A Drug Repositioning Strategy for Healthspan Extension

Aging is the single most important risk factor for a wide range of chronic illnesses, including diabetes, heart disease, cancer and neurodegenerative diseases. Hence, interventions that can slow aging have the potential to prevent or at least retard the onset of these debilitating diseases.  It was recently discovered that senescent cell clearance in mouse aging models improves healthspan and extends lifespan. Cellular senescence is a genetic program characterized by the irreversible arrest of proliferation and is integral to multiple in vivo processes including tumor suppression, embryonic development, wound healing and tissue repair. Senescent cells secrete inflammatory cytokines and accumulate with age due to a decline in immune system function. Thus, there is much interest in targeting senescent cells for clearance via pharmacological interventions, referred to as senolytic drugs, to alleviate pathologies of aging and improve healthspan. In this project we will characterize the heterogeneity of different forms of cellular senescence by single cell transcriptomics analysis and will study the regulatory networks specific to the different sub-classes of senescent cells. We will then use their transcriptional signatures to identify novel putative senolytic drugs by querying available drug databases such as the Connectivity Map (CMAP).