The researchers looked for genetic clues to longevity in a group of 214 Ashkenazi Jews who have passed or nearly reached 100 years of age. In the April 4 issue of PLoS Biology, they report that a specific genetic profile, or genotype, was associated with longevity as well as cardiovascular health, lower incidence of hypertension and healthy insulin metabolism.
"Since centenarians typically escape cardiovascular disease, diabetes, 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," said Dr. Nir Barzilai, director of the Institute for Aging Research at Einstein and senior author on the paper. "If so, then these genotypes should occur with higher frequency in centenarians than in the rest of us."
Dr. Barzilai and his colleagues recruited Ashkenazi Jews for the study, because this population--descended from a founder group of just 30,000 or so people--is more genetically uniform than other groups, simplifying the challenge of associating a genotype with its physical manifestation (phenotype).
When studying centenarians, finding an age-matched control group is obviously difficult. But since longevity runs in families, the researchers were able to get around this problem by recruiting children of the centenarians and matching them against a control group consisting of other Ashkenazi Jews the same age.
Each participant had blood drawn--to determine their genotype and to measure levels of several cardiovascular disease markers including insulin, cholesterol, triglycerides, high-density lipoproteins (HDL, the "good" cholesterol), low-density lipoproteins (LDL, the "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) in 36 genes involved in lipoprotein metabolism and other pathways linked to cardiovascular disease. (DNA contains four possible nucleotides--adenine, thymine, guanine and cytosine--and SNPs are variations of a single nucleotide in the DNA sequence.)
This analysis revealed a SNP in a gene with a clear pattern of age-dependent frequency: apolipoprotein C3 (APOC3). This polymorphism substitutes cytosine for adenine in the gene's promoter region, where gene transcription is initiated. The frequency of finding the APOC3 polymorphism in both copies of the gene was 25% among centenarians, 20% in their offspring, and only 10% in controls.
APOC3 codes for a protein that is a major component of very low density lipoproteins (VLDL, another type of "bad" cholesterol) and also occurs in HDL. The researchers expected that people carrying the APOC3 SNP would have a favorable lipoprotein profile. And indeed, all participants carrying the APOC3 polymorphism had better triglyceride and cholesterol levels, as well as the beneficial larger LDL and HDL particle sizes. In addition, they had a much lower prevalence of hypertension.
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, 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 as well. The Einstein researchers hope to uncover more clues regarding the genetic influences on aging--and begin to develop strategies to ease the inevitable slide into our twilight years.
In addition to Drs. Atzmon and Barzilai, the following researchers took part in the study: Marielisa Rincon and Drs.Clyde Schechter, Richard Lipton, and Aviv Bergman of the Albert Einstein College of Medicine and Dr. Alan Shuldiner of the University of Maryland School of Medicine.
Journal
PLoS Biology