Bridge Funding - Genetic variant-based drug discovery targeting conserved pathways of aging

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PROJECT SUMMARY/ABSTRACT (ADMINISTRATIVE SUPPLEMENT) Aging is the most important risk factor for common human diseases, such as diabetes, cardiovascular disease, and cancer. Hence, targeting basic mechanisms of aging rather than individual diseases is a rational strategy to develop treatments of age-related multi-morbidity. To test the validity of this approach investigators in this U19 leverage the human centenarian resource at the Albert Einstein College of Medicine to identify rare genetic variants associated with extreme human longevity to identify potential drug targets for promoting healthy aging. Using resequencing data of 400 candidate genes in 450 centenarians and 550 controls we identified, in the previous funding period, rare, functional genetic variants and associated pathways enriched in centenarians and potentially important for healthy longevity, including IGF-1, SIRT6, FOXO3A, NF-kB and SMAD3. Importantly, analysis of new, whole exome sequences of 555 centenarians and 508 controls, provided additional candidate variants, e.g., BLM, USP35, UBE3C. A number of the rare variant candidates were further characterized and evaluated functionally in human ES cells and differentiated lineages. We also generated mouse models of some of the variants for analysis of phenotypes relevant for late-life human health and subsequently used the ES cell and mouse model results as leads for developing assays and testing small molecules targeting the pathways affected by these rare variants. Interestingly, many of the rare variants and/or affected pathways could be linked to the DNA damage response, including cellular senescence. Based on the demonstrated success of our approach we now have expanded our whole exome-sequenced cohort to increase robustness of the analysis, identify additional variants and study candidate pathways through RNA-seq, functionalize additional candidate variants in ESCs and generate more mouse models. This should allow us to greatly extend the number of validated therapeutic targets for drug development.