Genetic variation in genome maintenance and aging
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Aging is characterized by a decline in the maintenance of homeostatic processes over time that increases the risk of disease and functional decline, ultimately resulting in death. To target aging, since it is the major cause of common diseases, it is essential to understand the underlying molecular mechanisms of aging. The focus of my project is on genome maintenance as a major Longevity Assurance Mechanism because genetic defects in this pathway cause a shorter life span and premature aging in humans and mice. I hypothesize that genetic variation at loci involved in genome maintenance can be related to individual differences in the rate, onset, and severity of aging phenotypes in humans, including exceptionally healthy aging. To address this hypothesis, I conducted a multidisciplinary functional genomics approach to (1) discover "functional genetic variants" involved in genome maintenance that are associated with age-related disease risk or its opposite (an unusual resistance to such diseases), and (2) assess the functional impact of associated variants to understand the underlying molecular mechanisms. I present the results from genetic association analysis of the San Antonio Longitudinal Study of Aging cohort, in which tagSNPs of 83 genes involved in genome maintenance were determined for association with age-related phenotypes including major chronic diseases and impairments. I further delineated the molecular mechanism for the association of SIRT1 SNPs with myocardial infarction (MI) by identifying a functional variant in the SIRT1 promoter and its role in recruitment of CTCF as a key event in activating SIRT1 expression in response to genotoxic stress. I also identified a small molecule activator of SIRT1 gene expression and its mechanism by which the increased SIRT1 transcription is mediated by FOXO3. Lastly, I investigated the role of genetic variation in telomerase genes in healthy aging by studying the cohort of Ashkenazi Jewish centenarians, their offspring and age-and gender-matched controls. Taken together, these integrated studies demonstrate a connection between genome maintenance and aging at different levels, i.e., from genetic variation to the molecular and cellular endpoints impacting on health and life span.