Researchers here report on the discovery of a novel mechanism by which senescent cells can be selectively destroyed. Short-term senolytic treatments to date seem to cluster tightly into two categories: (a) largely ineffective, and (b) able to destroy between 25-50% of senescent cells in tissues. Few have achieved greater clearance so far, and few lie in between these two outcomes. In the present environment, of ample seed stage funding and enthusiasm for targeting senescent cells as a treatment for aging, it seems likely that someone will pick up this new approach for clinical development in the near future.
Although cellular senescence is an important tumor-suppressive mechanism, emerging evidence demonstrates that the accumulation of senescent cells (SnCs) with age and after genotoxic or cytotoxic cancer therapy can lead to various age-related diseases and pathological conditions. The selective removal of SnCs depends on identifying their Achilles' heels, which can be targeted to selectively kill SnCs. Several senolytic targets have been identified, resulting in the discovery of a series of senolytic agents that can selectively kill SnCs in culture and effectively remove SnCs in mice. Unfortunately, some of these agents exhibit toxicities that may prevent their safe use in the clinic, particularly for systemic therapy. For example, navitoclax, a selective BCL-2/BCL-XL dual inhibitor, is a potent senolytic agent but can induce thrombocytopenia, an on-target and dose-limiting toxicity that has prevented its FDA-approval. Therefore, further studies are needed to identify new senolytic targets that can be exploited for the development of safer senolytic agents.
Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin-proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.