The ageing kidney: Molecular mechanisms and clinical implications

Abstract

As human life expectancy keeps increasing, ageing populations present a growing challenge for clinical practices. Human ageing is associated with molecular, structural, and functional changes in a variety of organ systems, including the kidney. During the ageing process, the kidney experiences progressive functional decline as well as macroscopic and microscopic histological alterations, which are accentuated by systemic comorbidities like hypertension and diabetes mellitus, or by preexisting or underlying kidney diseases. Although ageing per se does not cause kidney injury, physiologic changes associated with normal ageing processes are likely to impair the reparative capacity of the kidney and thus predispose older people to acute kidney disease, chronic kidney disease and other renal diseases. Mechanistically, cell senescence plays a key role in renal ageing, involving a number of cellular signaling mechanisms, many of which may be harnessed as interventional targets for slowing or even reversing kidney ageing. This review summarizes the clinical characteristics of renal ageing, highlights the latest progresses in deciphering the role of cell senescence in renal ageing, and envisages potential interventional strategies and novel therapeutic targets for preventing or improving renal ageing in the hope of maintaining long-term kidney health and function across the life course.

Age-related GSK3β overexpression drives podocyte senescence and glomerular aging

“…With age, many individuals experience a progressive decline in kidney function as well as macroscopic and microscopic histologic alterations, with the key feature being glomerular aging marked by global glomerulosclerosis (2,3). Glomerular aging involves senescence of various glomerular cells, in particular the terminally differentiated podocytes, which are a critical constituent of the glomerular filtration barrier (3,4). In addition, a characteristic senescence-associated secretory phenotype (SASP) is a pathognomonic feature of senescence in myriad tissues, including the glomeruli (1,(3)(4)(5).…”

“…Glomerular aging involves senescence of various glomerular cells, in particular the terminally differentiated podocytes, which are a critical constituent of the glomerular filtration barrier (3,4). In addition, a characteristic senescence-associated secretory phenotype (SASP) is a pathognomonic feature of senescence in myriad tissues, including the glomeruli (1,(3)(4)(5). Senescent glomerular cells like podocytes may affect nearby cells in the glomeruli via profibrogenic SASP paracrine signaling and cause glomerulosclerosis (5).…”

Chemotactic Cytokine Receptor 5 Genetic Polymorphism in Diabetic Nephropathy of the Type 2 Diabetes Mellitus

“…The duration of diabetes mellitus is related to the older age of the subject. Increasing age causes cell aging which involves cellular signaling mechanisms that disrupt the capacity of cells to repair themselves 10 . Older people tend to experience poorer nutritional status, are frail and weak, which increases morbidity and mortality 11 .…”

Therapeutic Targeting of SGLT2: A New Era in the Treatment of Diabetes and Diabetic Kidney Disease

“…Mechanistically, in addition to serving as an alternative fuel substrate, ketone bodies like β-HB, which is the predominant component of ketone bodies, are potent regulators of cellular signaling pathways including mTOR, AMPK, and HDACs and intercept multiple pathological processes, such as metabolic reprogramming, NLRP3 inflammasome, and pyroptosis, some of which have been implicated in kidney diseases. Indeed, the lastest evidence demonstrates that β-HB exerts a protective effect in glomerular podocytes against diabetes-elicited senescence response ( 51 ), which plays a key role in diabetes-accelerated kidney aging and degeneration ( 52 ). Thus, the ketogenic effect of SGLT2 inhibitors seems to provide extra benefits for patients with cardiovascular and renal complications of diabetes.…”