Cellular senescence and kidney aging

Abstract

Life expectancy is increasing worldwide, and by 2050 the proportion of the world's population over 65 years of age is estimated to surpass 1.5 billion. Kidney aging is associated with molecular and physiological changes that cause a loss of renal function and of regenerative potential. As the aging population grows, it is crucial to understand the mechanisms underlying these changes, as they increase the susceptibility to developing acute kidney injury (AKI) and chronic kidney disease (CKD). Various cellular processes and molecular pathways take part in the complex process of kidney aging. In this review, we will focus on the phenomenon of cellular senescence as one of the involved mechanisms at the crossroad of kidney aging, age-related disease, and CKD. We will highlight experimental and clinical findings about the role of cellular senescence in kidney aging and CKD. In addition, we will review challenges in senescence research and emerging therapeutic aspects. We will highlight the great potential of senolytic strategies for the elimination of harmful senescent cells to promote healthy kidney aging and to avoid age-related disease and CKD. This review aims to give insight into recent discoveries and future developments, providing a comprehensive overview of current knowledge on cellular senescence and anti-senescent therapies in the kidney field.

Keywords: Aging kidney; Cellular Senescence; chronic kidney disease; senolysis; senolytic therapy.

Figure 1. Age related changes in kidney function and structure

With natural aging, there is a loss of nephron mass (yellow) and total kidney volume (green) starting around the age of 30 years. This is paralleled by a steady decrease in glomerular filtration rate with a loss of approximately 1 ml/min/year (blue). The load of senescent cells within the kidney increases with age (red).

Figure 2. Pathways of cellular senescence

DNA damage and a variety of stresses can activate the cellular senescence program. DNA damage activates Ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR). ATM/ATR activate p53 and its transactivational target p21. Alternatively, activation of the RAS oncogene can also result in p53-p21 activation. Various stress signals can activate p16INK4a (p16), which similar to p21 is a cyclin-dependent kinase inhibitor. Both pathways converge on antagonizing the phosphorylation of tumor suppressor retinoblastoma (RB). Hypophosphorylated RB promotes cell cycle arrest by complexing EF2. Progression through the G1, S, G2, and M phases of cell division is halted at G1/S and G2/M.

Figure 3. Major kidney cell types are affected by cellular senescence

Evidence from the literature for senescence in indicated cell types is presented for tubular cells, endothelial cells and podocytes. References including human material are in bold.

Figure 4. Hypothetical trajectories of renal function and senescent cell load

(A) Loss in glomerular filtration rate with natural aging (I) and accelerated aging with increased senescent cell load (II, III). (B) Repetitive senolytic drug treatment diminishes the senescent cell load, leading to improved glomerular filtration rate.