The Clinical Potential of Senolytic Drugs

Abstract

Senolytic drugs are agents that selectively induce apoptosis of senescent cells. These cells accumulate in many tissues with aging and at sites of pathology in multiple chronic diseases. In studies in animals, targeting senescent cells using genetic or pharmacological approaches delays, prevents, or alleviates multiple age-related phenotypes, chronic diseases, geriatric syndromes, and loss of physiological resilience. Among the chronic conditions successfully treated by depleting senescent cells in preclinical studies are frailty, cardiac dysfunction, vascular hyporeactivity and calcification, diabetes mellitus, liver steatosis, osteoporosis, vertebral disk degeneration, pulmonary fibrosis, and radiation-induced damage. Senolytic agents are being tested in proof-of-concept clinical trials. To do so, new clinical trial paradigms for testing senolytics and other agents that target fundamental aging mechanisms are being developed, because use of long-term endpoints such as lifespan or healthspan is not feasible. These strategies include testing effects on multimorbidity, accelerated aging-like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age-related loss of physiological resilience, and frailty. If senolytics or other interventions that target fundamental aging processes prove to be effective and safe in clinical trials, they could transform geriatric medicine by enabling prevention or treatment of multiple diseases and functional deficits in parallel, instead of one at a time.

Keywords: SCAPs; cellular senescence; chronic diseases; geroscience hypothesis; senolytics.

Conflict of interest statement

Conflicts of Interest: J.L.K., T.T., Y.Z., P.D.R, L.J.N., the Mayo Clinic and The Scripps Research Institute have a financial interest related to this research. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic conflict of interest policies.

© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.