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Genes for Extreme Longevity

Scientists can predict who will live past 100 using a subset of 150 genetic variations.

By analyzing just 150 spots on the genome, researchers can predict who will live to extreme old age with almost 80 percent accuracy, according to a study published online today in the journal Science. Researchers from Boston University employed a widely used genetic-screening technology to find genetic variations that occur more frequently in centenarians–people age 100 and older.

In addition to providing a potential way to predict who might live into their 100s, the findings suggest that genetics play a major role in surviving to extreme old age. And the team hopes that identifying the genes and corresponding molecular mechanisms that promote longevity will give new insight into how to prevent or delay age-related diseases, such as heart disease, Alzheimer’s, and cancer.

“Centenarians are a model of aging well,” says Thomas Perls, director of the New England Centenarian Study at Boston Medical Center and an author of the study. Previous findings from the project, the largest study of centenarians in the world, show that 90 percent of them are free of disability to an average age of 93. “They seem to compress disability to the end of their lives,” says Perls. “I am very hopeful that understanding how centenarians do that will lead to new strategies for therapies.”

Perhaps most surprisingly, preliminary analysis showed that centenarians had just as many genetic variants linked to diseases as did people in the control group. “That suggests that what makes people live long lives is not lack of genetic disposition to disease but longevity-promoting genes,” says Paola Sebastiani, a biostatistician at Boston University and coauthor of the study. “If longevity variants cancel out disease-associated variants, it could open new ways of treating age-related diseases.” The findings also call into question genetic tests now available to consumers that calculate an individual’s risk for a specific disease, such as type 2 diabetes or cancer, based on common genetic variants. “The finding needs to be replicated, but if it’s true, trying to predict risk of disease out of context may be inaccurate,” says Sebastiani. “You need the overall genetic background to make an accurate prediction.”

The researchers used microarrays, chips dotted with specific sequences of DNA, to screen centenarians in the study for about 30,000 common genetic variations. They identified about 30 variants found at significantly higher rates in two groups of centenarians compared to a control group. Each individual variant had little impact, however, so the researchers developed an algorithm to combine the effects of multiple variants acting together. Using a list of the variants that differed most between the control groups and centenarians, they found that the predictive value topped out at about 150 variants; in an independent set of 250 centenarians and 350 controls, the model could accurately predict the centenarians 77 percent of the time. The remaining 23 percent may possess as-yet unidentified genetic factors or be the result of environmental factors not accounted for by the model.

Most centenarians possess a subset of the 150 variants, and the researchers found that their genetic profiles cluster into 19 different genetic signatures. The longest survivors, who live a median age of 108, have the highest number of longevity variants, says Sebastiani. “And some of the signatures correlate with the latest age of onset of age-related diseases, such as dementia or cardiovascular disease.”

“To have about 150 genes involved in exceptional longevity is really very few,” says Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine, in New York, who was not involved in the study. “I think it’s within our power to understand their mechanisms and to start to develop drugs against aging.”

David Altshuler, a geneticist at the Broad Institute, in Cambridge, MA, cautions that the findings need to be repeated, because the study groups and the control groups were drawn from two different populations, increasing risk for detecting genetic differences not linked to longevity. “The authors were very careful in their analysis to address these points, but it will nonetheless be important for independent investigators to confirm the results,” he says.

Scientists haven’t yet looked in detail at the genes implicated in the research; the microarrays used in these studies spotted genetic markers near genes, not the genes themselves. The next step will be to sequence some of the candidate genes in order to figure out what the longevity-linked variants do.

The study did highlight some genes previously associated with longevity, such as a protein involved in cholesterol metabolism and tied to relative risk of Alzheimer’s, as well as genes linked to chromosomal instability and the insulin pathway. “A lot of the genes have no function associated with them as of yet,” says Perls. “We will begin looking at genetic databases to figure out what pathways these genes point toward and maybe start to look at some animal models.”

The researchers caution that the study was limited to people of European descent. “We have to do these investigations all over again for different ethnicities and maybe different environments as well,” says Perls. “If you’re up in Greenland, it probably takes a whole different set of genetic variations to survive in that environment than in Arizona.” His team is already working with a group in Japan that is studying a group of Japanese centenarians.

The findings also raise the possibility of developing a genetic test to predict an individual’s chances of living past 100. But the scientists caution against use of this type of test, at least in the near term. “I think from a social point of view, it’s not ready for prime time. A lot more study has to be done in terms of what physicians can do for people with the results of this test,” says Perls. “If someone has tons of longevity marks, I start to worry about what insurance companies and others would do.”

However, people who have already had their genomes analyzed, through services such as 23andMe, will soon be able to predict their risk score through a free website that Perls’ collaborator is developing. But Perls hopes to head off commercial efforts to market this kind of test. “We are concerned that the marketing [for such a test] will not mention the shortcomings of the test,” says Perls.

“My hope has always been that we would learn much more about how to get lots of people to live to older ages in good health and delay the onset of disease to the end of life,” says Perls. “I do not think this will lead to a treatment that will get people to become centenarians, but rather make a dent in diseases like Alzheimer’s.”

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