Association between estimated glucose disposal rate (eGDR) and accelerated biological aging: the potential mediating role of uric acid-to-high-density lipoprotein cholesterol ratio (UHR) and atherogenic index of plasma (AIP)

Although accumulating evidence has demonstrated a significant inverse association between insulin resistance, as measured by the estimated glucose disposal rate (eGDR), and accelerated biological aging, the potential mediating links underlying this association remain unclear. Therefore, this study aimed to investigate the association between eGDR and biological aging acceleration and to identify potential mediators of this relationship. Data from 7,626 participants in the National Health and Nutrition Examination Survey (NHANES) were included. Accelerated biological aging was assessed using Phenotypic Age (PhenoAge) Advance, whereas insulin resistance was estimated by the estimated glucose disposal rate (eGDR). The Atherogenic Index of Plasma (AIP) was calculated as log₁₀(triglycerides/high-density lipoprotein cholesterol [HDL-C]), and the uric acid-to-HDL-C ratio (UHR) was calculated as serum uric acid divided by HDL-C, while the dietary inflammatory index (DII) was used to assess the inflammatory potential of dietary intake. Multivariable linear regression, restricted cubic spline (RCS) analyses, subgroup analyses, interaction tests and mediation analyses were performed to examine the association between eGDR and PhenoAge Advance and to identify the mediating effects of AIP, UHR and DII in this association. Among 7,626 participants, the median chronological age and PhenoAge were 49 (34–63) years and 61.47 (46.74–75.47) years, respectively. After adjusting for potential confounders, RCS analysis revealed a significant inverse association between eGDR and PhenoAge Advance ( P for non-linearity = 0.008). Specifically, each one-unit increase in eGDR was associated with a 0.74-year (95% CI: -0.94 to -0.54) decrease in PhenoAge Advance. A consistent trend in this association was observed in multiple sensitivity analyses, including excluding covariates that were closely related to eGDR or PhenoAge Advance, and using multiple imputation to handle missing data. Furthermore, subgroup analyses and interaction tests revealed that eGDR-PhenoAge Advance association was significantly modified by educational level, hyperlipidemia, and smoking status (all P for interaction < 0.05). The inverse relationship was more pronounced among individuals with higher education (β=-0.94), current smokers (β=-0.87), and those with hyperlipidemia (β=-0.82). Finally, mediation analyses identified AIP and UHR as significant mediators in the relationship between eGDR and PhenoAge Advance, accounting for 2.18% (ACME=-0.072, P = 0.03) and 7.04% (ACME=-0.231, P < 0.0001) of the total effect, respectively. The mediating effects of AIP and UHR remained robust across all sensitivity analyses, including those excluding key comorbidities (hypertension, diabetes, and hyperlipidemia) and BMI. Higher eGDR was significantly associated with lower PhenoAge Advance, with this association being statistically mediated in part by AIP and UHR.