Making sense of centenarians; genes and lifestyle help people live through a century.

My great-grandmother was born in 1897. She did most of her cooking on a wood-burning stove in her farmhouse in Cable, Wis. When I knew her, she slept on a cotton mattress that she had made herself in the 1940s and kept handmade lace doilies on the arms of all the chairs and sofas.

When I asked her to tell me what it was like living in the Roaring '20s and the Depression, I expected her to regale me with stories of wild dancing and ruined investors jumping from skyscrapers. Instead, Elizabeth Morey told me of logging, raising chickens, and cooking on a wood stove--stories typical of people living in rural Wisconsin during those times.

What wasn't typical about my great-grandmother was just how long she was able to tell her stories: She died in 1999, just shy of her 102nd birthday.

Although only about 1 in 10,000 people in developed countries live to be a hundred or more, these centenarians constitute one of the fastest-growing age groups in the United States. As sociologists, gerontologists, and other investigators collect centenarians' stories--and analyze their genes--these oldest old are transforming the way people think about aging.

The U.S. Census Bureau estimates that there were between 69,000 and 81,000 centenarians living in the United States in 2000. With current population trends in developed countries, the number of centenarians should double every 10 years, says John R. Wilmoth of the University of California, Berkeley.

Over the past 150 years, the average life span--and correspondingly, the maximum life span--has been steadily increasing, Wilmoth says. Since 1969, the estimated maximum age that people reach has increased by about a year every decade, he and his colleagues reported in the Sept. 29, 2000 SCIENCE. The team based its findings on data from Swedish populations from 1861 to 1999. The maximum estimated life span in that country is now about 108 years. (The longest documented human life was of Jeanne Calment, a Frenchwoman who died at age 122.)

Much of the rise in average and maximum life span is attributable to the increased life expectancy for healthy people over 70, Wilmoth says. "It's very important for people who are older and healthy to realize that their life expectancy is probably going to be longer than the rest of their peers and prepare accordingly," Wilmoth notes.

What lifestyle can these people expect?

Researchers divide centenarians into three roughly equal-size groups, based on how well they function and the severity of illness or disability they have, says Peter Martin of Iowa State University in Ames. Perhaps 30 percent of centenarians are both mentally and physically impaired by the time they reach 100. Another 40 percent have limitations to their vision, hearing, or mobility--and perhaps some mental impairment--but are able to function reasonably well. And another 30 percent--the population segment that fascinates both researchers and the public--show few signs of mental or physical impairment and are often still living independently.

Like most people who live to be 100 or older, my great-grandmother was ill only in the last few years of her life. Among centenarians in a New England study, almost 90 percent had been living independently when they were 92 years old. About 73 percent of the group had been independent when they were 97, and almost 35 percent of them were still independent when they were surveyed.

"People are ingrained with the idea that the older you get, the sicker you get," says Thomas Perls of Beth Israel Deaconess Medical Center in Boston and director of the New England Centenarian Study. "It's rather the older you get, the healthier you've been .... Compared with others in the older population, centenarians seem to either markedly delay, or in some cases, escape life-threatening diseases such as cancer and Alzheimer's disease."

Although male centenarians are fewer, they're often less likely to have significant mental or physical disabilities than are women who reach 100 are, says Margery Silver, also of Beth Israel Deaconess. She interviewed 177 people between 100 and 109--most, just over 100--to determine their mental functioning and their ability to manage daily tasks. Among those with mental impairment, women were able to live independently and live longer than men were, she says. Researchers still don't know why some people are better able than others to adapt to cognitive and functional impairment.

In his studies of about 100 centenarians in Iowa, Martin observed similar health in those living independently and those in nursing homes. But centenarians living in nursing homes are slightly more likely to have some cognitive impairment.

Martin and his colleagues also have found that about 25 to 30 percent of centenarians no longer have any siblings or children still living. These centenarians generally rely on nieces or nephews or on long-time friends who have become as close as family. Many studies of centenarians ignore the role of family support, Martin says, though he believes it plays an important role in keeping the oldest old alive and well.

Why do some people live longer than others? And why do some people function better than others at very old ages?

Probably the most important factors can be found in people's lifestyle: what they eat, how much they exercise, what social networks they have, how well they handle stress. About 70 percent of the survival differences between elderly twins is due to such factors, according to several studies. They indicate that no more than 30 percent of the variation in life span between centenarians and the rest of us is due to genetic differences.

Perls, however, suggests that after age 80, genetics plays an increasingly important role in determining which people survive to 100. We can all maximize the potential in our genes by eating right and having a healthy lifestyle, he says. But "to get to 100, to go the extra 20 years or so, I'd say you need these special genes, these genetic booster rockets," says Perls.

"This is a plausible hypothesis," says Martin, but probably "all factors, including personality factors and social support, become more important as people survive longer. If you don't have the inner strength and physical strength to survive adversity, you are not going to survive."

Because longevity seems to run in families, centenarians are an ideal group in which to search for longevity genes, says Perls. The problem is that their compatriots of average lifespan are no longer around.

