Advertisement

Current Psychiatry Reports

, 19:75 | Cite as

Traumatic Stress and Accelerated Cellular Aging: From Epigenetics to Cardiometabolic Disease

  • Erika J. WolfEmail author
  • Filomene G. Morrison
Disaster Psychiatry: Trauma, PTSD, and Related Disorders (MJ Friedman, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Disaster Psychiatry: Trauma, PTSD, and Related Disorders

Abstract

Purpose of Review

The aim of this paper is to review the recent literature on traumatic stress-related accelerated aging, including a focus on cellular mechanisms and biomarkers of cellular aging and on the clinical manifestations of accelerated biological aging.

Recent Findings

Multiple lines of research converge to suggest that PTSD is associated with accelerated aging in the epigenome, and the immune and inflammation systems, and this may be reflected in premature onset of cardiometabolic and cardiovascular disease.

Summary

The current state of research paves the way for future work focused on identifying the peripheral and central biological mechanisms linking traumatic stress to accelerated biological aging and medical morbidity, with an emphasis on processes involved in inflammation, immune functioning, oxidative stress, autonomic arousal, and stress response. Ultimately, such work could help reduce the pace of biological aging and improve health and wellness.

Keywords

Traumatic stress PTSD Accelerated aging Epigenetic clock Inflamm-aging Immunosenescence 

Notes

Acknowledgements

This work was supported in part by the National Institute on Aging of the National Institutes of Health award R03AG051877 to EJW and by Merit Review Award Number I01 CX-001276-01 to EJW from the US Department of Veterans Affairs (VA) Clinical Sciences Research and Development (CSRD) Service. This work was also supported by a Presidential Early Career Award for Scientists and Engineers (PECASE 2013A) to EJW as administered by the US Department of VA Office of Research and Development.

Compliance with Ethical Standards

Conflict of Interest

Erika J. Wolf reports grants from NIA(NIH) (R03AG051877), VA CSR&D Merit Award (I01 CX-001276-01), and PECASE via VA ORD (PECASE 2013A).

