Mendelian randomization identifies causal effects of major depressive disorder on accelerated aging

Background: Evidence links major depressive disorder (MDD) with aging, but it's unclear if MDD accelerates aging and what factors mediate this transition. Methods: Two-sample Mendelian randomization (MR) analyses were applied to estimate the causal association between MDD and frailty index (FI), telomere length (TL), and appendicular lean mass (ALM) from available genome-wide association studies in populations of European ancestry. Furthermore, we conducted mediation MR analyses to assess the mediating effects of 31 lifestyle factors or diseases on the causal relationship between MDD and aging. Results: MDD was significantly causally associated with increased FI (8IVW = 0.23, 95 % CI = 0.18 to 0.28, p = 1.20 x 10-17), shorter TL (8IVW = -0.04, 95 % CI = -0.07 to -0.01, p = 0.01), and decreased ALM (8IVW = -0.07, 95 % CI = -0.11 to -0.03, p = 3.54 x 10-4). The mediation analysis through two-step MR revealed smoking initiation (9.09 %), hypertension (6.67 %) and heart failure (5.36 %) mediated the causal effect of MDD on FI. Additionally, alcohol use disorders and alcohol dependence on the causal relationship between MDD and TL were found to be 17.52 % and 17.13 % respectively. Limitations: Confounding, statistical power, and Euro-centric focus limit generalization. Conclusion: Overall, individuals with MDD may be at a higher risk of experiencing premature aging, and this risk is partially influenced by the pathways involving smoking, alcohol use, and cardiovascular health. It underscores the importance of early intervention and comprehensive health management in individuals with MDD to promote healthy aging and overall well-being.