Accelerated biological aging and homeostatic dysregulation in diabetic kidney disease: Evidence from NHANES and Mendelian randomization

Accelerated biological aging may drive diabetic kidney disease (DKD) pathogenesis, but comprehensive evidence integrating observational and causal approaches remains limited. This study integrated cross-sectional analyses of 2418 diabetic adults (National Health and Nutrition Examination Survey 1999-2010) with bidirectional Mendelian randomization (MR). Associations between homeostatic dysregulation (HD), biological age acceleration (Klemera-Doubal method residual) (BioAgeAccel), and Phenotypic age acceleration (PhenoAgeAccel) with DKD were assessed using weighted logistic regression, restricted cubic splines, receiver operating characteristic curve analysis and mediation. Two-sample MR utilized genetic instruments for BioAgeAccel and PhenoAgeAccel with FinnGen DKD data (3283 cases/181,704 controls). Significant nonlinear threshold effects were observed: DKD risk increased markedly at BioAgeAccel > 2.13 years and HD > 3.16 units, while PhenoAgeAccel exhibited a linear dose-response relationship. Accelerated biological aging status (BioAgeAccel > 0) substantially increased DKD odds (OR = 3.25, 95% CI: 2.52-4.18), as did PhenoAgeAccel > 0 (OR = 1.44, 95% CI: 1.13-1.84). Similarly, highest-quartile HD conferred elevated risk (Q4 OR = 2.85, 95% CI: 1.87-4.36). Associations remained consistent across subgroups stratified by age, sex, body mass index, income, comorbidities, and lifestyle factors, though effect modification occurred with stroke history (BioAgeAccel/PhenoAgeAccel) and ethnicity/age (HD). Urinary albumin-to-creatinine ratio mediated 89% to 93% of associations between all aging metrics and DKD. Discriminatory accuracy was highest for HD (area under the curve (AUC) = 0.678, 95% CI: 0.654-0.703) versus BioAgeAccel (AUC = 0.660, 95% CI: 0.637-0.682) and PhenoAgeAccel (AUC = 0.562, 95% CI: 0.539-0.586). MR confirmed a causal effect of PhenoAgeAccel on DKD (IVW OR = 1.078, 95% CI: 1.029-1.129, P = .0014) but not BioAgeAccel. Accelerated biological aging independently predicts DKD risk, with PhenoAgeAccel demonstrating causal effects. HD emerges as a potent clinical predictor, while albuminuria mediates most aging-related renal damage. These findings advocate integrating biological aging assessment into DKD risk stratification frameworks.