Early Vascular Ageing and Cellular Senescence in Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) is a clinical model of premature ageing characterized by progressive vascular disease, systemic inflammation, muscle wasting and frailty. The predominant early vascular ageing (EVA) process mediated by medial vascular calcification (VC) results in a marked discrepancy between chronological and biological vascular age in CKD. Though the exact underlying mechanisms of VC and EVA are not fully elucidated, accumulating evidence indicates that cellular senescence - and subsequent chronic inflammation through the senescence-associated secretary phenotype (SASP) - plays a fundamental role in its initiation and progression. In this review, we discuss the pathophysiological links between senescence and the EVA process in CKD, with focus on cellular senescence and media VC, and potential anti-ageing therapeutic strategies of senolytic drugs targeting cellular senescence and EVA in CKD.

Keywords: Chronic kidney disease; Early vascular ageing; Senescence; Senolytic drugs; Vascular calcification.

Graphical abstract

Fig. 1

Triggers, effector pathways and features of senescence in tissue dysfunction, ageing and chronic diseases. Inducers triggering senescence vary depending on the context, including DNA damage, reactive oxygen species (ROS), oncogenic mutations, metabolic insults, proteotoxic stress and other unknown factors. Cellular senescence is activated via p53/p21, p16/pRB dependent pathways. One typical feature of senescent cells, the senescent cell anti-apoptotic pathways (SCAPs), predisposes senescent cells to be apoptosis-resistant, resulting in their accumulation in tissues. The SCAPs are thus key targets of senolytic drugs for targeting and inducing senescent cells to undergo apoptosis. Another feature of senescent cells is the senescence-associated secretory phenotype (SASP), characterized by a secretion profile of pro-inflammatory cytokines, growth factors and soluble receptors, which could further result in both local and systemic inflammation and tissue damage effect. Activation of interleukin-1 (IL-1), tumor growth factor β (TGF-β), nuclear factor (NF)-кB (NF-кB), p38 mitogen-activated protein kinases (p38 MAPK) and inflammasome signaling are factors promoting generation of SASP.

Fig. 2

Potential senotherapy: preventive strategies, SASPs inhibitors and senolytics. Adapted from Kirkland et al. [66].