Filomene G. Morrison declares no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Da Costa J. On irritable heart. Am J Med Sci. 1871;61:17–52.Google Scholar
  2. 2.
    Mackenzie J. The soldier’s heart. Br Med J. 1916;1(2873):117–9.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Rudolf RD. The irritable heart of soldiers (soldier’s heart). Can Med Assoc J. 1916;6(9):798–810.Google Scholar
  4. 4.
    Wolf EJ, Schnurr PP. PTSD-related cardiovascular disease and accelerated cellular aging. Psychiatr Ann. 2016;46:527–32.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Arenson M, Cohen B. Posttraumatic stress disorder and cardiovascular disease. PTSD Research Quarterly. 2017;28(1):1–9.Google Scholar
  6. 6.
    Dedart EA, Calhoun PS, Watkins LL, Sherwood A, Beckham JC. Posttraumatic stress disorder, cardiovascular, and metabolic disease: a review of the evidence. Ann Behav Med. 2010;39(1):61–78.CrossRefGoogle Scholar
  7. 7.
    Edmondson D, Cohen BE. Posttraumatic stress disorder and cardiovascular disease. Prog Cardiovasc Dis. 2013;55(6):548–56.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bartoli F, Carra G, Crocamo C, Carretta D, Clerici M. Metabolic syndrome in people suffering from posttraumatic stress disorder: a systematic review and meta-analysis. Metab Syndr Relat Disord. 2013;11(5):301–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Blessing EM, Reus V, Mellon SH, Wolkowitz OM, Flory JD, Bierer L, et al. Biological predictors of insulin resistance associated with posttraumatic stress disorder in young military veterans. Psychoneuroendocrinology. 2017;82:91–7.CrossRefPubMedGoogle Scholar
  10. 10.
    • Rosenbaum S, Stubbs B, Ward PB, Stell Z, Lederman O, Vancampfort D. The prevalence and risk of metabolic syndrome and its components among people with posttraumatic stress disorder: a systematic review and meta-analysis. Metabolism. 2015;64(8):926–33. This meta-analysis concluded that the prevalence of metabolic syndrome among individuals with PTSD was near 40%. CrossRefPubMedGoogle Scholar
  11. 11.
    • 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. Psychol Med. 2016;46(10):2215–26. This was the first longitudinal study of the association between PTSD and metabolic syndrome which controlled for baseline metabolic syndrome. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wolf EJ, Sadeh N, Leritz EC, Logue MW, Stoop TB, McGlinchey R, et al. Posttraumatic stress disorder as a catalyst for the association between metabolic syndrome and reduced cortical thickness. Biol Psychiatry. 2016;80(5):363–71.CrossRefPubMedGoogle Scholar
  13. 13.
    NCEP. Executive summary of the third report of the National Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486–97.CrossRefGoogle Scholar
  14. 14.
    Song SW, Chung JH, Rho JS, Lee YA, Lim HK, Kang SG, et al. Regional cortical thickness and subcortical volume changes in patients with metabolic syndrome. Brain Imaging Behav. 2015;9(3):588–96.CrossRefPubMedGoogle Scholar
  15. 15.
    Green E, Fairchild JK, Kinoshita LM, Art Noda MS, Yesavage J. Effects of posttraumatic stress disorder and metabolic syndrome on cognitive aging in veterans. Gerontologist. 2016;56(1):72–81.CrossRefPubMedGoogle Scholar
  16. 16.
    Sumner JA, Hagan K, Grodstein F, Roberts AL, Harel B, Koenen KC. Posttraumatic stress disorder symptoms and cognitive function in a large cohort of middle-aged women. Depress Anxiety. 2017;34(4):356–66.CrossRefPubMedGoogle Scholar
  17. 17.
    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(6):608–13.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Lindemer ER, Salat DH, Leritz EC,McGlinchey RE, Milberg WP. Reduced cortical thickness with increased lifetime burden of PTSD in OEF/OIF Veterans and the impact of comorbid TBI. Neuroimage Clin. 2013;2:601–11.Google Scholar
  19. 19.
    Mohlenhoff BS, O’Donovan A, Weiner MW, Neylan TC. Inflammation, sleep and dementia risk in posttraumatic stress disorder: a review. Curr Psychiatry Rep 2017: in press.Google Scholar
  20. 20.
    Edmondson D, Kronish IM, Shaffer JA, Falzon L, Burg MM. Posttraumatic stress disorder and risk for coronary heart dis­ease: a meta-analytic review. Am Heart J. 2013;166:806–814.Google Scholar
  21. 21.
    Beristianos MH, Yaffe K, Cohen B. Byers AL PTSD and risk of incident cardiovascular disease in aging veterans. Am J Geriatr Psychiatry. 2016;24(3):192–200.CrossRefPubMedGoogle Scholar
  22. 22.
