Secrets of the 'Wellderly'

Scientists Hope to Crack the Genetic Code of Those Who Live the Longest
By Robert Lee Hotz
Wall Street Journal
September 19, 2008

As the oldest person in the world, Henrikje van Andel-Schipper attributed her longevity to a slice of pickled herring and a tumbler of orange juice every day. If pressed, she'd say tartly that "breathing" also helped prolong life.

When this Dutch dowager died in 2005 at age 115, researchers discovered that she had almost none of the chronic physical or mental ailments associated with aging, according to a postmortem medical assessment published last month in the journal Neurobiology of Aging. She supported herself until she was 105. Up to her death, she was more alert and engaged than people half her age, cognitive testing showed. Indeed, when the anatomists actually counted her neurons, they discovered she had the brain of a woman 50 years younger.

"She was unbelievable," recalls neuroscientist Gert Holstege at the Groningen University Medical Center in the Netherlands, who documented her unusual well-being.

Whatever the virtues of fish and fruit juice, the secret of her longevity may have been hidden among her genes. Ascetic health habits apparently only take you so far; a surprising number of supercentenarians smoked, ignored their cholesterol and avoided exercise, research shows.

Based on animal experiments, gerontologists believe that one key to a healthy, longer lifespan may be found in a few master genes that affect cellular responses to famine, drought and other survival stresses. The more active these genes are, the longer an organism seems to survive -- at least in the laboratory. Moreover, researchers are convinced that some genes may protect us against the risks of heart disease, diabetes, cancer and dementia.

Among the elite of the aged -- those who live a century or more free of disease and mental ills -- researchers are seeking the genetic secrets of a longer, healthier life. In their quest, teams around the world are scrutinizing the oldest of the old -- elderly Ashkenazi Jews in New York, rural centenarians in the state of Georgia, century-old siblings in Holland and vigorous retirees in Okinawa -- as living test tubes in which nature has concentrated a vital essence of longevity.

Instead of focusing on what goes wrong as we age, these researchers want to understand why some people live so long without getting very sick. If they succeed, scientists one day may be able to do for humankind what they can already do for yeast, worms and mice: dramatically increase the normal life span. "Our hypothesis is that in order to live to 100 or more, you need sets of genes that protect you, by delaying aging and preventing age-related diseases," says Nir Barzilai, head of the Longevity Genes Project at Albert Einstein College of Medicine in New York.

Already there are hints.

Earlier this month, researchers at the Pacific Health Research Institute in Hawaii analyzing elderly Japanese-American men reported that a single biochemical misprint in the DNA typography of a gene called FOXO3A appeared to double or triple the chance of living to be 100 years old. They compared variations of five genes thought to influence aging in 213 men aged 95 or older to DNA samples from a group of 402 men who had died before reaching age 81.

Only the one variant stood out among the eldest. "If you got two copies of this gene -- inheriting one from each parent -- you hit the jackpot," says geriatrics expert Bradley Willcox who conducted the study.

Few of us, though, live to be 100. Even fewer can do so without suffering chronic ills associated with aging. All told, there are only 79 men and women alive today aged 110 years old or more, according to the Los Angeles Gerontology Research Group.

To pinpoint hereditary sources of longevity, researchers at the Scripps Research Institute in La Jolla, Calif., are recruiting 2,000 healthy people over 80 years old to compare the entire genetic sequences of these "wellderly" to those from people who died of common age-related illnesses before they reached 80.

"A great many people carry the genes that cause heart attack, cancer and other diseases, but some have modifier genes that cancel out their risk," says Eric Topol, director of Scripps Genomic Medicine. "We believe they actually have an inborn protection from aging."

In the study's first phase, Dr. Topol and his colleagues have targeted variations of 100 genes that may influence aging. They plan to broaden their search soon to 500 genes and then to entire genomes.

"What we are learning is that nature has found a solution in certain individuals to combat certain disease risks," said Samuel Levy, director of human genomics at the J. Craig Venter Research Institute in Rockville, Md., which is collaborating on the study.

Recent insights into the genetics of aging among simple organisms are stoking their enthusiasm. In January, for example, gerontologist Valter Longo at the University of Southern California reported that by altering two genes he made yeast that lived 10 times longer than normal. "We can really reprogram the lifespan of these organisms," he said. In March, scientists at the University of Washington identified 15 genes regulating lifespan in yeast and worms that resemble genes found in humans. At least three companies are working independently on potential therapies based on the discovery that life span in mammals may be regulated partly by genetically controlled enzymes called sirtuins.

Many experts in aging are skeptical. "We seem to know a lot about longevity in worms, but we don't know if any of it is relevant for humans," says Jan Vijg, who studies the genomics of aging at the Albert Einstein medical college. "The problem is that we don't really know the basic cause of aging."

Lifestyle, diet, education, exercise and health care are crucial to longevity. Just in the U.S., Asian-American women in New Jersey live on average to be 91, for example, while Native American men in South Dakota live to be 58, Harvard University researchers reported.

Earlier this year, researchers at the U.K.'s University of Cambridge and the Medical Research Council reported that people who exercise regularly, don't smoke, limit their alcohol intake and eat five servings of fruit and vegetables a day live, on average, 14 years longer than people who didn't.

Yet, there is little evidence of an abstemious lifestyle among the 450 people between the ages of 95 and 110 enrolled in the Longevity Genes Project at Albert Einstein College of Medicine. There are no vegetarians. At least a third of them were obese in middle-age. A third have been smoking tobacco for 40 years or more, despite health warnings. "I have a woman who recently celebrated 91 years of cigarette smoking," says Dr. Barzilai. "She is 106 now."

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