DNA methylation-derived age acceleration reveals neurodevelopmental and stress-linked pathways in depression and...

Major Depressive Disorder (MDD) is associated with markedly increased risk of premature mortality, including suicide, yet the biological mechanisms linking depression to reduced lifespan remain poorly understood. Emerging evidence suggests that accelerated biological aging, as measured by DNA methylation-based epigenetic clocks, is a key contributor to this mortality gap.

We examined epigenetic aging in the dorsolateral prefrontal cortex (dlPFC) from individuals who died by suicide (MDD + S) or by causes other than suicide, using multiple DNA methylation clocks (Horvath, Hannum, and GrimAge), providing a direct and biologically meaningful measure of neural aging. For each age acceleration, we used DMRcate to identify differentially methylated regions (DMR) with at least 10 CpGs, an FDR <0.05, and a 5% methylation difference.

All clocks exhibited strong correlations with chronological age, with GrimAge showing the highest concordance (r = 0.96, p < 2 × 10^-16). In covariate-adjusted regression models across different epigenetic age acceleration measures, group was significantly associated with AgeAccelGrim, and substance abuse was also a significant predictor. DMRs associated with high versus low epigenetic age acceleration identified clock-specific and overlapping genomic loci, enriched in pathways governing neural precursor proliferation, Rho-GTPase signaling, and smoothened (Hedgehog) pathway regulation.

The findings indicate that accelerated or dysregulated epigenetic aging in depression and suicide may manifest through alterations in neurodevelopmental and neuroplasticity-related methylation networks, reflecting stress-sensitive biological processes that contribute to mood disorder severity and suicide vulnerability.