Association of PTSD symptom trajectories with accelerated pace of epigenetic aging in U.S. military Veterans

Abstract: Background: Mental disorders such as posttraumatic stress disorder (PTSD) are prevalent among U.S. military veterans. PTSD is often a chronic and disabling condition characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and heightened arousal and reactivity. It is associated with poor mental and physical health outcomes, as well as accelerated biological (i.e., epigenetic) aging, the latter of which may serve as a mechanism linking PTSD to adverse health effects and premature mortality. While numerous studies have demonstrated cross-sectional associations between PTSD and accelerated epigenetic aging, the longitudinal impact of PTSD symptom trajectories on the pace of epigenetic aging remains poorly understood. Methods: We conducted a 10-year prospective study of 156 European American male U.S. military veterans and assessed PTSD symptoms at five time points over the study period. Saliva samples were collected at baseline and again at the 10-year follow-up for DNA methylation (DNAm) analysis. Epigenetic aging was estimated using the DNA Methylation Age Calculation for DNAm GrimAge2. PTSD symptom trajectories were identified using the “Traj” R package. The pace of epigenetic aging (PACE) was calculated as the difference in accelerated GrimAge2 between 2011 and 2021 (AccelGrimAge2021 - AccelGrimAge2011). Multivariable linear regression followed by a stepwise regression analyses were conducted to assess the relationship between PTSD symptom trajectories and PACE, adjusting for buccal cells CD4+ T cells, and monocytes. Additional cell types were removed to avoid multicollinearity. Results: Three distinct PTSD symptom trajectories emerged: stable/no change from baseline (N=48), increasing symptoms over time (N=36), and decreasing symptoms (N=10). A significant positive association was observed between the increasing PTSD symptom trajectory and GrimAge2 PACE (estimate=1.67,p=0.007), indicating that veterans with worsening PTSD symptoms over the 10-year period exhibited a more accelerated pace of biological aging relative to the stable condition. No significant association was identified for decreasing symptoms. Conclusion: Increases in PTSD symptoms over a 10-year period are associated with an accelerated pace of epigenetic aging in U.S. military veterans. These results underscore the biological toll of chronic stress and highlight the importance of early and sustained interventions for PTSD. Further research is needed to elucidate causal mechanisms and evaluate whether evidence-based treatments for PTSD mitigate accelerated epigenetic aging.

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