The biological mechanisms and environmental influences mediating exceptional survival (ES) into old age remain unknown, but genetic factors are likely to play an important role. ES is a complex phenotype characterized by exceptional longevity and by the lack of significant morbidity or disability. In preliminary work, we found that siblings of elderly probands with little decline in memory, cognitive function and activities of daily living skills were one-half as likely to die as siblings of probands with more rapid decline in these areas of performance. These findings suggest that long-lived families are characterized by preservation of cognitive and functional capacities and good health status. However, a wider exploration of other traits associated with ES is needed to identify groups of families with specific patterns of survival associated with ES to improve our ability to detect genetic loci. While it is critical to fully define and investigate the phenotype of ES, to detect contributing genes with large or small effects it is equally important to examine intermediate phenotypes that are manifestations of the phenotype of ES. Such studies rely on large numbers of well characterized families.The goal of this proposal is two-fold. First, we will determine the patterns of occurrence and modes of transmission of ES by a family history study of approximately 600 elderly residents, aged 95 years or older, residing in the New York, New Jersey, and Connecticut tri-state area. Participants will be identified and recruited from a population based sampling frame of 29,000 elderly individuals provided to us through the Center for Medicare and Medicaid Services. Second, we will identify and recruit approximately 300 families with exceptional survival in multiple family members from the family history study. We will conduct a family study of phenotypes that best characterize ES, including phenotypes for cognitive, physical, functional, disease status and physiologic capacities to determine heritable traits that subserve the overall phenotype of ES. We will also obtain information concerning environmental, social and behavioral factors that may contribute to ES. These families will be asked to provide blood to establish lymphoblastoid cell lines for subsequent genetic linkage studies. This team of investigators has worked together for the last 10 years and comprises researchers from epidemiology, genetics, neurology, neuropsychology and biostatistics. The investigative team has extensive experience in the use of CMS data to identify and recruit large cohorts for epidemiologic and genetic studies. The results of the proposed project will provide information on patterns of transmission of ES phenotypes for future genetic analyses. Identifying genes associated with ES will be an important step in understanding the processes underlying successful aging.
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