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"Methuselah" Mutation Linked to Longer Life

Study of long-lived Ashkenazi Jews may yield longevity genes galore



Michael Westhoff/iStockphoto

A type of gene mutation long known to extend the lives of worms, flies and mice also turns up in long-lived humans. Researchers found that among Ashkenazi Jews, those who survived past age 95 were much more likely than their peers to possess one of two similar mutations in the gene for insulinlike growth factor 1 receptor (IGF1R).

The mutations seem to make cells less responsive than normal to insulinlike growth factor 1 (IGF1), a key growth hormone secreted by the liver. In past studies, IGF1 disruption increased the life span of mice by 30 to 40 percent and delayed the onset of age-related diseases in the animals.

The finding suggests that the IGF1R mutations confer added "susceptibility" to longevity, perhaps in concert with other genetic variants, the research team reports in Proceedings of the National Academy of Sciences USA.

"This is the tip of an iceberg of potential genetic alterations or mutations that are associated with longevity," says study co-author Pinchas Cohen, a professor and chief of endocrinology at Mattel Children's Hospital at U.C.L.A. (University of California, Los Angeles).

IGF1 is well known among longevity genes. A regulator of growth and differentiation, it has a strong effect on body size, accounting for size extremes in dogs, for example. Animals fed restricted calorie diets live longer and show lower levels of IGF1. (Also implicated are changes in activity of the sirtuin or SIRT protein family.) When engineered specifically to produce less of the hormone, they don't grow as large, but their life span is 30 to 50 percent longer.

The case in humans was less clear. Searching for clues, researchers turned to a group of 384 Ashkenazi Jewish seniors with a family history of longevity, aged 95 to 108 (average age 97.7), recruited by Cohen's collaborator Nir Barzilai, director of the Institute for Aging Research at Yeshiva University's Albert Einstein College of Medicine in New York City. A control group of 312 living and dead individuals (average age 67.8), also Ashkenazi Jews, had no family history of longevity.

The team could not compare the two groups directly. "The problem with studying centenarians," Cohen notes, "is the control group died 30 years ago." Their solution was to look at each group's offspring, looking for signs of inherited mutations.

They found that among the offspring of centenarians (approximately 70 years old), the women were an average of 0.98 inch (2.5 centimeters) shorter than female children of the control group. Scanning the genes of these shorter offspring, researchers discovered two IGF1R mutations possessed by nine of the centenarians but only one of the control subjects.

Blood levels of IGF1 level were 35 percent higher in these centenarians who had mutations than in the control group (although their heights were not significantly different). Cohen says the body may increase production of the hormone to try to make up for a less sensitive receptor. Males may be unaffected by the mutation, he says, because other genes make them more susceptible to IGF1.

The hormone somatostatin can reduce IGF1 circulation in humans, but Cohen cautions against being too hasty in fingering IGF1as an anti-aging miracle. "It's likely that centenarians have not just one lucky gene, but several," he says.

He adds that he and Barzilai are examining other genes such as the one for human growth hormone, which stimulates IGF1 production. "Until we know what cocktail it should really be," he says, "don't try it at home."

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