Cellular senescence in renal ageing and disease

Abstract

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.

Senescence in Health and Disease

“…A few groups have studied the utility of p16 INK4a expression in this setting, looking at p16 INK4a mRNA level in ‘time zero’ biopsies of human kidneys at the time of their harvest for transplantation. Increased expression of p16 INK4a in renal biopsies was found to be a strong predictor of long-term graft function, providing greater predictive capacity than the chronological age of the donor or other molecular biomarkers (Sturmlechner et al, 2017). …”

Senescent cells: an emerging target for diseases of ageing

“…Rather than existing as a single, discrete cellular state, SNCs are diverse: SNCs of different origins secrete different (SASP) factors 41–44 , drive disease pathogenesis through varying mechanisms and can be triggered to enter apoptosis through distinct senolytic mechanisms 45 . Some of these differences may arise as a consequence of how these cells became senescent in the first place (that is, what stressor induced senescence, such as oncogene overexpression versus irradiation) or the tissue origin of the cell before senescence induction.…”

Renal regeneration after acute kidney injury

“…Therefore, acute induced senescence seems to contribute to tissue healing, while chronic senescence has a negative impact in regeneration. Senolytics, drugs that selectively induce death of senescent cells, are currently under investigation …”

“…Senolytics, drugs that selectively induce death of senescent cells, are currently under investigation. 95 Not surprisingly, dysfunction of mitochondria, the cell energy provider, is associated with kidney injury. 96 A recent review was performed highlighting novel therapeutic approaches for AKI targeting different types of mitochondrial damage namely development of activators of mitochondrial biogenesis, inhibitors of mitochondrial fragmentation, mitochondrial ROS modulators and mitophagy activators.…”