Werner's syndrome

One person says that the secret to a long life is vegetables and vigorous exercise, another swears by beef and gin, and a third gives the credit to daily prayer. Anyone who watches morning television or reads a local paper knows that centenarians have many different explanations for why they've lived so long.

And so, it turns out, does modem science. Experts no longer believe in a single model for longevity. Instead, it is quite likely that each of the nation's 52,000 centenarians reached that milestone because of a unique mix of environmental, behavioral, and genetic factors.

The behavioral and environmental elements in this equation are well known. Publications such as the Health Letter write constantly about ways to reduce the risks for heart disease, cancer, and other scourges by eating a healthful diet, exercising, and avoiding carcinogens such as cigarettes, sunshine, and radon.

At best, these strategies can reduce the risk of falling prey to specific maladies prematurely -- which for Americans means before age 75 or so. Ultimately, of course, the Grim Reaper calls. But why do some people outlive their friends by decades, despite having personal habits that are less than exemplary?

"It's probably because people are born with differing ranges of longevity," said geriatrician Jeanne Y. Wei, director of the Division on Aging at Harvard Medical School. Unlike a carton of milk, which is stamped with a fixed expiration date, nature hands each person a fuzzy upper and lower limit for life expectancy.

A million stories

Aging is probably the sum total of many biological processes. Among them are:

Oxidative damage. Normal cellular activities produce oxygen free radicals, highly reactive molecules that wreak havoc on cells and interfere with all their routine, life-sustaining activities. Oxidation has been implicated in atherosclerosis, cancer, neurologic diseases, diminished immune function, and a host of other changes associated with growing old.

Mounting mutations. Cancer research has been revolutionized by the discovery that a series of mutations in certain cells can lead to specific tumors, such as those of the breast or colon. At the same time, it is clear that the incidence of cancer increases with advancing age. One theory combines these observations to suggest that an individual who accumulates adverse mutations more slowly than his peers will probably outlive them.

Faulty DNA repair. In vibrant young cells, many genetic mistakes are quickly repaired. But in old cells "the garbage collectors come less often than they used to, and when they come they only pick up half of the trash," said Dr. Wei. This enables abnormal proteins within cells to do more harm than they would in a younger organism.

Accumulation of senescent cells, just as tenured professors sometimes resist retirement, depriving new ones of the opportunity to reinvigorate the classroom, old cells may hang around longer than they should. There is some evidence that senescent cells -- ones that can't divide anymore -- accumulate in aged creatures.

Dodging common bullets

Although most of the search for what the National Institute on Aging dubs "longevity assurance genes" is going on in animals, at least a few good candidates have turned up in humans. One rare gene causes people to produce extraordinary amounts of beneficial high-density lipoprotein (HDL), which guards against the development of atherosclerosis. Another, called Apo A-1 Milano, clears cholesterol from the bloodstream so fast that even those with elevated levels of harmful low-density lipoprotein (LDL) don't develop clogged arteries.

Variations in a third have been linked to both Alzheimer's and cardiovascular disease. The gene for apolipoprotein E, a cholesterol-carrying protein, comes in three forms: ApoE2, ApoE3, and ApoE4. People who inherit two copies of ApoE4 are at increased risk for developing atherosclerosis and late-onset Alzheimer's disease (the most common type). Their lives will probably be shortened; on the other hand, people with two copies of ApoE2 are likely to live quite a bit longer.

Although most scientists have given up on finding a "Methuselah gene" that exists for the sole purpose of extending life, they've had better luck at the other end of the spectrum. Last year an international team located a gene that accounts for a rare and dramatic form of premature aging.

People with Werner's syndrome seem perfectly normal at first, but in early adulthood a biological fast-forward switch is tripped. They develop wrinkles, gray hair, and cataracts and soon are struck down by heart disease, cancer, osteoporosis, and other classic scourges of old age. Most die before they are 50.

The most exciting part of this discovery is that the Werner's gene appears to direct production of a helicase, a special enzyme that is involved in repairing damaged DNA. As noted earlier, the accumulation of genetic mutations, coupled with the body's dwindling capacity to correct them, may shorten life.

Although only a handful of longevity-related mutations have been found in humans, the search has been more successful in animals such as Caenorhabditis elegans (a nematode, or tiny worm), Drosaphila (fruit flies), and rodents.

Once scientists locate a gene that is associated with longevity in a worm or fly, they can look for its equivalent in the DNA of very old people. A promising human gene might next be inserted into an experimental animal to see whether it prolongs life.

In 1994, biologists at Southern Methodist University in Dallas created some genetically engineered fruit flies that lived one-third longer than normal. The flies were given extra copies of genes that code for superoxide dismutase (SOD) and catalase, two natural antioxidants. In addition to living longer, the altered flies were more physically fit than the others and showed less oxidative damage to proteins.

