PTSD and epigenetic aging: a longitudinal meta-analysis

Xiang Zhao¹, Seyma Katrinli², Beth M McCormick^{3

4}, Mark W Miller^{3

4}, Nicole R Nugent^{5

6

7}, Agaz H Wani⁸, Anthony S Zannas^{9

10

11

12}, Allison E Aiello¹³, Dewleen G Baker¹⁴, Marco P Boks¹⁵, Chia-Yen Chen¹⁶, Catherine B Fortier^{17

18

19}, Joel Gelernter^{20

21}, Elbert Geuze^{22

23}, Karestan C Koenen^{24

25

26}, Sarah D Linnstaedt^{12

27}, Jurjen J Luykx^{28

29

30}, Adam X Maihofer^{14

31

32}, Samuel A McLean^{11

12}, William P Milberg^{17

18

19}, Andrew Ratanatharathorn^{25

33}, Kerry J Ressler^{17

34

35}, Victoria B Risbrough^{14

31

32}, Bart P F Rutten^{24

36}, Jordan W Smoller^{24

26

37}, Murray B Stein^{14

38

39}, Robert J Ursano⁴⁰, Eric Vermetten^{41

42}, Christiaan H Vinkers^{28

43

44}, Erin B Ware⁴⁵, Derek E Wildman⁸, Ying Zhao^{12

27}; PGC-PTSD Epigenetics Workgroup; Mark W Logue^{1

3

4

46}, Caroline M Nievergelt^{14

31

32}, Alicia K Smith^{2

34

47}, Monica Uddin⁸, Erika J Wolf^{3

4}

Affiliations

¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
² Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA.
³ Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁴ National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.
⁵ Department of Emergency Medicine, Alpert Brown Medical School, Providence, RI, USA.
⁶ Department of Pediatrics, Alpert Brown Medical School, Providence, RI, USA.
⁷ Department of Psychiatry and Human Behavior, Alpert Brown Medical School, Providence, RI, USA.
⁸ Genomics Program, University of South Florida College of Public Health, Tampa, FL, USA.
⁹ Carolina Stress Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Institute for Trauma Recovery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Epidemiology, Robert N Butler Columbia Aging Center, Columbia University, New York, NY, USA.
¹⁴ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
¹⁵ Department of Psychiatry, Brain Center University Medical Center Utrecht, Utrecht, Netherlands.
¹⁶ Translational Sciences, Biogen Inc., Cambridge, MA, USA.
¹⁷ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
¹⁸ Geriatric Research, Education and Clinical Center (GRECC), VA Boston Healthcare System, Boston, MA, USA.
¹⁹ Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS), VA Boston Healthcare System, Boston, MA, USA.
²⁰ Psychiatry Service, VA Connecticut Healthcare Center, West Haven, CT, USA.
²¹ Department of Genetics and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
²² Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, Netherlands.
²³ Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, Netherlands.
²⁴ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
²⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁶ Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA.
²⁷ Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁸ Amsterdam Neuroscience Research Institute, Mood, Anxiety, Psychosis, Stress & Sleep Program, Amsterdam University Medical Center, Amsterdam, Netherlands.
²⁹ Mental Health Program, Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Amsterdam, Netherlands.
³⁰ Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, Netherlands.
³¹ Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
³² Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
³³ Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA.
³⁴ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
³⁵ Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA.
³⁶ School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht Universitair Medisch Centrum, Maastricht, Netherlands.
³⁷ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
³⁸ School of Public Health, University of California San Diego, La Jolla, CA, USA.
³⁹ Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
⁴⁰ Department of Psychiatry, Center for the Study of Traumatic Stress, Uniformed Services University of Health Sciences, Bethesda, MD, USA.
⁴¹ Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands.
⁴² Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
⁴³ Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
⁴⁴ Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
⁴⁵ Survey Research Center, University of Michigan, Ann Arbor, MI, USA.
⁴⁶ Department of Biomedical Genetics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁴⁷ Department of Human Genetics, Emory University, Atlanta, GA, USA.

PMID: 40366073
PMCID: PMC12094664
DOI: 10.1017/S0033291725000558

Meta-Analysis

PTSD and epigenetic aging: a longitudinal meta-analysis

Xiang Zhao et al. Psychol Med. 2025.

. 2025 May 14:55:e142.

doi: 10.1017/S0033291725000558.

