Despite evidence for a substantial genetic component, the inherited biological factors that promote extended life span (longevity) in humans remain unknown. In this Program Project we plan to expand the evidence indicating that life span is strongly inherited in families with exceptional longevity. We have comprehensively characterized over 300 Ashkenazi Jewish families with exceptional longevity (survival in good health to at least age 95) and have identified several biological markers that may be causative in their longevity. We hypothesize that subjects with exceptional longevity have a 'genetic-hallmark'that provides protection against several age-related diseases. In preliminary data we show that these subjects and their offspring have 2-3 fold increases in rates of polymorphism in 2 genes regulating lipoprotein-cholesterol ester transfer protein (CETP) and apolipoprotein C-3 (APOC-S)-and decrease in plasma levels CETP and APOC-3. These contribute to large particles size of high-density lipoprotein (HDL) and low-density lipoprotein (LDL), and increase in HDL levels. We have also demonstrated that these genotypes and phenotypes are associated with less hypertension (HTN), cardiovascular disease (CVD) and metabolic syndrome (MS) (in offspring of the long-term survivors) and improved cognitive function (in probands). Using the strength of this established cohort, we now propose to utilize robust genetic technology with 500,000 SNPs (Genetic Core) and computational systems biology approach to characterize a cluster of genetic markers that will identify subjects with exceptional longevity with great accuracy. Furthermore, we will go back to the phenotypic data and associate this cluster with intermediate plasma phenotype and a reduced prevalence of age-related diseases. In addition, we will study the genetic basis of centenarians to overcome age-related diseases, in known and newly discovered pathways. These objectives will be accomplished using state-of-the-art computational biology, biochemical, molecular genetic, and statistics/bioinformatics (Statistics and Data management Core) approaches. This cohort of Ashkenazi Jews is ideal for this study since it is genetically homogeneous founder population that has been the basis of successful identification of other disease genes. Consequently, implicating this genotype in longevity will lead to fundamental insights into the molecular basis of several important age-related diseases. These insights may lead to novel preventive and treatment strategies for these diseases that will have a profound impact on morbidity and mortality, and will enhance the quality of life in the elderly.