    Vaccarino V, Goldberg J, Rooks C, Shah AJ, Veledar E, Faber TL, et al. Post-traumatic stress disorder and incidence of coronary heart disease: a twin study. J Am Coll Cardiol. 2013;62(11):970–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Roy SS, Foraker RE, Girton RA, Mansfield AJ. Posttraumatic stress disorder and incident heart failure among a community-based sample of US veterans. Am J Public Health. 2015;105(4):757–63.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sumner JA, Kubzansky LD, Roberts AL, Gilsanz P, Chen Q, Winning A, et al. Post-traumatic stress disorder symptoms and risk of hypertension over 22 years in a large cohort of younger and middle-aged women. Psychol Med. 2016;46(15):3105–16.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Gradus JL, Farkas DK, Svensson E, Ehrenstein V, Lash TL, Milstein A, et al. Associations between stress disorders and cardiovascular disease events in the Danish population. BMJ Open. 2015;5(12):e009334.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Sumner JA, Kubzansky LD, Elkind MS, Roberts AL, Agnew-Blais J, Chen Q, et al. Trauma exposure and posttraumatic stress disorder symptoms predict onset of cardiovascular events in women. Circulation. 2015;132:251–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Taylor-Clift A, Holmgreen L, Hobfoll SE, Gerhart JI, Richardson D, Calvin JE, et al. Traumatic stress and cardiopulmonary disease burden among low-income, urban heart failure patients. J Affect Disord. 2016;190:227–34.CrossRefPubMedGoogle Scholar
  28. 28.
    Koenen KC, Sumner JA, Gilsanz P, Glymour MM, Ratanatharathorn A, Rimm EB, et al. Post-traumatic stress disorder and cardiometabolic disease: improving causal inference to inform practice. Psychol Med. 2017;47(2):209–25.CrossRefPubMedGoogle Scholar
  29. 29.
    Levine AB, Levine LM, Levine TB. Posttraumatic stress disorder and cardiometabolic disease. Cardiology. 2014;127:1–19.CrossRefPubMedGoogle Scholar
  30. 30.
    •• Miller MW, Sadeh N. Traumatic stress, oxidative stress and post-traumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis. Mol Psychiatry. 2014;19(11):1156–62. This is an excellent review paper that outlines the case for PTSD and accelerated aging via oxidative stress. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Sumner JA, Duncan LE, Wolf EJ, Amstadter AB, Baker DG, Beckham JC, et al. Letter to the editor: posttraumatic stress disorder has genetic overlap with cardiometabolic traits. Psychol Med. 2017;4:1–4.Google Scholar
  32. 32.
    Pollard HB, Shivakumar C, Starr J, Eidelman O, Jacobowitz DM, Dalgard CL, et al. “Soldier’s heart”: a genetic basis for elevated cardiovascular disease risk associated with post-traumatic stress disorder. Front Mol Neurosci. 2016;9:87.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Breen MS, Maihofer AX, Glatt SJ, Tylee DS, Chandler SD, Tsuang MT, et al. Gene networks specific for innate immunity define post-traumatic stress disorder. Mol Psychiatry. 2015;20(12):1538–45.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wolf EJ, Miller DR, Logue MW, Sumner J, Stoop TB, Leritz EC. Contributions of polygenic risk for obesity to PTSD-related metabolic syndrome and cortical thickness. Brain Behav Immun. 2017;65:328–336. https://www.ncbi.nlm.nih.gov/pubmed/28579519.
  35. 35.
    Lavagnino L, Arnone D, Cao B, Soares JC, Selvaraj S. Inhibitory control in obesity and binge eating disorder: a systematic review and meta-analysis of neurocognitive and neuroimaging studies. Neurosci Biobehav. 2016;68:714–26.CrossRefGoogle Scholar
  36. 36.
    Campisi J, Fagagna FDA. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8(9):729–40.CrossRefPubMedGoogle Scholar
  37. 37.
    Fougère B, Boulanger E, Nourhashémi F, Guyonnet S, Cesari M. Chronic inflammation: accelerator of biological aging. J Gerontol A Biol Sci Med Sci 2016: glw240. https://www.ncbi.nlm.nih.gov/pubmed/28003373.
  38. 38.
    Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, et al. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A. 2004;101(49):17312–5.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    •• Epel ES. Psychological and metabolic stress: a recipe for accelerated cellular aging. Hormones (Athens). 2009;8(1):7–22. This is an excellent review of the link between stress and telomere length. CrossRefGoogle Scholar
  40. 40.
    Lindqvist D, Epel ES, Mellon SH, Penninx BW, Révész D, Verhoeven JE, et al. Psychiatric disorders and leukocyte telomere length: underlying mechanisms linking mental illness with cellular aging. Neurosci Biobehav Rev. 2015;55:333–64.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Darrow SM, Verhoeven JE, Révész D, Lindqvist D, Penninx BW, Delucchi KL, et al. The association between psychiatric disorders and telomere length: a meta-analysis involving 14,827 persons. Psychosom Med. 2016;78(7):776–87.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Roberts AL, Koenen KC, Chen Q, Gilsanz P, Mason SM, Prescott J, et al. Posttraumatic stress disorder and accelerated aging: PTSD and leukocyte telomere length in a sample of civilian women. Depress Anxiety. 2017;34(5):391–400.CrossRefPubMedGoogle Scholar
  43. 43.