Authors

Affiliations

¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
² Department of Gynecology and Obstetrics, Emory University, Atlanta, GA, USA.
³ Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁴ National Center for PTSD, VA Boston Healthcare System, Boston, MA, USA.
⁵ Department of Emergency Medicine, Alpert Brown Medical School, Providence, RI, USA.
⁶ Department of Pediatrics, Alpert Brown Medical School, Providence, RI, USA.
⁷ Department of Psychiatry and Human Behavior, Alpert Brown Medical School, Providence, RI, USA.
⁸ Genomics Program, University of South Florida College of Public Health, Tampa, FL, USA.
⁹ Carolina Stress Initiative, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Institute for Trauma Recovery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Department of Epidemiology, Robert N Butler Columbia Aging Center, Columbia University, New York, NY, USA.
¹⁴ Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
¹⁵ Department of Psychiatry, Brain Center University Medical Center Utrecht, Utrecht, Netherlands.
¹⁶ Translational Sciences, Biogen Inc., Cambridge, MA, USA.
¹⁷ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
¹⁸ Geriatric Research, Education and Clinical Center (GRECC), VA Boston Healthcare System, Boston, MA, USA.
¹⁹ Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS), VA Boston Healthcare System, Boston, MA, USA.
²⁰ Psychiatry Service, VA Connecticut Healthcare Center, West Haven, CT, USA.
²¹ Department of Genetics and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
²² Netherlands Ministry of Defence, Brain Research and Innovation Centre, Utrecht, Netherlands.
²³ Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, Netherlands.
²⁴ Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, MA, USA.
²⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
²⁶ Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA.
²⁷ Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁸ Amsterdam Neuroscience Research Institute, Mood, Anxiety, Psychosis, Stress & Sleep Program, Amsterdam University Medical Center, Amsterdam, Netherlands.
²⁹ Mental Health Program, Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Amsterdam, Netherlands.
³⁰ Department of Psychiatry, Amsterdam University Medical Center, Amsterdam, Netherlands.
³¹ Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
³² Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
³³ Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA.
³⁴ Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
³⁵ Division of Depression and Anxiety, McLean Hospital, Belmont, MA, USA.
³⁶ School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht Universitair Medisch Centrum, Maastricht, Netherlands.
³⁷ Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
³⁸ School of Public Health, University of California San Diego, La Jolla, CA, USA.
³⁹ Psychiatry Service, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
⁴⁰ Department of Psychiatry, Center for the Study of Traumatic Stress, Uniformed Services University of Health Sciences, Bethesda, MD, USA.
⁴¹ Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands.
⁴² Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
⁴³ Department of Anatomy and Neurosciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
⁴⁴ Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
⁴⁵ Survey Research Center, University of Michigan, Ann Arbor, MI, USA.
⁴⁶ Department of Biomedical Genetics, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁴⁷ Department of Human Genetics, Emory University, Atlanta, GA, USA.

PMID: 40366073
PMCID: PMC12094664
DOI: 10.1017/S0033291725000558

Abstract

Background: Posttraumatic stress disorder (PTSD) has been associated with advanced epigenetic age cross-sectionally, but the association between these variables over time is unclear. This study conducted meta-analyses to test whether new-onset PTSD diagnosis and changes in PTSD symptom severity over time were associated with changes in two metrics of epigenetic aging over two time points.

Methods: We conducted meta-analyses of the association between change in PTSD diagnosis and symptom severity and change in epigenetic age acceleration/deceleration (age-adjusted DNA methylation age residuals as per the Horvath and GrimAge metrics) using data from 7 military and civilian cohorts participating in the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (total N = 1,367).

Results: Meta-analysis revealed that the interaction between Time 1 (T1) Horvath age residuals and new-onset PTSD over time was significantly associated with Horvath age residuals at T2 (meta β = 0.16, meta p = 0.02, p-adj = 0.03). The interaction between T1 Horvath age residuals and changes in PTSD symptom severity over time was significantly related to Horvath age residuals at T2 (meta β = 0.24, meta p = 0.05). No associations were observed for GrimAge residuals.

Conclusions: Results indicated that individuals who developed new-onset PTSD or showed increased PTSD symptom severity over time evidenced greater epigenetic age acceleration at follow-up than would be expected based on baseline age acceleration. This suggests that PTSD may accelerate biological aging over time and highlights the need for intervention studies to determine if PTSD treatment has a beneficial effect on the aging methylome.

Keywords: DNA methylation; PTSD; accelerated aging; longitudinal; meta-analysis.

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Figures

**Figure 1.**
Forest plot for the effect of the interaction term reflecting T1 Horvath DNAm age residuals by new-onset PTSD diagnosis on T2 Horvath DNAm age residuals (controlling for all other main effects in the model).

**Figure 2.**
Forest plot for the effect of the interaction term reflecting T1 Horvath DNAm age residuals by change in harmonized PTSD symptom severity on T2 Horvath DNAm age residuals (controlling for all other main effects in the model).

See this image and copyright information in PMC

References

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PTSD and epigenetic aging: a longitudinal meta-analysis

Affiliations

PTSD and epigenetic aging: a longitudinal meta-analysis

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

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