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

Current Psychiatry Reports

Volumn 19, Issue 10, 2017, Pages

  Wolf, Erika J ^a,b   Morrison, Filomene G ^c  

^a VA BOSTON HEALTHCARE SYSTEM   (United States)

^b BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c MCLEAN HOSPITAL   (United States)

Author keywords

Accelerated aging; Epigenetic clock; Immunosenescence; Inflamm aging; PTSD; Traumatic stress

Indexed keywords

BIOLOGICAL MARKER;

CARDIOVASCULAR DISEASE; CELL AGING; CEREBROVASCULAR ACCIDENT; DISEASE ASSOCIATION; EPIGENETICS; HEART DISEASE; HEART FAILURE; HEART INFARCTION; HUMAN; HYPERTENSION; IMMUNE RESPONSE; IMMUNE SYSTEM; INDUCED PLURIPOTENT STEM CELL; LIFE STRESS; METABOLIC DISORDER; METABOLIC SYNDROME X; NONHUMAN; NUCLEAR REPROGRAMMING; OXIDATIVE STRESS; POSTTRAUMATIC STRESS DISORDER; REVIEW; IMMUNOSENESCENCE; METABOLISM; PATHOPHYSIOLOGY; PHYSIOLOGY; PREMATURE AGING; PSYCHOLOGY;

AGING, PREMATURE; CARDIOVASCULAR DISEASES; CELLULAR SENESCENCE; EPIGENOMICS; HUMANS; IMMUNOSENESCENCE; OXIDATIVE STRESS; STRESS DISORDERS, TRAUMATIC;

EID: 85028397047     PISSN: 15233812     EISSN: 15351645     Source Type: Journal    
DOI: 10.1007/s11920-017-0823-5     Document Type: Review

References (106)

1. Da Costa J. On irritable heart. Am J Med Sci. 1871;61:17–52.
2. Mackenzie J. The soldier’s heart. Br Med J. 1916;1(2873):117–9.
3. Rudolf RD. The irritable heart of soldiers (soldier’s heart). Can Med Assoc J. 1916;6(9):798–810.
4. Wolf EJ, Schnurr PP. PTSD-related cardiovascular disease and accelerated cellular aging. Psychiatr Ann. 2016;46:527–32.
5. Arenson M, Cohen B. Posttraumatic stress disorder and cardiovascular disease. PTSD Research Quarterly. 2017;28(1):1–9.
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.
7. Edmondson D, Cohen BE. Posttraumatic stress disorder and cardiovascular disease. Prog Cardiovasc Dis. 2013;55(6):548–56.
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.
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.
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%.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
29. Levine AB, Levine LM, Levine TB. Posttraumatic stress disorder and cardiometabolic disease. Cardiology. 2014;127:1–19.
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.
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.
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.
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.
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. 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.
36. Campisi J, Fagagna FDA. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8(9):729–40.
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. 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.
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.
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.
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.
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.
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.
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.
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.
46. Lowe D, Horvath S, Raj K. Epigenetic clock analyses of cellular senescence and ageing. Oncotarget. 2016;7(8):8524–31.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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. 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.
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.
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).
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.
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.
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. Pawelec G. Immunity and ageing in man. Exp Gerontol. 2006;41:1239–42.
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.
66. Macaulay R, Akbar AN, Henson SM. The role of the T cell in age-related inflammation. Age. 2013;35:563–72.
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.
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.
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.
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.
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.
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.
73. Miller MW, Lin AP, Wolf EJ, Miller DM. Oxidative stress, inflammation, and neuroprogression in chronic PTSD. Harv Rev Psychiatry 2017:in press.
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.
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.
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.
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.
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.
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.
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.
81. Cannizzo ES, Clement CC, Sahu R, Follo C, Santambrogio L. Oxidative stress, inflamm-aging and immunosenescence. J Proteome. 2011;74(11):2313–23.
82. Williamson JB, Porges EC, Lamb DG, Porges SW. Maladaptive autonomic regulation in PTSD accelerates physiological aging. Front Psychol. 2015;5:1571.
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.
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.
85. Wagner W. Epigenetic aging clocks in mice and men. Genome Biol. 2017;18(1):107.
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.
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.
88. Mehta D, Binder EB. Gene x environment vulnerability factors for PTSD: the HPA-axis. Neuropharmacology. 2012;62(2):654–62.
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.
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.
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.
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.
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.
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.
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. 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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.