Identification of Longevity Genes in Founder Populations

Nir Barzilai, M.D. Albert Einstein College of Medicine of Yeshiva University Contact Dr. Barzilai

Despite evidence for a substantial genetic component, the inherited factors that define life span (longevity) in humans remain unknown. The overall objective of this proposal is to identify chromosomal loci (and ultimately genes) that influence longevity and longevity-related traits in humans, and to define how these genes exert their effects phenotypically. This objective will be accomplished using state-of-the-art epidemiological, molecular and statistical genetic approaches in two unique founder populations, the Old Order Amish and Ashkenazi Jews. These populations are ideal for these studies since (i) there are many long-lived individuals in these populations, (ii) they are relatively genetically homogeneous recent founder populations, and (iii) they previously have been the basis of successful identification of disease genes. We hypothesize: (1) genes for extreme longevity exist in humans and are relatively common, (2) these gene variants act by slowing aging-related processes and/or through protection from age-associated diseases, (3) phenotypic expression of these gene variants will be measurable through examination of specific traits in long-lived probands and their offspring, and (4) longevity assurance gene variants can be identified through state-of-the-art molecular genetic approaches in founder populations. We plan to Identify and recruit long-lived probands (>95 years of age) and family members, and define aging-related intermediate phenotypes. We will perform a genome-wide search for longevity assurance genes and genome-wide linkage analysis for age-related quantitative trait loci (QTLs). Finally we hope to begin fine mapping and positional cloning of longevity assurance genes. Thus, we expect to:

· Characterize two unique family collections enriched for longevity and longevity-related phenotypes in which genetic and nongenetic (environmental) influences on longevity may be studied.
· Identify specific chromosomal regions that are likely to harbor longevity assurance genes for subsequent identification through positional cloning and positional candidate approaches.
· Establish an offspring cohort that will be studied longitudinally, in order define the relevant intermediate longevity phenotypes and to correlate inheritance of longevity genes/genetic markers to their longevity phenotypes.