Targeting Premature Renal Aging: from Molecular Mechanisms of Cellular Senescence to Senolytic Trials

Abstract

The biological process of renal aging is characterized by progressive structural and functional deterioration of the kidney leading to end-stage renal disease, requiring renal replacement therapy. Since the discovery of pivotal mechanisms of senescence such as cell cycle arrest, apoptosis inhibition, and the development of a senescence-associated secretory phenotype (SASP), efforts in the understanding of how senescent cells participate in renal physiological and pathological aging have grown exponentially. This has been encouraged by both preclinical studies in animal models with senescent cell clearance or genetic depletion as well as due to evidence coming from the clinical oncologic experience. This review considers the molecular mechanism and pathways that trigger premature renal aging from mitochondrial dysfunction, epigenetic modifications to autophagy, DNA damage repair (DDR), and the involvement of extracellular vesicles. We also discuss the different pharmaceutical approaches to selectively target senescent cells (namely, senolytics) or the development of systemic SASP (called senomorphics) in basic models of CKD and clinical trials. Finally, an overview will be provided on the potential opportunities for their use in renal transplantation during ex vivo machine perfusion to improve the quality of the graft.

Keywords: DNA damage repair; extracellular vesicles; metformin; mitochondrial dysfunction; rapamycin; renal ageing; senescence; senolytics.

FIGURE 1

Graphical abstract indicating the main causes leading to renal aging and possible therapeutic intervention strategies (in the left). The key molecular mechanisms inducing renal aging are mitochondrial dysfunction, autophagy, epigenetic changes, DNA damage repair (DDR), extracellular vesicles, and others. Abbreviations: DGF, delay graft function; FSGS, focal segmental glomerulosclerosis; IgAN, IgA nephropathy; CKD, chronic kidney disease; PGC-1α, peroxisome proliferator-activated receptor γ coactivator-1; ROS, oxygen reactive species; GROα, growth-regulated oncogene α; MCP-1, monocyte chemoattractant protein-1; CTGF, connective tissue growth factor; PAI-1, plasminogen activator inhibitor-1; ATM, ataxia telangiectasia mutated.

FIGURE 2

Senolytic agents in transplantation field. The administration of senolytic agents in donor (left), in normothermic-perfusion device (middle), and in recipient (right) is considered a therapeutic approach to improve the quality of older donor organs that have traditionally been considered unusable for transplantation. Adapted from Lau A, Kennedy BK, Kirkland JL, Tullius SG. Mixing old and young: enhancing rejuvenation and accelerating aging. J Clin Invest. 2019 Jan 2; 129 (1), 4–11.