Of Twins and Centenarians

These two unique groups have a lot to tell us about the role of genes in aging.

When asked to what extent human life span is controlled by genes, endocrinologist Nir Barzilai likes to tell a story about his own family. "My grandfather was 68 when he got his heart attack, and he died," says Barzilai, who is director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York City. "My father also got his heart attack at the age of 68, but he had bypass surgery," he says. Barzilai's father survived the operation and has already lived 10 years longer than his own father did. So although both men were genetically predisposed to heart problems, advances in medical technology accounted for the differences in the lengths of their lives. Human longevity, Barzilai says, is partly genetic but is influenced a great deal by the environment.

The question of what proportion of life span is genetically determined isn't simply academic. If researchers can identify genes that promote long life, they might then develop pharmaceutical fixes that would mimic these genes' activities. Scientists at the Cambridge, Massachusetts, firm Elixir Pharmaceuticals are already searching for such drugs. Their entrepreneurial quest relies heavily on research into the genetics of aging in two very different human populations: twins and centenarians. Studying the first group should reveal the magnitude of the genetic component to life span; studying the second could lead scientists to longevity genes.

Twin studies have long provided crucial data to scientists who seek to separate how genes and the environment contribute to particular human traits. Although most twins grow up in the same environment, identical twins share all of their genes whereas fraternal twins share only half. By comparing the two different types of twins, scientists can tease out the role played specifically by genes. If genes were important for determining human life span, for example, one would expect identical twins to live to the same age much more frequently than do fraternal twins.

That doesn't seem to be the case, however. Somewhere between 15% and 30% of life span is based on our genes, according to behavioral geneticist Matthew McGue of the University of Minnesota, Twin Cities. The figure derives from an examination of the Danish Twin Registry, which maintains records of more than a century's worth of twins born in Denmark from 1870 to the present. McGue and other scientists studied 2872 pairs of Danish twins born between 1870 and 1900--a group selected because by now their life experiment has run its course--and found that life span is "only moderately heritable." How long we live depends, for the most part, on our environment and on chance factors such as random genetic alterations that take place during a lifetime.

The Danish twin studies provide a ballpark figure for how much of life span is inherited. However, some gerontologists think that those who live to extraordinarily advanced ages might prove an exception to the rule. They posit that centenarians owe their good fortune to their inheritance of a small number of powerfully acting longevity genes, variants that are uncommon in the population at large but that have dramatic life-extending effects at older ages. Such genes might, for example, allow centenarians to stave off the inflammation that exacerbates many of the diseases of old age.

If such genes can be found, it would imply that genes play a bigger role in parceling out the years then twin studies would suggest, at least as we reach the outer limits of the human life span. As Claudio Franceschi, director of the Italian National Research Center on Aging and a longevity-gene believer, puts it: "To reach age 80, or 85, probably genetics is not so important. But from that age onwards, probably the genetic component is higher."

The idea that single genes can dramatically influence longevity draws support from the discovery that simple genetic manipulations can greatly extend life span in flies, worms, and mice. Furthermore, genetic studies in humans have shown that the siblings of centenarians have a dramatically higher likelihood of becoming centenarians themselves, compared with the general population. In a 2002 paper in the Proceedings of the National Academy of Sciences, a group headed by Thomas Perls, director of the New England Centenarian Study and a founder of Elixir Pharmaceuticals, reported that the sisters and brothers of those over 100 were between 8 and 17 times more likely to reach that age than "the average person" born in the same era. These data suggest a strong role for heredity in making centenarians what they are.

Perls's findings are not necessarily inconsistent with the data derived from Danish twins. Those studies might have overlooked the unique genetics of the oldest old because twin centenarians are so rare. This scarcity, notes Franceschi, makes it difficult for researchers to collect enough subjects to perform meaningful statistical analyses.

Finding the gene or genes responsible for extremely long life, and harnessing their ability to promote longevity, could help reduce society's investment in medical care of the elderly. Perls has shown that when centenarians die in hospitals, the average medical cost of their care is 61% lower than that of people between the ages of 60 and 69--and that the cost of acute care for those over the age of 90 tends to be lower than for younger seniors.

Some researchers, however, remain skeptical of the notion that special genes dictate exceptional longevity. Epidemiologist James Vaupel of the Max Planck Institute for Demographic Research in Rostock, Germany, is one of them. "Centenarians are amazingly diverse," he says. "You have all sorts of centenarians, and there doesn't seem to be any secret of success." In other words, according to Vaupel, centenarians do not seem to share a particular genetic legacy. Instead, centenarians might represent a small percentage of people who manage to slip through to extreme old age by avoiding a wide range of diseases--the luckiest of the lucky.

For the present, the only thing that's absolutely certain about centenarians is that they defy expectations. Barzilai mentions a 103-year-old woman he knows who recently celebrated her sister's 100th birthday. "She's been smoking for 90 years now," he says. Only time and more research will tell whether this centenarian, and all of the others, have special genes that explain their long lives--and whether the rest of us will be able to borrow some of that magic by swallowing a pill sometime in the future.

Chris Mooney is neither a twin nor a centenarian, but a freelance writer living in Berkeley, California.