Aging is associated with an increase in all the components of the metabolic syndrome and decline in the endocrine axis. We asked if healthy centenarians are over-represented with phenotype and genotype for exceptional longevity that protects them from the endocrine causes of aging. For that, we recruited a genetically homogenous population of unrelated ashkenazi jews with exceptional longevity (n~450). To validate the genetic and physiological findings we also recruited the offspring of these subjects with exceptional longevity (n~400). We assessed their clinical (NCEPIII guidelines), their metabolic (lipoproteins, insulin), and endocrine (IGF-1 and its bonding proteins, TSH) phenotype. We used a several method to genotype numerous SNPs in promoters, exons or introns of genes associated with this phenotype, and a method to discover new mutations. We show that centenarians have a unique liporotein profile that is inherited by their offspring. We demonstrate 3 genotypes in cholesterol ester transfer protein (CETP), apo-lipoprotein c-3 (APOC3), and adiponectin (ADIPOQ) that monotonically increase between ages 60110 in unrelated individuals, and are over represented by 23 folds in the oldest old group, suggesting that they may be necessary to assure exceptional survival. Furthermore, we show that these genotypes are associated with changes in their protein plasma levels and out come related to the metabolic syndrome. We also demonstrate the role of IGF-1 receptor mutation in exceptional longevity and of length of telomeres in the metabolic syndrome. We will support the notion that exceptional longevity is associated with enrichment in the several genotypes, and significant measurable phenotype. These genotypes and their associated phenotype may play a role in conferring survival to exceptionally old age by providing protection from the metabolic syndrome and other endocrine manifestation of aging.
03 - 07 May 2008
European Society of Endocrinology