So, Perls and other researchers have compared siblings of centenarians with siblings of people born in the same years as the centenarians but who died at 73, the average life expectancy for people born in the late 1800s. The centenarians' siblings are about 3.5 times as likely to live to age 80, and about 4 times as likely to live to 90 as the siblings of people who died at 73 are, Perls says.

Several research groups have begun collecting data on the children of centenarians in order to compare this group with the children of people who were born around the same time as the centenarians but died at age 73.

In Perls' study, the 88 children of centenarians and 118 children of septuagenarians are currently about age 71. The centenarians' children weigh markedly less and are less likely to be taking multiple medications or to have high blood pressure or heart disease. The children of centenarians might have better genes, or they might have learned better eating and exercise habits from their parents or take better care of themselves because they expect to live longer.

Some researchers are beginning to look for longevity genes in the confined gene pool of a population already extensively studied for various genetic disorders. Nir Barzilai of the Albert Einstein College of Medicine in New York suspects longevity genes might be detectable among Ashkenazi Jews, who originated in central and eastern Europe and typically marry within the group.

However, says Barzilai, it may not be easy to detect physiological clues to underlying age-related genes. "When we get to centenarians, their health is already on the way down," he says. "They may not have simple biological markers for their longevity, but differences between [the centenarians'] children and their spouses may point to such markers," which then may point to genes.

Therefore, he and his colleagues identified 100 centenarians who are Ashkenazi Jews and have at least one child living in the United States or Europe. To learn how people in such long-lived families differ from others, the team compared health characteristics and family histories of the centenarians' children with those of the children's spouses. In support of the idea that old age runs in families, Barzilai found that the parents of the centenarians typically lived into their mid-80s, while the grandparents of the children's spouses died, on average, in their early 70s. Children of centenarians were more than nine time as likely as the spouses to have a grandparent who lived to 90.

Last November at the Gerontological Society of America's annual meeting in Washington, D.C., Barzilai reported that the centenarians themselves are of average weight for their height. The children of centenarians tend to be slightly heavier than their parents but still more slender than their spouses. Compared with the group of spouses, children of centenarians showed other characteristics that indicate a lower risk of developing diabetes and cardiovascular disease.

The hunt for longevity genes in humans is not new," but more and more people are looking these days, says Giovanni B. Frisoni of the National Institute for Research and Care at San Giovanni del Dio-Fatebenefratelli in Brescia, Italy. He notes that studies across the world have tentatively linked aging to several factors: variants of genes for cholesterol transport, protein tags that enable the immune system to recognize blood cells as part of oneself, and an enzyme for a protein that regulates blood pressure.

Frisoni studies Alzheimer's disease, a condition whose likelihood increases with age and is linked to a common variant in a gene that produces a cholesterol-carrying protein called apolipoprotein E. The high-risk gene is known as APO-E4. Another variant of the same gene, called APO-E2, is much rarer--found in just 5 to 10 percent of the population--and is associated with lower-than-normal blood cholesterol concentrations and lower risk of cardiovascular disease and Alzheimer's.

In a study published in the February JOURNAL OF GERONTOLOGY: MEDICAL SCIENCES, Frisoni and his colleagues show that among 179 centenarians living in Finland in 1991, 10 (9 percent) of the 117 people ages 100 to 101 had the APO-E2 allele, compared with 9 (21 percent) of the 42 people ages 102 to 103 and 5 (25 percent) of the 20 people 104 years and older. The gene variant clearly isn't required for longevity, says Frisoni, but the finding that it's more prevalent among the oldest centenarians indicates that it can play an important role.

Giovanna De Benedictis of the University of Calabria in Italy and her colleagues are comparing genes of high-functioning centenarians with those of healthy young people. "Our aim is to understand the key to successful aging, not just [of] living for a long time," she says.

De Benedictis and her team are also looking at the role that immune function might play in aging. "With aging there is an increase in inflammation," which may cause health problems, says Claudio Franceschi of the Italian National Institute on Aging and the University of Bologna. At the November gerontology meeting in Washington, D.C., he presented "very preliminary data" suggesting that centenarians show fewer signs of immune-function decline and inflammation than most people do as they age.

The questions to ask are much more complicated and complex than we thought when we met our first centenarians in the 1980s," says Martin. Besides genetic, environmental, and social factors that contribute to both long lives and healthy aging, researchers are pursuing a variety of other topics.

Teams in the United States, Europe, and Japan are collaborating to study whether cultural factors and living conditions affect which centenarians are in relatively good health and living independently, while others are physically or mentally impaired. They also plan to assemble genetic databases of centenarians in several countries.

"Down the road, my hope is that we can make some genetic discoveries so that we can understand why some people age so differently than others," Perls says. "My hope is that we will actually see the development [from genetic research] of medications within the next 10 years or so that would allow people to age more slowly and either markedly delay or escape some of these terrible diseases like Alzheimer's."

Perls joins other gerontologists in saying it's important for young and old people alike to have an optimistic view of aging. Researchers hope not only to identify factors that help people reach very old ages, but also to identify people who will age well and others who will age poorly so physicians can target treatments appropriately.

The details of this research might not have meant much to my great-grandmother, who'd had only a second-grade education. But she surely would have supported the quest for longer, healthier, and more independent lives.