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

Abstract

Posttraumatic stress disorder (PTSD) is associated with shortened lifespan and healthspan, which suggests accelerated aging. Emerging evidence suggests that methylation age may be accelerated in PTSD. It is important to examine whether transcriptional age is also accelerated because transcriptome is highly dynamic, associated with age-related outcomes, and may offer greater insight into the premature aging in PTSD. This study is the first reported investigation of the relationship between transcriptional age and PTSD. Using RNA-Seq data from our previous study on 324 World Trade Center responders (201 never had PTSD, 81 with current PTSD, and 42 with past PTSD), as well as a transcriptional age calculator (RNAAgeCalc) recently developed by our group, we found that responders with current PTSD, compared with responders without a PTSD diagnosis, showed accelerated transcriptional aging (p = 0.0077) after adjustment for chronological age and race. We compared our results to the epigenetic aging results computed from several epigenetic clock calculators on matching DNA methylation data. GrimAge methylation age acceleration was also associated with PTSD diagnosis (p = 0.0097), and the results remained significant after adjustment for the proportions of immune cell types. PhenoAge, Hannum, and Horvath methylation age acceleration were not reliably related to PTSD. Both epigenetic and transcriptional aging may provide biological insights into the mechanisms underpinning aging in PTSD.

Fig. 1. Scatter plots comparing the four DNAm ages (Horvath, Hannum, PhenoAge, and GrimAge), transcriptional age and chronological age.

The correlation coefficients between each pair is shown on the upper triangular matrix. All correlation coefficients were significant at p < 0.01.

Fig. 2. Age acceleration versus PTSD diagnosis.

A Box plot comparing transcriptional age acceleration to PTSD diagnosis. B Box plot comparing GrimAge age acceleration to PTSD diagnosis.

Fig. 3. Heat map summarizing the associations between each of the four DNAm age acceleration (column) and PTSD (row) after adjustment for age and race.

The color of each cell represents the magnitude of the standardized coefficient β, whereas asterisks indicate p value ranges, i.e., **p < 0.05; *0.05 < p < 0.1.