Meanwhile, when nematodes face overcrowding or starvation, they transform themselves into dauer larvae. In this state they don't move around or eat, and when external conditions improve they emerge not a day older biologically. In 1993, researchers demonstrated that daf genes, which control dauer formation, can also be used to double the lifespan of worms. Subsequent experiments have produced creatures that live five times longer than normal.

So-called dock genes are the latest entrants in the life extension sweepstakes -- at least for C. elegans. In 1996, researchers from Canada's McGill University demonstrated that worms with mutations in four genes survived nearly five times as long as ordinary worms.

Unlike worms with daf mutations, which essentially hibernate, these worms continue to feed and swim, but at a much slower pace. They appear listless -- which is not what most people have in mind when they think about extending their golden years.

Scientists who comb the animal kingdom for clues to longevity have not focused exclusively on DNA. Some of the most promising other substances are heat shock proteins (HSPs), which have been studied mainly in fruit flies. When cells are attacked by toxins, infectious agents, or anything else, these chemical sentinels rouse other proteins to fight back and stabilize them in stressful situations.

In fruit flies, several types of HSPs appear to promote longevity. In rats, HSPs help limit permanent damage in heart muscle temporarily deprived of blood. Because they are such versatile cellular defense mechanisms, HSPs will probably turn out to be major players in human longevity.

Meanwhile, a series of animal experiments that began in the 1930s demonstrates that calorie restriction can extend the average and maximum life expectancy for creatures as diverse as fish, fleas, fruit flies, and rodents. Still lacking, however, is proof that humans and other primates will reap similar benefits.

Pushing the age envelope

People in some families routinely live into their 90s, or even past 100, while members of others often die "before their time." Medical centers have begun banking DNA samples from people in long-lived kindreds so that it will be easier to test the relevance of life-extending mutations found in animals.

Experts believe that the people they call super survivors, or "the oldest old," probably are endowed with genes that protect them against common diseases and with traits that keep their cells and tissues in good working order far longer than expected.

In his observations of people over 95, Harvard researcher Thomas T. Perls has found them to be generally healthier, and more cognitively intact, than people in their 80s. Centenarians may embody "the survival of the fittest," according to Dr. Perls, a geriatrician at Beth Israel Deaconess Medical Center in Boston. Some interesting gender differences emerge among super survivors. Women outnumber men at age 95, but the men fare better in terms of mental function and physical health. Geriatricians say that men with dementia die before their 90s, whereas women with the same degree of deterioration hang on longer. Character attributes also seem to play a role. (See sidebar, "Proceed with Caution")

When people think about having a long life, they aren't looking for an additional decade of being in a wheelchair or forgetting their grandchildren's names. Instead, they want to stretch the years spent in healthy, independent living. So far, the best intervention for this is exercise. Although there is no proof that physical activity extends life, there is evidence that it reduces illness and disability.

And who knows? A combination of exercise and diet may turn out to have the same impact as longevity genes. If that's the case, people who weren't necessarily born to have a long life might be able to get there anyway.

RELATED ARTICLE: Proceed with Caution

You might hesitate for just a moment if a friend, inviting you to a dinner party, breathlessly announced that the other guests would all be "very conscientious." It certainly lacks the pizazz of being asked to spend the evening with "highly sociable" people with "a great sense of humor."

The older you get, however, the more likely you are to find that the cautions, belt-and-suspenders types outnumber the cheerful party animals. At least that's the word from a unique examination of the relationship between childhood personality traits and longevity.

Back in 1921, Stanford University psychologist Lewis M. Terman rounded up 1,500 children, 11 years old on average, who scored 135 or higher on an I.Q. test that he helped devise. Ever since, the "Termites," as they are called, have been tested and interviewed every 5 to 10 years. About 60% of the original participants are alive; they are in their late 80s.

Although numerous studies have linked a single adult personality trait (such as hostility) to a specific malady (like heart disease), little was known about how a group of characteristics, over a long period, might predict mortality. The Termite archives gave researchers from two University of California campuses (Riverside and San Diego) and the State University of New York (Stony Brook) a chance to investigate this question.

The team assessed early manifestations of five personality traits thought to affect longevity: sociability, self-esteem and confidence, conscientiousness and social dependability, cheerfulness and optimism, and energy level. The records showed that people hadn't changed much as they aged, which was unfortunate for some, because the risk of dying before age 70 was higher for people who had been cheerful, optimistic, and good-humored children.

In contrast, the likelihood of dying before 70 was lowest for those who had been cautious and conscientious as children. They were about 30% less likely than their peers to die in any given year.

Conscientious people may have better health habits, for example, or be less drawn to risky behaviors -- such as smoking, drinking, or racing motorcycles -- than the optimistic, fun-loving types, the researchers speculated.

As for the social impact of these findings, look on the bright side: although there may not be a lot of laughter around the table, the meal will surely be served on time.

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