New Trends in Aging Drug Discovery

Abstract

Aging is considered the main risk factor for many chronic diseases that frequently appear at advanced ages. However, the inevitability of this process is being questioned by recent research that suggests that senescent cells have specific features that differentiate them from younger cells and that removal of these cells ameliorates senescent phenotype and associated diseases. This opens the door to the design of tailored therapeutic interventions aimed at reducing and delaying the impact of senescence in life, that is, extending healthspan and treating aging as another chronic disease. Although these ideas are still far from reaching the bedside, it is conceivable that they will revolutionize the way we understand aging in the next decades. In this review, we analyze the main and well-validated cellular pathways and targets related to senescence as well as their implication in aging-associated diseases. In addition, the most relevant small molecules with senotherapeutic potential, with a special emphasis on their mechanism of action, ongoing clinical trials, and potential limitations, are discussed. Finally, a brief overview of alternative strategies that go beyond the small molecule field, together with our perspectives for the future of the field, is provided.

Keywords: aging; drug discovery; senescence.

Figure 1

Main signaling pathways and molecular targets for senolytic and senomorphic therapeutic intervention.

Figure 2

Structure of selected senolytics. (A) Natural products. (B) Repurposed compounds targeting key enzymes/pathways and representative examples of other approaches based on prodrugs and PROTACs.

Figure 2

Structure of selected senolytics. (A) Natural products. (B) Repurposed compounds targeting key enzymes/pathways and representative examples of other approaches based on prodrugs and PROTACs.

Figure 3

Structure of selected senomorphic compounds.