Strategies targeting cellular senescence

Abstract

Cellular senescence is a physiological phenomenon that has both beneficial and detrimental consequences. Senescence limits tumorigenesis and tissue damage throughout the lifetime. However, at the late stages of life, senescent cells increasingly accumulate in tissues and might also contribute to the development of various age-related pathologies. Recent studies have revealed the molecular pathways that preserve the viability of senescent cells and the ones regulating their immune surveillance. These studies provide essential initial insights for the development of novel therapeutic strategies for targeting senescent cells. At the same time they stress the need to understand the limitations of the existing strategies, their efficacy and safety, and the possible deleterious consequences of senescent cell elimination. Here we discuss the existing strategies for targeting senescent cells and upcoming challenges in translating these strategies into safe and efficient therapies. Successful translation of these strategies could have implications for treating a variety of diseases at old age and could potentially reshape our view of health management during aging.

Figure 1. Strategies targeting cellular senescence.

Three principal approaches could be implemented to block deleterious effects of senescent cells. (A) The leading options are strategies that induce apoptosis selectively in senescent cells with the use of senolytic drugs, which block prosurvival pathways. (B) The second type of strategy is to potentiate an immune response against senescent cells in a way that would lead to their clearance from tissues. (C) A third strategy proposes specific blockade of SASP components by targeting of their upstream regulators and effectors. ADCC, antibody-dependent cell-mediated cytotoxicity; DDR, DNA damage response; GOS, galacto-oligosaccharides; ITAM, immunoreceptor tyrosine-based activation motif.