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.

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Diabetic kidney disease (DKD) is one of the most common complications of diabetes and is clinically featured by progressive albuminuria, consequent to glomerular destruction that involves podocyte senescence.Burgeoning evidence suggests that ketosis, in particular bhydroxybutyrate, exerts a beneficial effect on aging and on myriad metabolic or chronic diseases, including obesity, diabetes and chronic kidney diseases. Its effect on DKD is largely unknown. In vitro in podocytes exposed to a diabetic milieu, b-hydroxybutyrate treatment substantially mitigated cellular senescence and injury, as evidenced by reduced formation of gH2AX foci, reduced staining for senescence-associated-b-galactosidase activity, diminished expression of key mediators of senescence signaling like p16 INK4A and p21, and preserved expression of synaptopodin. This beneficial action of b-hydroxybutyrate coincided with a reinforced transcription factor Nrf2 antioxidant response. Mechanistically, b-hydroxybutyrate inhibition of glycogen synthase kinase 3b (GSK3b), a convergent point for myriad signaling pathways regulating Nrf2 activity, seems to contribute. Indeed, trigonelline, a selective inhibitor of Nrf2, or ectopic expression of constitutively active mutant GSK3b abolished, whereas selective activation of Nrf2 was sufficient for the antisenescent and podocyte protective effects of bhydroxybutyrate. Moreover, molecular modeling and docking analysis revealed that b-hydroxybutyrate is able to directly target the ATP-binding pocket of GSK3b and thereby block its kinase activity. In murine models of streptozotocin-elicited DKD, b-hydroxybutyrate therapy inhibited GSK3b and reinforced Nrf2 activation in glomerular podocytes, resulting in lessened podocyte senescence and injury and improved diabetic glomerulopathy and albuminuria. Thus, our findings may pave the way for developing a b-hydroxybutyrate-based novel approach of therapeutic ketosis for treating DKD.

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