Functional interaction between advanced glycation end-products and IGFBP-3 contributes to renal pathology in aging-associated chronic kidney disease

Chronic kidney disease (CKD) rises sharply with age, yet the molecular drivers underlying renal functional decline during physiological aging remain incompletely defined. Advanced glycation end products (AGEs), which accumulate over time, and insulin-like growth factor binding protein-3 (IGFBP-3), which is elevated in CKD and inversely correlated with renal function, have each been implicated in renal pathology. However, their interplay in age-associated kidney injury remains unclear. To address this gap, we analyzed a human kidney tissue microarray spanning a broad age spectrum to assess the expression of Nε-(1-carboxymethyl)-L-lysine (CML), a major AGE, and IGFBP-3. In parallel, naturally aged male C57BL/6 mice aged 92 weeks were treated with the AGE formation inhibitor aminoguanidine or an IGFBP-3 neutralizing antibody. Both CML and IGFBP-3 were markedly elevated in the kidneys from elderly donors. Aged mice exhibited pronounced renal dysfunction, structural deterioration, and collagen accumulation. Pharmacological inhibition of AGE formation or IGFBP-3 neutralization significantly ameliorated these age-associated impairments. Mechanistically, AGE accumulation and IGFBP-3 expression were reciprocally attenuated by both interventions, suggesting a functional interplay between these pathways. Collectively, our findings identify AGEs and IGFBP-3 as interrelated drivers of renal aging and provide evidence that targeting this axis may represent a promising therapeutic strategy to mitigate CKD progression in the elderly.