Proteolysis targeting chimeras as senolytics: An emerging senotherapy for combating aging

Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives aging-related phenotypes. Clearance of senescent cells decreases chronic, low-grade inflammation and restores tissue repair capacity, thus improving human health and lifespan. Senolytics that selectively eliminate senescent cells have become a promising antiaging strategy. To date, current senolytics are largely developed by repurposing anticancer agents. Therefore, senolytics usually possess various on- and off-target toxicities. These toxicities could preclude their clinical use as antiaging agents, as elderly people are more susceptible to adverse drug effects than young individuals. Proteolysis targeting chimeras as senolytics, termed "SenoTACs," are attractive for more effective treatment of aging-related diseases. In comparison to small molecule inhibitors, SenoTACs can eliminate senescent cells by degrading targeted proteins in a substoichiometric manner, providing better target ability, longer-lasting therapeutic effect, broadened target capability, and decreased drug resistance. Recent efforts have led to the development of several senescence-targeting proteolysis targeting chimeras, including ARV825, PZ15227, 753B, Gal-ARV-771, and Gal-MS99, which exhibit selective senolytic activity and improved safety and efficacy profiles when compared with small molecule inhibitors. In this minireview, we summarize the development of the emerging field. SIGNIFICANCE STATEMENT: The severe toxicities associated with current senolytics may limit their clinical utility as antiaging agents, as older populations are more susceptible to adverse drug effects. PROteolysis TArgeting Chimeras (PROTACs) that induce selective degradation of target proteins, are emerging as a promising therapeutic strategy to address this unmet medical need. Recently, PROTACs have been explored as novel senolytics-termed "SenoTACs," which display improved safety and efficacy in targeting senescent cells for fighting aging-related diseases.