Project 2 - Cellular Senescence and Skeletal Muscle Aging

PROJECT 2 Cellular Senescence and Skeletal Muscle Aging – SUMMARY Project 2 (formerly Project 4) has identified the cell populations in skeletal muscle that are prone to senes- cence with chronological aging, defined their distinguishing traits, and generated compelling evidence for their contribution to skeletal muscle loss and dysfunction. Our published and new experimental findings, robust ana- lytical pipeline, and innovative genetic and pharmacological tools strongly position us to now determine the fun- damental roles of p16Ink4a and p21Cip1 in skeletal muscle senescence, define the therapeutic potential of novel senotherapeutic compounds for age-related skeletal muscle dysfunction, and study the contribution of senescent cells in inter-tissue communication between skeletal muscle, bone (Project 1), and brain (Project 3). In this renewal, we will use new systems biology approaches (Core A), innovative genetic models (Core B), next gen- eration pharmacological strategies (Core C), and advanced molecular phenotyping (Core D) in three comple- mentary Specific Aims. In Aim 1, we will dissect the contributions of p16Ink4a and p21Cip1 to core properties of the senescence program (e.g., DNA damage response, anti-apoptosis pathway activation, heterogenoussecre- tory phenotype), and core features of skeletal muscle aging (e.g., loss of mass, strength, and/or function) using mice that permit inducible deletion of floxed p16Ink4a, p21Cip1, or both at advanced ages. In Aim 2, we will test novel senotherapeutics designed for the elimination of either p16Ink4a- or p21Cip1-positive senescent cells as well as a newskeletal-muscle targeting senolytic on the molecular phenotype of skeletal muscle and conserved fea- tures of skeletal muscle, bone, and brain aging. In Aim 3 we will investigate the effects of genetic and pharma- cological elimination of senescent cell populations on skeletal muscle adaptation. Here we will use innovative mouse models that enable targeted elimination of high p16Ink4a-expressing FAPs and high p21Cip1-expressing myofibers and a new skeletal muscle-targeting senotherapeutic compound and study their influence on skeletal muscle regeneration in response to acute injury and adaptations of skeletal muscle, bone, and brain in older mice to progressive exercise training. We expect that successful completion of these aims will advance the the overall goal of this PPG to build a firm foundation of multidisciplinary discovery science in cellular senescence that leads to a pipeline of therapeutic strategies that slow or prevent age-associated diseases to drive transla- tional geroscience forward.