DNA methylation changes consistently throughout life and age-dependent alterations in DNA methylation can be used to estimate one's epigenetic age. Post-mortem studies revealed higher epigenetic age in brains of patients with major depressive disorder, as compared with controls. Since MDD is highly correlated with anxiety, we hypothesized that symptoms of anxiety, as well as lower volume of grey matter (GM) in depression-related cortical regions, will be associated with faster epigenetic clock in a community-based sample of young adults. Participants included 88 young adults (53% men; 23-24 years of age) from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) who participated in its neuroimaging follow-up and provided saliva samples for epigenetic analysis. Epigenetic age was calculated according to Horvath (Horvath, 2013). Women had slower epigenetic clock than men (Cohen's d = 0.48). In women (but not men), slower epigenetic clock was associated with less symptoms of anxiety. In the brain, women (but not men) with slower epigenetic clock had greater GM volume in the cerebral cortex (brain size-corrected; R2 = 0.07). Lobe-specific analyses showed that in women (but not men), slower epigenetic clock was associated with greater GM volume in frontal lobe (R2 = 0.16), and that GM volume in frontal lobe mediated the relationship between the speed of epigenetic clock and anxiety trait (ab = 0.15, SE = 0.15, 95% CI [0.007; 0.369]). These findings were not replicated, however, in a community-based sample of adolescents (n = 129; 49% men; 12-19 years of age), possibly due to the different method of tissue collection (blood vs. saliva) or additional sources of variability in the cohort of adolescents (puberty stages, socioeconomic status, prenatal exposure to maternal smoking during pregnancy).

Bloorview Research Institute Holland Bloorview Kids Rehabilitation Hospital 150 Kilgour Rd East York Toronto ON M4G1R8 Canada; Departments of Psychology and Psychiatry University of Toronto 100 St George Street Toronto ON M5S3G3 Canada

Brain and Mind Research Central European Institute of Technology Masaryk University 5 Kamenice Brno 62500 Czech Republic

Hospital for Sick Children University of Toronto 686 Bay Street Toronto ON M5G0A4 Canada

Institute for Clinical Evaluative Sciences 2075 Bayview Avenue Toronto ON M4N3M5 Canada

Molecular Medicine Central European Institute of Technology Masaryk University 5 Kamenice Brno 62500 Czech Republic

RECETOX Faculty of Science Masaryk University 5 Kamenice Brno 62500 Czech Republic

RECETOX Faculty of Science Masaryk University 5 Kamenice Brno 62500 Czech Republic; Faculty of Informatics Masaryk University 68A Botanicka Brno 60200 Czech Republic

Zobrazit více v PubMed

Ustun T.B., Ayuso-Mateos J.L., Chatterji S., Mathers C., Murray C.J. Global burden of depressive disorders in the year 2000. Br. J. Psychiatry. 2004;184:386–392. PubMed

Kessler R.C., Berglund P., Demler O., Jin R., Merikangas K.R., Walters E.E. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry. 2005;62:593–602. PubMed

America AaDAo (2018): Facts and Statistics.

Jacobson N.C., Newman M.G. Anxiety and depression as bidirectional risk factors for one another: a meta-analysis of longitudinal studies. Psychol. Bull. 2017;143:1155–1200. PubMed

Sibille E. Molecular aging of the brain, neuroplasticity, and vulnerability to depression and other brain-related disorders. Dialogues Clin. Neurosci. 2013;15:53–65. PubMed PMC

Rozycka A., Liguz-Lecznar M. The space where aging acts: focus on the GABAergic synapse. Aging Cell. 2017;16:634–643. PubMed PMC

Ding Y., Chang L.C., Wang X., Guilloux J.P., Parrish J., Oh H. Molecular and genetic characterization of depression: overlap with other psychiatric disorders and aging. Mol. Neuropsychiatry. 2015;1:1–12. PubMed PMC

Schutte N.S., Malouff J.M. The association between depression and leukocyte telomere length: a meta-analysis. Depress Anxiety. 2015;32:229–238. PubMed

Ridout K.K., Ridout S.J., Price L.H., Sen S., Tyrka A.R. Depression and telomere length: a meta-analysis. J. Affect. Disord. 2016;191:237–247. PubMed PMC

Han L.K.M., Aghajani M., Clark S.L., Chan R.F., Hattab M.W., Shabalin A.A. Epigenetic aging in major depressive disorder. Am. J. Psychiatry. 2018;175:774–782. PubMed PMC

Hannum G., Guinney J., Zhao L., Zhang L., Hughes G., Sadda S. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol. Cell. 2013;49:359–367. PubMed PMC

Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14:R115. PubMed PMC

Ducharme S., Albaugh M.D., Nguyen T.V., Hudziak J.J., Mateos-Perez J.M., Labbe A. Trajectories of cortical thickness maturation in normal brain development–The importance of quality control procedures. Neuroimage. 2016;125:267–279. PubMed PMC

Walhovd K.B., Fjell A.M., Giedd J., Dale A.M., Brown T.T. Through Thick and thin: a need to reconcile contradictory results on trajectories in human cortical development. Cereb. Cortex. 2017;27:1472–1481. PubMed PMC

