Recent evidence suggests a significant overlap in biological changes between major depression and aging across the lifespan. We aim to evaluate the impact of a major depressive episode on the Senescence-Associated Secretory Phenotype (SASP) index, a dynamic secretory molecular pattern indicative of cellular senescence. We also tested the potential moderators of the association between major depression and the SASP index. We included 1165 young and middle-aged adults (527 with a current major depressive episode (cMDE) and 638 with no lifetime history of depression) from a community-based cohort from the Netherlands. We calculated the SASP index based on a previously developed composite index involving 19 biomarkers. cMDE had higher SASP index values (t(1163) = 2.93, p = 0.003) compared to controls in the univariate analysis. After controlling for sociodemographic and somatic health covariates, there was no significant association between cMDE and SASP index (F(1,1158) = 1.09, p = 0.29). Those with the most severe depressive episodes had significantly higher SASP indices compared to those with mild-to-moderate cMDE and controls (F(2,1162) = 6.73, p = 0.001). We found a significant interaction between cMDE and overweight (F(1,1164) = 5.1, p = 0.028): those with comorbid cMDE and overweight had the highest SASP index. Our study demonstrated a complex interaction between cMDE and medical morbidity, especially overweight, on the SASP index, suggesting that their coexistence aggravate age-related biological processes. Moreover, higher SASP index can be a biomarker for more severe depressive episodes.