Genetics of extreme human longevity

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PROJECT SUMMARY/ABSTRACT The world's population is aging. Since most of older people have at least one but more commonly multiple debilitating chronic diseases, this demographic shift will result in a dramatic increase in morbidity and a burden on our healthcare systems. This U19 proposes an integrated study to test a new approach for developing therapies for age-related diseases. Rather than focusing on individual diseases, we explore genetic differences between successfully aged, healthy centenarians and control individuals with no family history of extreme longevity. Our long-term goal is to use gene variants found enriched in the centenarian genome as potential targets for developing drugs that prevent, delay onset and progression, and possibly even revert many of the multiple age-related diseases. The overall objective of Project 1 is to elucidate genetic variants enriched in the centenarian genome, based on our central hypothesis that rare variants constitute an important part of the genetic architecture of human aging and influence human lifespan on the polygenic risk background defined by common variants. This hypothesis has been formulated on the basis of our recent whole exome sequencing study of longevity using the Einstein centenarian cohort and will be tested by pursuing three specific aims: (I) To identify and replicate rare variant-based longevity association; (II) To develop an integrated common variant- based polygenic score of longevity; and (III) To study gene regulatory pathways associated with extreme human longevity using single-cell and single-molecule analyses of centenarian blood cells. The research rationale for Project 1 is that such variants can be functionalized by Projects 2 and 3 and used as targets for drug screening assays to be developed by Project 4. Our proposed research will have an important positive impact: better understanding of the genetics of extreme human longevity provided by our study of centenarian cohorts will enable us to identify novel therapeutics that slow or mitigate aging and all associated diseases.