    Bersani FS, Lindqvist D, Mellon SH, Epel ES, Yehuda R, Flory J, et al. Association of dimensional psychological health measures with telomere length in male war veterans. J Affect Disord. 2016;190:537–42.CrossRefPubMedGoogle Scholar
  44. 44.
    Barrett JH, Iles MM, Dunning AM, Pooley KA. Telomere length and common disease: study design and analytical challenges. Hum Genet. 2015;134(7):679–89.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Müezzinler A, Zaineddin AK, Brenner H. A systematic review of leukocyte telomere length and age in adults. Ageing Res Rev. 2013;12(2):509–19.CrossRefPubMedGoogle Scholar
  46. 46.
    Lowe D, Horvath S, Raj K. Epigenetic clock analyses of cellular senescence and ageing. Oncotarget. 2016;7(8):8524–31.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Mathur MB, Epel E, Kind S, Desai M, Parks CG, Sandler DP, et al. Perceived stress and telomere length: a systematic review, meta-analysis, and methodologic considerations for advancing the field. Brain Behav Immun. 2016;54:158–69.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet. 2009;5(8):e1000602.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    •• Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115. This paper describes the development of the multi-tissue DNA methylation age algorithm. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    •• 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(2):359–67. This paper describes the development of the blood-based DNA methylation age algorithm which has been subsequently associated with PTSD. CrossRefPubMedGoogle Scholar
  51. 51.
    Durso DF, Bacalini MG, Sala C, Pirazzini C, Marasco E, Bonafé M, et al. Acceleration of leukocytes’ epigenetic age as an early tumor and sex-specific marker of breast and colorectal cancer. Oncotarget. 2017;8(14):23237–45.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Levine AJ, Quach A, Moore DJ, Achim CL, Soontornniyomkii V, Masliah E, et al. Accelerated epigenetic aging in brain is associated with pre-mortem HIV-associated neurocognitive disorders. J Neuro-Oncol. 2016;22(3):366–75.Google Scholar
  53. 53.
    Levine ME, Lu AT, Bennett DA, Horvath S. Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning. Aging. 2015;7(12):1198–211.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Horvath S, Ritz BR. Increased epigenetic age and granulocyte counts in the blood of Parkinson’s disease patients. Aging. 2015;7(12):1130–42.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Chen BH, Marioni RE, Colicino E, Peters MJ, Ward-Caviness CK, Tsai PC, et al. DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging. 2016;8(9):1844–65.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    •• 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. This was the first study to show an association between accelerated DNA methylation age and mortality, an important step towards validating the clinical utility of the DNA methylation age metric. Google Scholar
  57. 57.
    Perna L, Zhang Y, Mons U, Holleczek B, Saum KU, Brenner H. Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort. Clin Epigenetics. 2016;8(1):64. https://www.ncbi.nlm.nih.gov/pubmed/27274774.
  58. 58.
    Boks MP, van Mierlo HC, Rutten BP, Radstake TR, De Witte L, Geuze E, et al. Longitudinal changes of telomere length and epigenetic age related to traumatic stress and post-traumatic stress disorder. Psychoneuroendocrinology. 2015;51:506–12.CrossRefPubMedGoogle Scholar
  59. 59.
    Zannas AS, Arloth J, Carrillo-Roa T, Iurato S, Röh S, Ressler KJ, et al. Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome Biol. 2015;16:266.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    •• Wolf EJ, Logue MW, Hayes JP, Sadeh N, Schichman SA, Stone A, et al. Accelerated DNA methylation age: associations with PTSD and neural integrity. Psychoneuroendocrinology. 2016;63:155–62. This is the first paper to show an association between PTSD and accelerated DNA methylation age (controlling for chronological age). CrossRefPubMedGoogle Scholar
  61. 61.
    Wolf EJ, Logue MW, Stoop TB, Schichman SA, Stone A, Sadeh N, Hayes JP, Miller MW. Accelerated DNA methylation age: associations with PTSD and mortality. Psychosom Med 2017:in press.Google Scholar
  62. 62.
    Wolf EJ, Maniates H, Nugent N, Maihofer AX, Armstrong D, Ratanatharathorn A, et al. Traumatic stress and accelerated DNA methylation age: a meta-analysis. 2017:under review.Google Scholar
  63. 63.
    Ratanatharathorn A, Boks MP, Maihofer AX, Aiello AE, Amstadter AB, Ashley-Koch AE, et al. Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline. Am J Med Genet B Neuropsychiatr Genet 2017. http://dx.doi.org/10.1002/ajmg.b.32568.
  64. 64.
    Pawelec G. Immunity and ageing in man. Exp Gerontol. 2006;41:1239–42.CrossRefPubMedGoogle Scholar
  65. 65.
    Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Löfgren S, et al. An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol. 2005;60:556–65.CrossRefGoogle Scholar
  66. 66.
    Macaulay R, Akbar AN, Henson SM. The role of the T cell in age-related inflammation. Age. 2013;35:563–72.CrossRefPubMedGoogle Scholar
  67. 67.
    Franceschi C, Valensin S, Bonafè M, Paolisso G, Yashin A, Monti D, et al. The network and the remodeling theories of aging: historical background and new perspectives. Exp Gerontol. 2000;35:879–96.CrossRefPubMedGoogle Scholar
  68. 68.
    • Fülöp T, Dupuis G, Witkowski JM, Larbi A. The role of immunosenescence in the development of age-related diseases. J Clin Res. 2016;68:84–91. This is a very accessible review paper concerning the link between immune system decline and age-related disorders. Google Scholar
  69. 69.
    Baylis D, Bartlett DB, Syddall HE, Ntani G, Gale CR, Cooper C, et al. Immune-endocrine biomarkers as predictors of frailty and mortality: a 10-year longitudinal study in community-dwelling older people. Age. 2013;35:963–71.CrossRefPubMedGoogle Scholar
  70. 70.
    • 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. This is the largest study to date of the association between immune parameters and PTSD. CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Sommershof A, Aichinger H, Engler H, Adenauer H, Catani C, Boneberg EM, et al. Substantial reduction of naïve and regulatory T cells following traumatic stress. Brain Behav Immun. 2009;23(8):1117–24.CrossRefPubMedGoogle Scholar
  72. 72.
    O’Donovan A, Cohen BE, Seal KH, Bertenthal D, Margaretten M, Nishimi K, et al. Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder. Biol Psychiatry. 2015;77(4):365–74.CrossRefPubMedGoogle Scholar
  73. 73.
    Miller MW, Lin AP, Wolf EJ, Miller DM. Oxidative stress, inflammation, and neuroprogression in chronic PTSD. Harv Rev Psychiatry 2017:in press.Google Scholar
  74. 74.
    Rosen RL, Levy-Carrick N, Reibman J, Xu N, Shao Y, Liu M, et al. Elevated C-reactive protein and posttraumatic stress pathology among survivors of the 9/11 Word Trade Center attacks. J Psychiatr Res. 2017;89:14–21.CrossRefPubMedGoogle Scholar
  75. 75.
    O’Donovan A, Ahmadian AJ, Neylan TC, Pacult MA, Edmondson D, Cohen BE. Current posttraumatic stress disorder and exaggerated threat sensitivity associated with elevated inflammation in the Mind Your Heart Study. Brain Behav Immun. 2017;60:198–205.CrossRefPubMedGoogle Scholar
  76. 76.
    • Sumner JA, Qixuan C, Roberts AL, Winning A, Rimm EB, Gilsanz P, et al. Cross-sectional and longitudinal associations of chronic posttraumatic stress disorder with inflammatory and endothelial function markers in women. Biol Psychiatry 2017:in press. This is a very recent manuscript providing evidence of longitudinal associations between PTSD and reduced endothelial functioning . Google Scholar
  77. 77.
    Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015;2(11):1002–12.CrossRefPubMedGoogle Scholar
  78. 78.
    Grenon SM, Owens CD, Alley H, Perez S, Whooley MA, Neylan TC, et al. Posttraumatic stress disorder is associated with worse endothelial function among veterans. J Am Heart Assoc. 2016;5(3):e003010.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    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(2):419–46.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Horvath S, Gurven M, Levine ME, Trumble BC, Kaplan H, Allayee H, et al. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol. 2016;17(1):171.Google Scholar
  81. 81.
    Cannizzo ES, Clement CC, Sahu R, Follo C, Santambrogio L. Oxidative stress, inflamm-aging and immunosenescence. J Proteome. 2011;74(11):2313–23.CrossRefGoogle Scholar
  82. 82.
    Williamson JB, Porges EC, Lamb DG, Porges SW. Maladaptive autonomic regulation in PTSD accelerates physiological aging. Front Psychol. 2015;5:1571.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Dennis PA, Kimbrel NA, Sherwood A, Calhoun PS, Watkins LL, Dennis MF, et al. Trauma and autonomic dysregulation: episodic-versus systemic-negative affect underlying cardiovascular risk in posttraumatic stress disorder. Psychosom Med. 2017;79(5):496–505.CrossRefPubMedGoogle Scholar
  84. 84.
    • Stubbs TM, Bonder MJ, Stark AK, Krueger F, von Meyenn F, BI Ageing Clock Team, et al. Multi-tissue DNA methylation age predictor in mouse. Genome Biol. 2017;18(1):68. This study extending DNA methylation age to mouse models provides an approach for testing the biological mechanisms of accelerated aging. CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Wagner W. Epigenetic aging clocks in mice and men. Genome Biol. 2017;18(1):107.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Lu AT, Hannon E, Levine ME, Crimmins EM, Lunnon K, Mill J, et al. Genetic architecture of epigenetic and neuronal ageing rates in human brain regions. Nat Commun. 2017;8:15353.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299(11):1291–305.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Mehta D, Binder EB. Gene x environment vulnerability factors for PTSD: the HPA-axis. Neuropharmacology. 2012;62(2):654–62.CrossRefPubMedGoogle Scholar
