The senescence programme is implicated in diverse biological processes, including embryogenesis, tissue regeneration and repair, tumorigenesis, and ageing. Although in vivo studies of senescence are in their infancy, evidence suggesting that senescent cells are a heterogeneous cell type is accumulating: senescence can be induced by different stressors, and senescent cells have varying degrees of genomic and epigenomic instability and different cell origins, contributing to their diversity. Two main classes of senescent cells have been identified: acute and chronic senescent cells. Acute senescent cells are generated during coordinated, beneficial biological processes characterized by a defined senescence trigger, transient senescent-cell signalling functions, and eventual senescent-cell clearance. In contrast, chronic senescent cells arise more slowly from cumulative, diverse stresses and are inefficiently eliminated, leading to their accumulation and deleterious effects through a secretory phenotype. Senescent cells have been identified in many tissues and organs, including the kidney. Here, we discuss the emerging roles of senescent cells in renal development, homeostasis, and pathology. We also address how senotherapy, or targeting of senescent cells, might be used to improve renal function with normal ageing, disease, or therapy-induced damage.

Damaged cells at risk of neoplastic transformation can be neutralized by apoptosis or engagement of the senescence program, which induces permanent cell-cycle arrest and a bioactive secretome that is implicated in tumor immunosurveillance. While from an evolutionary perspective senescence is beneficial in that it protects against malignancies, the accumulation of senescent cells in tissues and organs with aging and at sites of various pathologies is largely detrimental. Because induction of senescence in cancer cells is emerging as a therapeutic concept, it will be important to consider these detrimental effects, including tumor-promoting properties that may drive the formation of secondary tumors or cancer relapse. In this review we discuss the complex relationship between senescence and cancer, and highlight important considerations for therapeutics.

The clock is ticking for senescent cells Senescent cells promote their own recognition and removal through the immune system by generating a bioactive secretome called the senescence-associated secretory phenotype (SASP). Sturmlechner et al . report that the cell cycle regulator p21 directs an early form of the SASP, which they call the p21-activated secretory phenotype (PASP) (see the Perspective by Reen and Gil). As part of the PASP, the chemokine CXCL14 attracts macrophages, which monitor stressed cells expressing elevated p21. If stressed cells recuperate and p21 levels return to normal within 4 days, then macrophages disengage from their targets. Otherwise, macrophages recruit cytotoxic T cells that facilitate target cell removal. Other cell cycle regulators such as p16 can induce many factors overlapping with the PASP, but p21 uniquely drives this CXCL14-mediated “timer” mechanism of senescent cell immunosurveillance. —STS