Genetic variant-based drug discovery targeting conserved pathways of aging

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ABSTRACT (OVERALL) Aging is the greatest risk factor for most common chronic human diseases and a logical target for developing interventions to prevent, mitigate or reverse multiple age-related morbidities. Over the past two decades, genetic and pharmacologic interventions targeting conserved pathways of growth and metabolism have consistently led to substantial extension of the lifespan and healthspan in model organisms as diverse as nematodes, flies and mice. It is imperative to extend the results obtained with model organisms to aging humans. In this proposed renewal of our U19 project “Genetic variant-based drug discovery targeting conserved pathways of aging” we propose to continue using human centenarians to identify genetic variants as targets for developing drugs that improve human healthy aging. During the first funding period, we identified rare variants and longevity pathways in our centenarian cohort including coding variants in IGF-1R, SIRT6, and ATM, and functional non-coding variants in FOXO3A, SIRT6 and components of the IKK/NF-B pathway, RelA/p65, NFKB1/p50 and NFKB1a (IB). Having established the feasibility of using the genetics of human centenarians to identify genes and pathways as candidates for potential drug targets for promoting human healthspan, the focus of this renewal application will be to expand the program through whole exome analysis of our own, significantly expanded cohort and other centenarian cohorts, further gene functionalization, the use of novel mouse models of accelerated aging to validate the role of the rare variants and pathways in healthy longevity, and expansion of our pipeline of screening for candidate interventions. To accomplish these goals, we propose an interdisciplinary approach, making full use of the latest advances in cellular genomics, high-throughput functional screening, stem cell biology, mouse and human genetics and drug screening. This renewal application is comprised of four projects. Project 1: Genetic analysis of extreme human longevity (Zhang, Dong, and Vijg); Project 2: Identification of functional genetic rare variants (Suh and Yu), Project 3: Validation and characterization of rare variants in mouse models of aging (Niedernhofer) and Project 4: Development of novel therapeutics targeting the identified variants and pathways (Robbins and Gorbunova). There is also one Research Resource Core for Data Integration and Sharing (Core B; Zhang and Dong) as well as an Administrative Core (Core A; Vijg, Robins and Barzilai). We expect that the continued and expanded use of the human centenarian cohorts will allow us to obtain more detailed genetic information critical for identifying targets for the development of drugs for extending human healthspan, for example, by increasing resilience to Alzheimer’s Disease pathology.