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 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. Access through your institution Buy

or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and

online access $259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes

which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY

OTHERS DNA METHYLATION GRIMAGE ACCELERATION IN US MILITARY VETERANS WITH PTSD Article 01 February 2023 PTSD IS ASSOCIATED WITH ACCELERATED TRANSCRIPTIONAL AGING IN WORLD TRADE CENTER

RESPONDERS Article Open access 24 May 2021 POSTTRAUMATIC STRESS DISORDER, TRAUMA, AND ACCELERATED BIOLOGICAL AGING AMONG POST-9/11 VETERANS Article Open access 06 January 2024 DATA

AVAILABILITY All datasets for selected cohorts are available with permission through the SysBioCube, at https://sysbiocube-abcc.ncifcrf.gov. CHANGE HISTORY * _ 10 JULY 2020 A Correction to

this paper has been published: https://doi.org/10.1038/s41380-020-0837-y _ REFERENCES * McLeay SC, Harvey W, Romaniuk NM, Crawford D, Colquhoun DM, Young R, et al. Physical comorbidities of

post-traumatic stress disorder in Australian Vietnam War veterans. Med J Aust. 2017;206:251–7. Article  Google Scholar  * Wolf EJ, Schnurr PP. Posttraumatic stress disorder-related

cardiovascular disease and accelerated cellular aging. Psychiatr Ann. 2016;46:527–32. Article  Google Scholar  * Cohen BE, Marmar C, Ren L, Bertenthal D, Seal KH. Association of

cardiovascular risk factors with mental health diagnoses in Iraq and Afghanistan war veterans using VA health care. JAMA. 2009;302:489–92. Article  CAS  Google Scholar  * Schlenger WE, Corry

NH, Williams CS, Kulka RA, Mulvaney-Day N, DeBakey S, et al. A prospective study of mortality and trauma-related risk factors among a nationally representative sample of vietnam veterans.

Am J Epidemiol. 2015;182:980–90. PubMed  Google Scholar  * Lohr JB, Palmer BW, Eidt CA, Aailaboyina S, Mausbach BT, Wolkowitz OM, et al. Is post-traumatic stress disorder associated with

premature senescence? A review of the literature. Am J Geriatr Psychiatry. 2015;23:709–25. Article  Google Scholar  * Wolf EJ, Morrison FG. Traumatic stress and accelerated cellular aging:

from epigenetics to cardiometabolic disease. Curr psychiatry Rep. 2017;19:75. Article  Google Scholar  * Darrow SM, Verhoeven JE, Révész D, Lindqvist D, Penninx BWJH, Delucchi KL, et al. The

Association between psychiatric disorders and telomere length: a meta-analysis involving 14,827 persons. Psychosom Med. 2016;78:776–87. Article  Google Scholar  * Aiello AE, Dowd JB,

Jayabalasingham B, Feinstein L, Uddin M, Simanek AM, et al. PTSD is associated with an increase in aged T cell phenotypes in adults living in Detroit. Psychoneuroendocrinology.

2016;67:133–41. Article  CAS  Google Scholar  * Jylhävä J, Pedersen NL, Hägg S. Biological age predictors. EBioMed. 2017;21:29–36. Article  Google Scholar  * Weng N-P, Akbar AN, Goronzy J.

CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009;30:306–12. Article  CAS  Google Scholar  * Wolf EJ, Maniates H, Nugent N, Maihofer AX,

Armstrong D, Ratanatharathorn A, et al. Traumatic stress and accelerated DNA methylation age: a meta-analysis. Psychoneuroendocrinology. 2018;92:123–34. Article  CAS  Google Scholar  *

Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S, et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell. 2013;49:359–67. Article  CAS 

Google Scholar  * Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:R115–R115. Article  Google Scholar  * Levine ME, Lu AT, Quach A, Chen BH, Assimes TL,

Bandinelli S, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging. 2018;10:573–91. Article  Google Scholar  * Lu AT, Quach A, Wilson JG, Reiner AP, Aviv A, Raj K, et

al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging. 2019;11:303–27. Article  CAS  Google Scholar  * Horvath S, Oshima J, Martin GM, Lu AT, Quach A, Cohen H, et al.

Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging. 2018;10:1758–75. Article  CAS  Google Scholar  * Marioni RE, Shah S,

McRae AF, Chen BH, Colicino E, Harris SE, et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 2015;16:25. Article  Google Scholar  * Dean KR,

Hammamieh R, Mellon SH, Abu-Amara D, Flory JD, Guffanti G, et al. Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder. Mol

Psychiatry. 2019;1–13. * Flory JD, Yehuda R. Comorbidity between post-traumatic stress disorder and major depressive disorder: alternative explanations and treatment considerations.

Dialogues Clin Neurosci. 2015;17:141–50. Article  Google Scholar  * Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, Nelson HH, et al. DNA methylation arrays as surrogate

measures of cell mixture distribution. BMC Bioinforma. 2012;13:86. Article  Google Scholar  * Chen X, Liu Q, Xiang AP. CD8+CD28- T cells: not only age-related cells but a subset of

regulatory T cells. Cell Mol Immunol. 2018;15:734–6. Article  CAS  Google Scholar  * Verhoeven JE, Yang R, Wolkowitz OM, Bersani FS, Lindqvist D, Mellon SH, et al. Epigenetic age in male

combat-exposed war veterans: associations with posttraumatic stress disorder status. Mol Neuropsychiatry. 2018;4:90–99. Article  CAS  Google Scholar  * Kievit R, Frankenhuis WE, Waldorp L,

Borsboom D. Simpson’s paradox in psychological science: a practical guide. Front Psychol. 2013;4:513. Article  Google Scholar  * Wolf EJ, Bovin MJ, Green JD, Mitchell KS, Stoop TB, Barretto

KM, et al. Longitudinal associations between post-traumatic stress disorder and metabolic syndrome severity. Psychological Med. 2016;46:2215–26. Article  CAS  Google Scholar  * Ahmadi N,

Hajsadeghi F, Mirshkarlo HB, Budoff M, Yehuda R, Ebrahimi R. Post-traumatic stress disorder, coronary atherosclerosis, and mortality. Am J Cardiol. 2011;108:29–33. Article  Google Scholar  *

Yaffe K, Vittinghoff E, Lindquist K, Barnes D, Covinsky KE, Neylan T, et al. Posttraumatic stress disorder and risk of dementia among US veterans. Arch Gen Psychiatry. 2010;67:608–13.

Article  Google Scholar  * Wolf EJ, Logue MW, Stoop TB, Schichman SA, Stone A, Sadeh N, et al. Accelerated DNA methylation age: associations with PTSD and mortality. Psychosomatic Med.

2017;80:42–8. Article  Google Scholar  * Chou JP, Effros RB. T cell replicative senescence in human aging. Curr Pharm Des. 2013;19:1680–98. CAS  PubMed  PubMed Central  Google Scholar  *

Cesari M, Pahor M, Incalzi RA. REVIEW: plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cardiovascular

Therapeutics. 2010;28:e72–e91. Article  CAS  Google Scholar  * Ferguson TW, Komenda P, Tangri N. Cystatin C as a biomarker for estimating glomerular filtration rate. Curr Opin Nephrol

Hypertension. 2015;24:295–300. Article  CAS  Google Scholar  * Levin A, Lan JH. Cystatin C and cardiovascular disease. J Am Coll Cardiol. 2016;68:946. Article  Google Scholar  * Ashutosh,

Chao C, Borgmann K, Brew K, Ghorpade A. Tissue inhibitor of metalloproteinases-1 protects human neurons from staurosporine and HIV-1-induced apoptosis: mechanisms and relevance to

HIV-1-associated dementia. _Cell Death Dis._ 2012; 3:e332. * Song G, Xu S, Zhang H, Wang Y, Xiao C, Jiang T, et al. TIMP1 is a prognostic marker for the progression and metastasis of colon

cancer through FAK-PI3K/AKT and MAPK pathway. J Exp Clin Cancer Res. 2016;35:148. Article  Google Scholar  * Rivera S, Tremblay E, Timsit S, Canals O, Ben-Ari Y, Khrestchatisky M. Tissue

inhibitor of metalloproteinases-1 (TIMP-1) is differentially induced in neurons and astrocytes after seizures: evidence for developmental, immediate early gene, and lesion response. J

Neurosci. 1997;17:4223. Article  CAS  Google Scholar  * Mills JA, Beach SRH, Dogan M, Simons RL, Gibbons FX, Long JD, et al. A direct comparison of the relationship of epigenetic aging and

epigenetic substance consumption markers to mortality in the framingham heart study. Genes (Basel). 2019;10:51. Article  Google Scholar  * Stejskalova L, Dvorak Z, Pavek P. Endogenous and

exogenous ligands of aryl hydrocarbon receptor: current state of art. Curr Drug Metab. 2011;12:198–212. Article  CAS  Google Scholar  * Hammamieh R, Chakraborty N, Gautam A, Muhie S, Yang R,

