Long-lived people distinguished by DNA

Study finds genetic signatures of the extremely old

People who live to be 100 often credit particular dietary or lifestyle habits, religious faith or a generally positive outlook for their aging success. But scientists have long believed extreme longevity is at least partly in the genes.

Certainly long lives seem to run in families. People who have a centenarian sibling stand a better chance of also living to 100 than most people do, and twin studies suggest that genes are responsible for about 20 to 30 percent of a person’s ability to live to 85. Yet despite efforts to comb the genetic blueprints of the very, very old for versions of genes that might make a person into the next Methuselah, scientists have largely come up empty.

Now, a group of researchers has identified a set of 281 genetic variants that together distinguish people who live to be 110 or more from the rest of us with about 85 percent accuracy.  

Further analysis revealed several different genetic signatures among centenarians, indicating that there could be lots of ways to live beyond 100, researchers led by Paola Sebastiani and Thomas Perls of Boston University report January 18 in the online journal PLoS ONE. While the findings are drawing some criticism, the results suggest that there is a genetic component to longevity, especially at the oldest ages.

Centenarians in the study have just as many disease-associated genetic variants as other people, so the researchers think that the inherited component probably includes versions of genes that protect against age-related diseases. As people get older and older, being born with the right genetic stuff becomes more and more important for continued survival, they conclude.

“What we have is a provocative set of findings that need to be replicated,” Sebastiani says.

Controversial is the adjective many other researchers use to describe the research. In an earlier version of the study that was published online in Science in 2010, the Boston University researchers claimed to have found a set of 150 genetic variants that could correctly predict who would be a centenarian 77 percent of the time. But the study soon came under fire for technical flaws. The researchers fixed the technical problem and engaged an independent lab at Yale University to analyze the data.

Despite those revisions, the study was retracted from Science last year because the journal said the results no longer met standards for publication. Science’s reasoning is disingenuous, says Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine in New York City. “The results, if anything, are stronger,” he says. “The data are the data, and it’s very striking.”

But other geneticists have expressed vague unease with the findings.

“The obvious technical issues have been corrected,” says geneticist Greg Cooper of the HudsonAlpha Institute for Biotechnology in Huntsville, Ala. “It certainly is worth putting out there as observations to think about.” But longevity “is a messy trait,” one that may be too complicated to explain with a small number of genetic variants. “I’m not totally sold” that the study really explains centenarians’ staying power, Cooper says.

Part of the discomfort stems from the method used to generate the genetic profiles. Most modern genetic studies are really exercises in statistics. Researchers compare large groups of people with a trait or disease to other large groups that don’t share that trait, looking for genetic variants that appear more often in the group that has the disease.

Another challenge: It’s hard to find a large group of centenarians. Only one in 5,000 Americans lives that long, and only one person in 7 million will become a supercentenarian — someone who is 110 or older.

In the new study, the researchers combed the genetic blueprints of 801 centenarians and 914 healthy younger people for longevity-associated variants. The researchers also replicated the findings with two additional rounds of testing; first with a separate group of 253 people in their 90s and 100s and a control group of 341 younger people, then with a third set of 60 centenarians and 2,863 other people.

The researchers detected only one individual variant — one linked to the APOE gene, which is associated with Alzheimer’s disease — that meets statistical standards for separating supercentenarians from people with a more average life span. Many other variants also looked as if they might be tied to longevity, but none passed statistical muster.

So Sebastiani and her team began summing the effects of variants that didn’t quite rise to the statistical threshold to see if those individual differences added up to a genetic signature that could predict longevity. Although none of the variants alone could distinguish the extremely long-lived from those with average life spans, together the variants began to form an overall picture of the genetic makeup of a centenarian. As the researchers added in more and more variants, up to the 281 reported in the study, their power to predict centenarians increased.

Such grouping of genetic variants has been used to study characteristics such as height, body mass and intelligence. That type of analysis may help detect an underlying genetic component to a trait, but doesn’t indicate which biological processes are important, says Elizabeth Cirulli, a human geneticist at Duke University’s Center for Human Genome Variation.

“It’s not that it’s invalid, it’s just not helpful,” she says.

David Hinds, a statistical geneticist at the genetic testing company 23andMe, contends that the genetic profile may be an overly optimistic interpretation of the data and may be a result of strong genetic signatures from some ethnic groups. Hinds used the 281 variants to see if he could pick out the 58 centenarians in the 23andMe database from about 90,000 other people. He couldn’t.

His analysis also indicates that the 281 variants are really a signature that identifies people of Ashkenazi Jewish ancestry. The demographic history of Jews might mean that fewer people of Ashkenazi ancestry have lived to become centenarians. “It could be that the model predicts who will be a centenarian in the United States, but for the uninteresting reason that centenarians in the northeastern U.S. tend not to be Jewish,” he says.

Sebastiani says that the centenarians and control groups were carefully selected to eliminate any chance that the results would be skewed by ancestry. Hinds’ failure to replicate the findings may be because the centenarians in his database aren’t really centenarians at all. “There are a lot of false claims about old ages,” she says.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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