Senescent cells, senolytics and tissue repair: the devil may be in the dosing

Abstract

There is tremendous interest in the development of drugs that target senescent cells (‘senolytic’ drugs) to treat a range of age-related morbidities. However, studies in mice that demonstrate impaired tissue repair following clearance of senescent cells raise questions about the potential risks of senolytic therapies. Closer examination of the available studies reveals the hopeful possibility of a ‘therapeutic window’ in which these risks can be minimized.

Fig. 1 |. Schematic of postulated effects of continuous versus intermittent senolytic treatment on tissue repair.

Tissue injury triggers the appears of p16^Ink4a- and p21^Cip1 (p16^Ink4a/p16^Cip1)-expressing ‘injury’ cells that express multiple features of senescent cells, including a SASP. The relationship of these cells to canonical, growth-arrested senescent cells associated with aging remains unclear and requires further study (depicted by question mark). Continuous senolytic treatment, leading to elimination of these p16^Ink4a- and p21^Cip1-expressing injury cells, results in impaired tissue repair. By contrast, intermittent senolytic treatment, as would generally be used clinically, reduces the burden of these cells and leads to improved tissue repair (or at least to no adverse effects). Although consistent with existing data, this hypothesis clearly needs to be directly tested by treating various types of injuries in preclinical models with continuous versus intermittent senolytic drugs.