  89. 89.
    Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16(1):33–41.CrossRefPubMedGoogle Scholar
  90. 90.
    Sadeh N, Wolf EJ, Logue MW, Hayes JP, Stone A, Griffin LM, et al. Epigenetic variation at SKA2 predicts suicide phenotypes and internalizing psychopathology. Depress Anxiety. 2016;33(4):308–15.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Boks MP, Rutten BP, Geuze E, Houtepen LC, Vermetten E, Kaminsky Z, et al. SKA2 methylation is involved in cortisol stress reactivity and predicts the development of post-traumatic stress disorder (PTSD) after military deployment. Neuropsychopharmacology. 2016;41(5):1350–6.CrossRefPubMedGoogle Scholar
  92. 92.
    •• Logue MW, Baldwin C, Guffanti G, Melista E, Wolf EJ, Reardon AF, et al. A genome-wide association study of post-traumatic stress disorder identifies the retinoid-related orphan receptor alpha (RORA) gene as a significant risk locus. Mol Psychiatry. 2013;18(8):937–42. This was the first published genome-wide association study of PTSD which revealed evidence for a link between the RORA gene and PTSD, which is the basis for further interest between PTSD and oxidative stress. CrossRefPubMedGoogle Scholar
  93. 93.
    Miller MW, Wolf EJ, Sadeh N, Logue M, Spielberg JM, Hayes JP, et al. A novel locus in the oxidative stress-related gene ALOX12 moderates the association between PTSD and thickness of the prefrontal cortex. Psychoneuroendocrinology. 2015;62:359–65.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell. 2015;161(5):1202–14.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Soliman MA, Aboharb F, Zeltner N, Studer L. Pluripotent stem cells in neuropsychiatric disorders. Mol Psychiatry. 2017; doi: 10.1038/mp.2017.40.
  96. 96.
    Huh CJ, Zhang B, Victor MB, Dahiya S, Batista LFZ, Horvath S, et al. Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts. elife. 2016;5:e18648.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Liu XS, Wu H, Ji X, Stelzer Y, Wu X, Czauderna S, et al. Editing DNA methylation in the mammalian genome. Cell. 2016;167(1):233–47.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Reddy TP, Manczak M, Calkins MJ, Mao P, Reddy AP, Shirendeb U, et al. Toxicity of neurons treated with herbicides and neuroprotection by mitochondria-targeted antioxidant SS31. Int J Environ Res Public Health. 2011;8:203–21.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Nalecz KA, Miecz D, Berezowski V, Cecchelli R. Carnitine: transport and physiological functions in the brain. Mol Asp Med. 2004;24(5–6):551–67.Google Scholar
  100. 100.
    Pettegrew JW, Levine J, McClure RJ. Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer’s disease and geriatric depression. Mol Psychiatry. 2000;5:616–32.CrossRefPubMedGoogle Scholar
  101. 101.
    Ribas GS, Vargas CR, Wajner M. L-carnitine supplementation as a potential anti- oxidant therapy for inherited neurometabolic disorders. Gene. 2014;533:469–76.CrossRefPubMedGoogle Scholar
  102. 102.
    Sitta A, Vanzin CS, Biancini GB, Manfredini V, De Oliveira AB, Wayhs CA, et al. Evidence that L-carnitine and selenium supplementation reduces oxidative stress in phenylketonuric patients. Cell Mol Neurobiol. 2011;31:429–36.CrossRefPubMedGoogle Scholar
  103. 103.
    Yang R, Daigle BJ Jr, Muhie SY, Hammamieh R, Jett M, Petzold L, et al. Core modular blood and brain biomarkers in social defeat mouse model for posttraumatic stress disorder. BMC Syst Biol 2013:7(80).Google Scholar
  104. 104.
    Mauro C, De Rosa V, Marelli-Berg F, Solito E. Metabolic syndrome and the immunological affair with the blood-brain barrier. Front Immunol. 2015;5:677.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Hurtado-Alvarado G, Dominguez-Salazar E, Velazquez-Moctezuma J, Gomez-Gonzalez B. A2A adenosine receptor antagonism reverts the blood-brain barrier dysfunction induced by sleep restriction. PLoS One. 2016;11(11):e0167236.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Orr AG, Hsiao EC, Wang MM, Ho K, Kim DH, Wang X, et al. Astrocytic adenosine receptor A2A and Gs-couples signaling regulate memory. Nat Neurosci. 2015;18(3):423–34.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© US Government (outside the USA) 2017

Authors and Affiliations

  1. 1.National Center for PTSDVA Boston Healthcare SystemBostonUSA
  2. 2.Department of PsychiatryBoston University School of MedicineBostonUSA
  3. 3.McLean Hospital, Harvard Medical SchoolBelmontUSA

Personalised recommendations