Biological aging may contribute to the pathogenesis of major depressive disorder (MDD). However, whether and how peripheral transcriptomic aging increases the risk of MDD onset remains unclear.

Transcriptomic age was estimated using peripheral blood RNA sequencing data from 141 individuals with MDD and 134 healthy controls. The residuals of transcriptomic age regressed on chronological age were calculated to indicate transcriptomic aging acceleration. Enrichment analysis was performed to explore potential biological mechanisms underlying aging- and MDD-associated transcriptomic alterations. Associations between transcriptomic aging and clinical, neurocognitive, environmental, genetic, and neuroimaging phenotypes were examined.

Participants with MDD exhibited significantly accelerated transcriptomic aging both before (t = 2.06, P = 0.040) and after adjusting for chronological age and sex (t = 3.72, P < 0.001). Enrichment analysis revealed shared terms in innate immune-related inflammation, ribosome biogenesis, and mitochondrial energy metabolism, while telomere length maintenance was specifically enriched in aging but not in MDD. No significant associations were found between transcriptomic aging and clinical symptoms, neurocognitive functions, childhood trauma exposure, or polygenic risk score. Neuroimaging analyses demonstrated that transcriptomic aging was associated with structural (t = −3.30, P = 0.001) and functional (t = 2.64, P = 0.009) alterations in the right insular cortex. Further analyses indicated that insular abnormalities partially mediated the impact of transcriptomic aging on MDD vulnerability.

Transcriptomic aging may represent a novel risk factor for MDD. Disruption in the insular cortex may serve as a critical neural substrate through which accelerated transcriptomic aging increases vulnerability to MDD.