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Have you ever wondered how long you might live? New research suggests that an important indicator of your probable life span may be your genes. Scientists have identified unique genetic signatures strongly associated with a long and healthy life, findings that could help to further the understanding of how certain genes may offer protection from common age-related diseases like cancer, dementia and cardiovascular disease. And one day the data might lead to the development of genetic tests to predict whether a person can expect to live into old age as well as guide intervention efforts to prevent age-related illness.

The study, led by Paola Sebastiani, professor of biostatistics at Boston University (B.U.) School of Pubic Health, and Thomas Perls, professor of medicine and geriatrics at the B.U. School of Medicine, was published online July 1 in Science.

A person's life span is thought to be largely determined by the combined effects of genetics and environmental factors. Twin studies, however, suggest genetics only account for approximately 20 to 30 percent of an individual's chance of surviving to age 85.

Lifestyle choices, particularly diet, exercise and smoking habits, play an undisputed role in determining not only how long one will live, but also how well one ages. Studies show that Seventh-Day Adventists, whose church encourages behaviors that promote healthy aging, have a well-documented average life span of 88 years, approximately eight years longer than the average U.S. citizen. For the most part, Adventists exercise regularly, are vegetarian, and don't smoke or drink alcohol.

Nevertheless, a glance at your family tree may indicate whether you have a familial tendency toward longevity. Research suggests that exceptional longevity (EL)living one to three decades beyond the average U.S. life span of approximately 80 yearsruns strongly in families. "Thathas always made us believe that genetics is playing a very important role in this wonderful trait," Perls said Wednesday in a press conference.

Genetic factors can contribute to the degree of longevity in at least two important ways: An individual may inherit certain genetic variations that predispose him or her to disease that decreases longevity; other gene variants may confer disease resistance, thereby increasing it.

To better understand the genetic components of longevity, the researchers analyzed the DNA of more than 800 subjects between the ages of 95 to 119 and compared it with DNA from random controls. The genome-wide survey identified specific genetic variations, or SNPs (single-nucleotide polymorphisms), that were associated with the longevity group.

Next, the researchers developed a genetic model comprising 150 SNPs in order to compute the predisposition of an individual toward EL. Their model successfully predicted exceptional longevity in a different sample of centenarians (individuals that live to age 100) with 77 percent accuracy. This demonstrates that EL is strongly associated with complex combinations of genetic variants.

The researchers found that, based on subjects' genetic profiles, the centenarians could be further divided into 19 subgroups, some of which were associated with delayed onset of age-related diseases such as dementia, hypertension and cardiovascular disease. These signatures represent different genetic paths to age 100 and beyond, Sebastiani said in the press conference.

"Centenarians are indeed a model of aging well," Perls said. Previous work has shown that 90 percent of centenarians are disability-free at the age of 93. In industrialized nations approximately one out of every 6,000 people lives beyond the age of 100. Supercentenarians, or individuals that are older than 110, are even rareronly one in seven million fall into this category.

Surprisingly, the researchers found that approximately 15 percent of control subjects also had the genetic signature associated with longevity. This suggests that many more people have the genetic potential to survive into old age than previously thought. "We know a lot about the human genome, but we also know that there is a lot that remains to be discovered," Sebastiani said. "Genetics is fundamental in EL, but it's not the only thing. So there may be other factors like environment or other lifestyles that may help people live longer and healthier lives," he added.

Importantly, there was no difference in the presence of known disease-associated gene variants between the longevity and control groups. The researchers conclude that EL may result from an enrichment of longevity-associated gene variants that may counteract the effects of having a disease-associated gene.

"I think this is a step towards making sense out of a lot of datagenetic data, environmental data, epidemiological datato help us understand factors that contribute to long and healthy life," says Winifred Rossi, deputy director of the Division of Geriatrics and Clinical Gerontology at the National Institute on Aging, who wasn't involved in the study.

"We're starting to get to the point where it might be possible to use the information about these variants to predict someone's likelihood of achieving EL," says Matt Kaeberlein, professor of pathology at the University of Washington in Seattle, also not involved in the study. He added that the challenge was to next move beyond this correlative study to figure out how these gene variations may lead to functional changes that contribute to the molecular process of aging.

The authors caution that further study and replication of their results in different populations is needed to verify their model before it will be useful for individual genetic testsor before longevity "cocktails" are created.

"My hope has always been with the study that we would learn much more about how to get lots of people to live to older age in good health and markedly delay their disability and age of onset of diseases," Perls said. "I look at the complexity of this puzzle and feel very strongly that this will not lead to treatments that will get a lot of people to become centenarians, but rather will make a dent in the onset of age-related diseases like Alzheimer's, for example."

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Live Long and Proper: Genetic Factors Associated with ...

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