The mediating role of insulin resistance in depression driving phenotypic age acceleration

Depression, characterized by significant psychological and physiological alterations, has been proved to tightly associate with insulin resistance (IR) and hallmarks of biological aging. Phenotypic Age Acceleration (PhenoAgeAccel), which quantifies the discrepancy between biological and chronological age, serves as a robust indicator of accelerated aging. However, the interplay between depression, IR, and accelerated aging remains unclear. This study aims to explore the relationship between depression and PhenoAgeAccel, and the potential mediating role of IR in this association.

A total of 4,555 adults participants from the National Health and Nutrition Examination Survey (NHANES) database with complete data on depression, PhenoAgeAccel, and other essential covariates were included in this study. Depression severity was assessed by the nine-item Patient Health Questionnaire (PHQ-9), with a PHQ-9 score ≥ 10 used to define depression. Four indicators, including triglyceride-glucose index (TyG), TyG-body mass index (TyG-BMI), TyG-waist height ratio (TyG-WHTR), and metabolic score for insulin resistance (METS-IR), were used to assess IR. Weighted multivariable linear regression analyses were performed to identify the association of depression/PHQ-9 score with PhenoAgeAccel. Moreover, subgroup analyses, interaction tests, and adjusted restricted cubic spline (RCS) analyses were employed to explore the robustness, stability, and potential nonlinearity of the associations between PHQ-9/depression and PhenoAgeAccel. Additionally, mediation analysis was conducted to investigate the mediating role of IR biomarkers in the association between PHQ-9 score and PhenoAgeAccel.

In the fully-adjusted model, being depressive and one-unit increment in PHQ-9 score were associated with a 1.93-year (95% CI: 0.95-2.92) and 0.14-year (95% CI: 0.07-0.21) increase in PhenoAgeAccel, respectively. A positive linear dose-response relationship between PHQ-9 score and PhenoAgeAccel was identified via RCS analysis (P for overall = 0.001, P_{non-linearity}=0.867). Subgroup analyses and interaction tests revealed a more pronounced association between depression/PHQ-9 and PhenoAgeAccel in subgroups with diabetes, moderate-to-heavy alcohol consumption, and higher education levels (all P_interaction<0.05). IR biomarkers were observed to mediated 3.6-8.4% of the total effect, with METS-IR showing the highest mediation (8.4%, 95% CI: 0.024-0.222).

Depression was associated with accelerated PhenoAgeAccel, with insulin resistance acting as a partial mediator. In depression management, interventions targeting metabolic issues like insulin resistance should also be considered to mitigate depression-associated aging.