A novel sex-specific association between insulin resistance and depressive symptoms in older adults: The potential mediating role of Vascular Endothelial Growth Factor

Background: Insulin resistance (IR) and depression are increasingly recognized as interconnected conditions in aging, potentially linked through chronic low-grade inflammation (“inflammaging”). The triglyceride-glucose (TyG) index has emerged as a validated surrogate marker of IR, yet its relationship with inflammatory biomarkers and depressive symptoms in older adults remains underexplored. Objective: This study investigated the association between the TyG index, depressive symptoms, and circulating inflammatory molecules in cognitively healthy older adults, with emphasis on sex-specific differences and the potential mediating role of vascular endothelial growth factor (VEGF). Methods: In this retrospective study, 118 non-diabetic older adults (mean age 74.1 years; 52.5 % men) with preserved cognition (MMSE ≥27) were assessed. Depressive symptoms were measured using the Geriatric Depression Scale (GDS), while cytokines and growth factors were quantified via multiplex immunoassay. The TyG index was calculated from fasting glucose and triglyceride levels. Multiple linear regression models controlled for age, sex, BMI, and medication use. Results: Depressive symptoms (GDS ≥5) were present in 31.35 % of participants. Those with depression had lower levels of anti-inflammatory cytokines and elevated levels of VEGF and MCP-1. TyG index correlated with both GDS scores (r = 0.239, p = 0.017) and VEGF (r = 0.271, p = 0.005), with significant associations observed only in women. VEGF emerged as a key mediator in the TyG-depression link in women (R2 = 0.425). Conclusions: These findings suggest a sex-specific metabolic-inflammatory signature in late-life depression. VEGF may serve as a mechanistic link between IR and depressive symptoms in older women, supporting sex-tailored interventions.