializing in cancer research at the University of Texas Southwestern Medical Center in Dallas, does not rule it out. Instead of engineering genes, he says, "we might be able to squirt some chemical to trigger telomerase at a particular site. The enzyme would turn on for a few weeks, change the expression of cells and revert them to a younger profile. We wouldn't have to treat the whole body."

Still other researchers are using what they've learned about telomeres and the other cellular mechanisms to attack the diseases that keep the very old from becoming still older. Researchers at Geron Pharmaceuticals recently published a study in which telomerase RNA was used to block the enzyme in a cancer culture, leading to withering of telomeres and the death of the no-longer-so-prolific cells. Elsewhere, investigators are looking into using the anticaramelization drug pimagedine to help clear arteries and improve cardiac health. Remove heart disease from the constellation of late-life illnesses, and you add three years to the national life expectancy. The detection of a gene that seems to confer protection against Alzheimer's disease may help treat yet another scourge of the aged, currently afflicting 4 million Americans.

While none of these therapies would take human beings anywhere near the tripled and quadrupled life-spans achieved in fruit flies and nematodes, they could at least improve our life expectancies--the number of years even our shortened telomeres and caramel-gummed cells would allow us to achieve if illness didn't claim us first. For much of the time our species has been on the planet, that figure is thought to have been a mere 20 years--barely long enough for contemporary people living contemporary lives to move out of their parents' home. The fact that those lives now routinely exceed 80 years is a monumental achievement. A little more progress in studying telomerase, glycosylation and other aspects of senescence science, and researchers like Butler believe there's no reason today's adults could not realistically hope to see 120.

For people dreaming of immortality, that prospect may fall a little short. But for those of us who are contemplating a life that ends around age 80, four or five additional decades sounds like a splendid first step.