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

Molecular Psychiatry volume 26, pages 4999–5009 (2021)Cite this article

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A Correction to this article was published on 10 July 2020

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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 cross-sectional 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.

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Fig. 1: Cross-sectional and longitudinal association of AgeAccelGrim with PTSD diagnosis and symptom severity.
Fig. 2: Association of AgeAccelGrim and CD8 + CD28− T cells.
Fig. 3: Correlations of AgeAccelGrim with other epigenetic age clocks.

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Data availability

All datasets for selected cohorts are available with permission through the SysBioCube, at https://sysbiocube-abcc.ncifcrf.gov.

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Acknowledgements

This work was supported by funding from the U.S. Army Research Office, through award numbers W911NF-13-1-0376, W911NF-17-2-0086, W911NF-18-2-0056, by the Army Research Laboratory under grant number W911NF-17-1-0069, and from the U.S. Department of Defense under W81XWH-10-1-0021, W81XWH-09-2-0044, and W81XWH-14-1-0043. Additional members of the PTSD Systems Biology Consortium are acknowledged in Supplementary information Appendix.

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Author notes

  1. These authors jointly supervised this work: Rasha Hammamieh, Synthia H. Mellon, Owen M. Wolkowitz

Authors and Affiliations

  1. Medical Readiness Systems Biology, Walter Reed Army Institute of Research, Silver Spring, MD, USA

    Ruoting Yang, Aarti Gautam, Marti Jett & Rasha Hammamieh

  2. Weill Institute for Neurosciences and Department of Psychiatry, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA, USA

    Gwyneth W. Y. Wu, Victor I. Reus & Owen M. Wolkowitz

  3. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands

    Josine E. Verhoeven

  4. Institute of Behavioral Science in Medicine & Department of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea

    Jee In Kang

  5. James J Peters VA Medical Center, Bronx, NY, USA

    Janine D. Flory & Rachel Yehuda

  6. Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Janine D. Flory & Rachel Yehuda

  7. Department of Psychiatry, New York University School of Medicine, New York, NY, USA

    Duna Abu-Amara & Charles R. Marmar

  8. Institute for Systems Biology, Seattle, WA, USA

    Leroy Hood

  9. John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, MA, USA

    Francis J. Doyle III

  10. Department of OB-GYN and Reproductive Sciences, UCSF School of Medicine, San Francisco, CA, USA

    Synthia H. Mellon

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PTSD Systems Biology Consortium

Contributions

RY, GWYW, RH, OMW, and SHM designed research; all authors performed research and proofed or contributed to the manuscript; RY and GWYW analyzed data; and RY, GWYW, SHM, and OMW wrote the paper.

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Correspondence to Ruoting Yang.

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Members of the PTSD Systems Biology Consortium are listed in Supplementary information.

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Yang, R., Wu, G.W.Y., Verhoeven, J.E. et al. A DNA methylation clock associated with age-related illnesses and mortality is accelerated in men with combat PTSD. Mol Psychiatry 26, 4999–5009 (2021). https://doi.org/10.1038/s41380-020-0755-z

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