Senotherapeutics: Experimental therapy of cellular senescence

Our global population is aging, and this changing demographic portends unprecedented levels of chronic diseases and healthcare burden. In response, new efforts to extend human healthspan are underway, informed by the “geroscience hypothesis, " which holds that incidence of aging-related chronic disease can be prevented, delayed, or attenuated by therapeutically targeting fundamental biology shared by the aging process and common chronic diseases. The promise of geroscience is that interventions will be found that target biological aging processes, thereby delaying the onset of multiple chronic diseases simultaneously. A major geroscience accomplishment has been to frame a set of tightly interrelated cellular biologic processes that are altered with aging that could be targeted to extend lifespan and healthspan: macromolecular damage, metabolism, proteostasis, inflammation, adaptation to stress, epigenetics, cell senescence, stem cells/regeneration, and pleiotropic processes. One of these biologic processes, cellular senescence and its related senescence-associated secretory phenotype, is an underlying contributor to age-related loss of physiologic integrity and function. Thus, interventions that mitigate senescent cell burden, termed “senotherapeutics, " would be expected to improve function, chronic diseases, and geriatric syndromes. This chapter is intended as an in-depth summary of research evaluating the clinical potential of senotherapeutics, with a focus on current testing of preclinical and clinical drugs, and practical considerations on translation of experimental therapy of cellular senescence to humans.