A DNA methylation clock associated with age-related illnesses and mortality is accelerated in men with combat PTSD

Abstract

DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites predictably change with age and can be used to derive "epigenetic age", an indicator of biological age, as opposed to merely chronological age. A relatively new estimator, called "DNAm GrimAge", is notable for its superior predictive ability in older populations regarding numerous age-related metrics like time-to-death, time-to-coronary heart disease, and time-to-cancer. PTSD is associated with premature mortality and frequently has comorbid physical illnesses suggestive of accelerated biological aging. This is the first study to assess DNAm GrimAge in PTSD patients. We investigated the acceleration of GrimAge relative to chronological age, denoted "AgeAccelGrim" in combat trauma-exposed male veterans with and without PTSD using crosssectional and longitudinal data from two independent well-characterized veteran cohorts. In both cohorts, AgeAccelGrim was significantly higher in the PTSD group compared to the control group (N = 162, 1.26 vs −0.57, p = 0.001 and N = 53, 0.93 vs −1.60 Years, p = 0.008), suggesting accelerated biological aging in both cohorts with PTSD. In 3-year follow-up study of individuals initially diagnosed with PTSD (N = 26), changes in PTSD symptom severity were correlated with AgeAccelGrim changes (r = 0.39, p = 0.049). In addition, the loss of CD28 cell surface markers on CD8 + T cells, an indicator of T-cell senescence/exhaustion that is associated with biological aging, was positively correlated with AgeAccelGrim, suggesting an immunological contribution to the accelerated biological aging. Overall, our findings delineate cellular correlates of biological aging in combat-related PTSD, which may help explain the increased medical morbidity and mortality seen in this disease. Members of the PTSD Systems Biology Consortium are listed in Supplementary information.

PTSD is associated with accelerated transcriptional aging in World Trade Center responders

“…A possible explanation for this finding is that Horvath's method is a multi-tissue calculator trained across multiple non-cancer and cell lines, whereas the other three DNAm age calculators were trained on blood samples. Our study also replicated the findings of the two recent studies which showed that GrimAge age acceleration was significantly associated with PTSD diagnosis 21,22 . GrimAge was constructed based on CpGs associated with smoking and plasma proteins previously found to predict mortality or morbidity, and has been shown to outperform its predecessors in mortality prediction 17 .…”

“…GrimAge was constructed based on CpGs associated with smoking and plasma proteins previously found to predict mortality or morbidity, and has been shown to outperform its predecessors in mortality prediction 17 . Taken together, the findings from these three PTSD studies (including the current study) 21,22 suggest that GrimAge is a powerful epigenetic age predictor in PTSD.…”

“…Specifically, Katrinli et al 21 found that GrimAge age acceleration was significantly higher in current and lifetime PTSD compared to control, however the results using other DNAm age predictors were not reported. Yang et al 22 found that both GrimAge and Horvath age acceleration were significantly higher in PTSD compared to control, however the results were not significant for Hannum or PhenoAge age acceleration. The authors also reported significant positive correlations between changes in GrimAge age acceleration and changes in PTSD symptom severity in a subset of participants with PTSD at baseline, however the correlation was not significant in a subset that included participants without PTSD at baseline.…”

“…Additionally, using Horvath's calculator, Mehta et al 11 did not find a significant association between DNAm age acceleration and PTSD diagnosis or severity. Two recent studies in (1) African American urban population using an expanded sample size 21 and (2) male veterans 22 showed significant association between GrimAge age acceleration and PTSD. Specifically, Katrinli et al 21 found that GrimAge age acceleration was significantly higher in current and lifetime PTSD compared to control, however the results using other DNAm age predictors were not reported.…”

Epigenetic biotypes of post-traumatic stress disorder in war-zone exposed veteran and active duty males

“…DNA methylation (DNAm) is a cellular process of epigenetic regulation employed by cells to control gene expression without altering the genetic sequence. Commercial epigenome-wide arrays (Illumina series) have been proven to be highly reproducible and yielded the identification of DNAm markers that can be accurate and stable enough to estimate white blood cell composition [13], smoking history [14], and age [15][16][17]. Moreover, there is growing evidence that epigenetic processes play an important role in the etiology of psychological disorders [18] and PTSD [19][20][21][22].…”