Post-traumatic stress disorder moderates the association between BrainAge acceleration and GrimAge acceleration.

Abstract

Individuals with post-traumatic stress disorder (PTSD) are at higher risk for age-related physical comorbidities, such as cardiovascular disorders, and exhibit accelerated epigenetic and brain aging. The present study examined PTSD as a moderator of the association between DNA methylation (DNAm)-based systemic aging (GrimAge, PhenoAge) and brain aging, indexed by MRI-based and DNAm-derived BrainAge estimates, in 174 lifetime PTSD cases and 138 trauma-exposed controls from four cohorts. Peripheral DNAm assayed with the MethylationEPIC BeadChip was used to calculate epigenetic age acceleration (EAA), using multiple clocks (GrimAge, PC GrimAge, PC PhenoAge), and DNAm-based BrainAge acceleration. Neuroimaging-derived BrainAge estimates were calculated with T1-weighted MRI scans that were processed using FreeSurfer v5.3 and run on BrainageR. Meta-analysis of the four cohorts examined the interactions between lifetime PTSD and EAA on BrainAge acceleration. EAA measures were intercorrelated (0.43 < rmeta < 0.84), but MRI-based BrainAge acceleration was not correlated with any EAA estimate (rmeta = 0.03, p = 0.56). Lifetime PTSD moderated the association between PC GrimAge acceleration and DNAm-based BrainAge acceleration (Standardized Mean Difference [SMD] = 0.84 [95% CI: -1.51, -0.17], p = 0.01), and the association between GrimAge acceleration and MRI-based BrainAge acceleration (SMD = -0.40 [95% CI: -0.74, -0.07], p = 0.02). Stratified analyses confirmed that the positive associations between GrimAge acceleration and BrainAge acceleration were attenuated or absent in PTSD cases relative to trauma-exposed controls. Trauma-exposed individuals represent a vulnerable population who may benefit from personalized approaches guided by multi-modal measures of biological aging to prevent and manage modifiable medical disease processes.