A genetic profile in 214 Ashkenazi Jewish centenarians and nonagenarians linked to longevity and discovered by two Israeli researchers at New York's Albert Einstein College of Medicine lends clues to healthy aging in non-Ashkenazi and non-Jewish populations around the world. The study is being published in the April 4 edition of the Public Library of Science on-line journal (www.plos.org), run by a non-profit organization of scientists and physicians committed to making the world's scientific and medical literature a freely available public resource. Dr. Nir Barzilai, director of the Institute for Aging Research at Yeshiva University's medical school, and Dr. Gil Atzmon looked for genetic clues to longevity in the Ashkenazim. They chose this group because - as shown by historical records and modern genetic evidence - Ashkenazim are descended from a founder group of just 30,000 people and thus are more genetically uniform than other demographic groups. This, they explained, simplified the challenge of associating a gene profile (genotype) with its physical manifestation (phenotype). Many studies show that "tweaking" a single gene can extend life span in animal models. But Barzilai and Atzmon have for the first time found that people carry alleles (alternative forms of a gene) that confer the same sort of longevity advantage. Not only was the genotype connected with longevity, but it was also linked with cardiovascular health, a lower incidence of hypertension and proper insulin metabolism. The Einstein researchers hope to uncover more clues to the genetic influences on aging - and then begin to develop strategies to ease the inevitable slide into one's twilight years. Asked to comment, Prof. Karl Skorecki, director of the Technion's Rappaport Research Institute and director of medical and research development at Rambam Hospital in Haifa, had high praise for the discovery. "I have been following Barzilai's work for some time, and we collaborate on certain projects. His work in general and this paper in particular are brilliant, and the findings are of great importance - beyond the Ashkenazi community itself," he said. "By utilizing the special population genetics characteristics of the community, he and his colleagues have been able to uncover important genes and metabolic mechanisms that contribute to healthy aging and whose disturbance is involved in common diseases of aging. What has been especially brilliant about their work is his elegant use of an appropriate control group." Skorecki discovered four "founding mothers" living in Europe a millennium ago who gave rise to 40 percent of today's Ashkenazi Jews and a priestly tribe gene handed down over generations from kohanim to their sons. "Since centenarians typically escape cardiovascular disease, diabetes, cancer and other age-related disorders, we suspected these most senior of senior citizens might possess gene variations that help them reach a ripe old age," explained Barzilai. "If so, then these genotypes should occur with higher frequency in centenarians than in the rest of us." When studying centenarians and nonagenarians, finding an age-matched control group is obviously difficult. But since longevity runs in families, the researchers avoided this problem by recruiting children of the centenarians and matching them against a control group consisting of other Ashkenazim the same age. Blood was taken from each participant to determine their genotype and measure levels of several cardiovascular disease markers, including insulin, cholesterol, triglycerides, high-density lipoproteins (HDL or "good" cholesterol), low-density lipoproteins (LDL or "bad" cholesterol), and concentrations of two lipoprotein components called apolipoproteins (APO). In a previous study, the researchers had found that centenarians‚ LDL and HDL particle sizes are larger than normal, so these were also measured. To identify genes associated with long life, they looked for single nucleotide polymorphisms (SNPs, variations of a single nucleotide in the DNA sequence) in 36 genes involved in lipoprotein metabolism and other pathways linked to cardiovascular disease. This analysis revealed a SNP in a gene with a clear pattern of age-dependent frequency: apolipoprotein C3 (APOC3). The frequency of finding the APOC3 polymorphism in both copies of the gene was 25 percent among centenarians, 20% in their offspring and only 10% in controls. The researchers expected that people carrying the APOC3 SNP would have a favorable lipoprotein profile. And indeed, all participants carrying it had better triglyceride and cholesterol levels, as well as the beneficial larger LDL and HDL particles. In addition, they were much less likely to have high blood pressure. Altogether, the statistical links between APOC3 and longevity and the significant associations between favorable lipoprotein-related traits and longevity strongly suggest that the genotype contributes in several ways to cardiovascular health and longevity. While the genetic pathways driving longevity remain unknown, the researchers said, it seems clear that lipoprotein metabolism plays an important role. The favorable lipoprotein profiles reported by the Einstein researchers correlate with studies of Japanese and Italian centenarians.

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