Donohue D, et al. Whole-genome DNA methylation status associated with clinical PTSD measures of OIF/OEF veterans. Transl Psychiatry. 2017;7:e1169. Article  CAS  Google Scholar  * Triche TJ

Jr, Weisenberger DJ, Van Den Berg D, Laird PW, Siegmund KD. Low-level processing of Illumina Infinium DNA methylation beadarrays. Nucleic Acids Res. 2013;41:e90–e90. Article  CAS  Google

Scholar  * Blom G. Statistical estimates and transformed beta-variables. New York, Stockholm: J. Wiley & sons; Almqvist & Wiksell; 1958. Google Scholar  * Quach A, Levine ME, Tanaka

T, Lu AT, Chen BH, Ferrucci L, et al. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging. 2017;9:419–46. Article  CAS  Google Scholar  Download references

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. AUTHOR INFORMATION Author notes * These authors jointly supervised this work: Rasha Hammamieh, Synthia H. Mellon,

Owen M. Wolkowitz AUTHORS AND AFFILIATIONS * Medical Readiness Systems Biology, Walter Reed Army Institute of Research, Silver Spring, MD, USA Ruoting Yang, Aarti Gautam, Marti Jett & 

Rasha Hammamieh * 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 * Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands Josine

E. Verhoeven * Institute of Behavioral Science in Medicine & Department of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea Jee In Kang * James J Peters VA Medical

Center, Bronx, NY, USA Janine D. Flory & Rachel Yehuda * Icahn School of Medicine at Mount Sinai, New York, NY, USA Janine D. Flory & Rachel Yehuda * Department of Psychiatry, New

York University School of Medicine, New York, NY, USA Duna Abu-Amara & Charles R. Marmar * Institute for Systems Biology, Seattle, WA, USA Leroy Hood * John A. Paulson School of

Engineering & Applied Sciences, Harvard University, Cambridge, MA, USA Francis J. Doyle III * Department of OB-GYN and Reproductive Sciences, UCSF School of Medicine, San Francisco, CA,

USA Synthia H. Mellon Authors * Ruoting Yang View author publications You can also search for this author inPubMed Google Scholar * Gwyneth W. Y. Wu View author publications You can also

search for this author inPubMed Google Scholar * Josine E. Verhoeven View author publications You can also search for this author inPubMed Google Scholar * Aarti Gautam View author

publications You can also search for this author inPubMed Google Scholar * Victor I. Reus View author publications You can also search for this author inPubMed Google Scholar * Jee In Kang

View author publications You can also search for this author inPubMed Google Scholar * Janine D. Flory View author publications You can also search for this author inPubMed Google Scholar *

Duna Abu-Amara View author publications You can also search for this author inPubMed Google Scholar * Leroy Hood View author publications You can also search for this author inPubMed Google

Scholar * Francis J. Doyle III View author publications You can also search for this author inPubMed Google Scholar * Rachel Yehuda View author publications You can also search for this

author inPubMed Google Scholar * Charles R. Marmar View author publications You can also search for this author inPubMed Google Scholar * Marti Jett View author publications You can also

search for this author inPubMed Google Scholar * Rasha Hammamieh View author publications You can also search for this author inPubMed Google Scholar * Synthia H. Mellon View author

publications You can also search for this author inPubMed Google Scholar * Owen M. Wolkowitz View author publications You can also search for this author inPubMed Google Scholar CONSORTIA

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. CORRESPONDING AUTHOR Correspondence to Ruoting Yang. ETHICS DECLARATIONS CONFLICT OF INTEREST The authors declare that they have no conflict

of interest. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Members of the

PTSD Systems Biology Consortium are listed in Supplementary information. SUPPLEMENTARY INFORMATION SUPPLEMENTAL MATERIAL SUPPORTING DATASET 1 SUPPORTING DATASET 2 RIGHTS AND PERMISSIONS

Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 29 January 2020 * Revised: 20 March 2020 *

Accepted: 23 April 2020 * Published: 07 May 2020 * Issue Date: September 2021 * DOI: https://doi.org/10.1038/s41380-020-0755-z SHARE THIS ARTICLE Anyone you share the following link with

will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt

content-sharing initiative