Targeting Cellular Senescence to Extend Healthspan

OVERALL: Targeting Cellular Senescence to Extend Healthspan – SUMMARY This proposal is for the renewal of P01 AG62413, Targeting Cellular Senescence to Extend Healthspan. In the initial funding cycle, we made major conceptual and technical advances in the understanding of cellular senescence, its mechanistic role in the aging of three distinct tissues, and its modifiability by pharmacological intervention. The influence and impact of this highly collaborative PPG are highlighted by over 130 publications, complementary grants, career development awards, and significant engagement in the Common Fund Cellular Senescence Network. Moreover, several clinical trials have been initiated, consistent with the overall goal 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 translational geroscience forward. Our progress has also yielded several exciting and critical questions centered on the molecular underpinnings of the senescence program, including the unique and overlapping roles of p16Ink4a and p21Cip1, the role of specific senescent cell sub-types in tissue and systemic aging, and the tractability of these cell populations by next-generation small molecules engineered to promote their elimination (senolytics) or alter their behavior (senomorphics). We have assembled a uniquely qualified, highly collaborative, and multidisciplinary team to pursue these new and important scientific directions in the renewal through three tissue-centered projects and four highly complementary cores. The projects are Cellular Senescence and Bone Aging (Project 1), Cellular Senescence and Skeletal Muscle Aging (Project 2), and Cellular Senescence and Brain Aging (Project 3). The multidisciplinary cores consist of an Administrative and Systems Biology Core (Core A), a Common Mouse Models Core (Core B), a Drug Discovery and Development Core (Core C), and a Senescence Molecular Phenotyping Core (Core D), each armed with innovative technologies and the appropriate expertise. Collectively, through the coordination, integration, and analysis of research activities and results across the three projects and four cores detailed in this application, this PPG will yield fundamental insights into the governing roles of p16Ink4a and p21Cip1 in cellular senescence and aging, critical data on the therapeutic potential of senotherapeutic compounds for age-related tissue dysfunction, and an advanced understanding and new hypotheses regarding cellular senescence as a mediator of inter-organ communication between bone, skeletal muscle, and brain.