Petanjek Z., Judas M., Simic G., Rasin M.R., Uylings H.B., Rakic P. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc. Natl. Acad. Sci. USA. 2011;108:13281–13286. PubMed PMC

Miller D.J., Duka T., Stimpson C.D., Schapiro S.J., Baze W.B., McArthur M.J. Prolonged myelination in human neocortical evolution. Proc. Natl. Acad. Sci. USA. 2012;109:16480–16485. PubMed PMC

Shaw P., Kabani N.J., Lerch J.P., Eckstrand K., Lenroot R., Gogtay N. Neurodevelopmental trajectories of the human cerebral cortex. J. Neurosci. 2008;28:3586–3594. PubMed PMC

Giedd J.N., Rapoport J.L. Structural MRI of pediatric brain development: what have we learned and where are we going? Neuron. 2010;67:728–734. PubMed PMC

Fjell A.M., Grydeland H., Krogsrud S.K., Amlien I., Rohani D.A., Ferschmann L. Development and aging of cortical thickness correspond to genetic organization patterns. Proc. Natl. Acad. Sci. USA. 2015;112:15462–15467. PubMed PMC

Pfefferbaum A., Rohlfing T., Rosenbloom M.J., Chu W., Colrain I.M., Sullivan E.V. Variation in longitudinal trajectories of regional brain volumes of healthy men and women (ages 10 to 85 years) measured with atlas-based parcellation of MRI. Neuroimage. 2013;65:176–193. PubMed PMC

Fletcher E., Gavett B., Harvey D., Farias S.T., Olichney J., Beckett L. Brain volume change and cognitive trajectories in aging. Neuropsychology. 2018;32:436–449. PubMed PMC

Giedd J.N., Blumenthal J., Jeffries N.O., Castellanos F.X., Liu H., Zijdenbos A. Brain development during childhood and adolescence: a longitudinal MRI study. Nat. Neurosci. 1999;2:861–863. PubMed

Gotlib I.H., Joormann J. Cognition and depression: current status and future directions. Annu. Rev. Clin. Psychol. 2010;6:285–312. PubMed PMC

Joormann J., Quinn M.E. Cognitive processes and emotion regulation in depression. Depress Anxiety. 2014;31:308–315. PubMed

Joormann J., Tanovic E. Cognitive vulnerability to depression: examining cognitive control and emotion regulation. Curr. Opin. Psychol. 2015;4:86–92.

Salthouse T.A. How general are the effects of trait anxiety and depressive symptoms on cognitive functioning? Emotion. 2012;12:1075–1084. PubMed PMC

Frodl T.S., Koutsouleris N., Bottlender R., Born C., Jager M., Scupin I. Depression-related variation in brain morphology over 3 years: effects of stress? Arch. Gen. Psychiatry. 2008;65:1156–1165. PubMed

Schmaal L., Hibar D.P., Samann P.G., Hall G.B., Baune B.T., Jahanshad N. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol. Psychiatry. 2017;22:900–909. PubMed PMC

Davis E.G., Humphreys K.L., McEwen L.M., Sacchet M.D., Camacho M.C., MacIsaac J.L. Accelerated DNA methylation age in adolescent girls: associations with elevated diurnal cortisol and reduced hippocampal volume. Transl. Psychiatry. 2017;7 PubMed PMC

Pausova Z., Paus T., Abrahamowicz M., Bernard M., Gaudet D., Leonard G. Cohort Profile: The Saguenay Youth Study (SYS) Int. J. Epidemiol. 2017;46 PubMed PMC

Tanaka C., Matsui M., Uematsu A., Noguchi K., Miyawaki T. Developmental trajectories of the fronto-temporal lobes from infancy to early adulthood in healthy individuals. Dev. Neurosci. 2012;34:477–487. PubMed

Organization WH (2002): Gender Disparities in Mental Health.

Organization WH (2016): Global Health Estimates 2015: Disease burden by Cause, Age, Sex, by Country and by Region, 2000-2015.

Prokhorskas R., Ignatyeva R., Dragonas T., Golding J. European longitudinal study of pregnancy and childhood (ELSPAC) Paediatr. Perinat. Epidemiol. 1989;3:460–469. PubMed

Piler P., Kandrnal V., Kukla L., Andryskova L., Svancara J., Jarkovsky J. Cohort Profile: The European Longitudinal Study of Pregnancy and Childhood (ELSPAC) in the Czech Republic. Int. J. Epidemiol. 2017;46 1379–1379f. PubMed PMC

Tian Y., Morris T.J., Webster A.P., Yang Z., Beck S., Feber A. ChAMP: updated methylation analysis pipeline for Illumina BeadChips. Bioinformatics. 2017;33:3982–3984. PubMed PMC

Teschendorff A.E., Marabita F., Lechner M., Bartlett T., Tegner J., Gomez-Cabrero D. A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data. Bioinformatics. 2013;29:189–196. PubMed PMC

Spielberger C.D., Gorsuch R.L., Lushene R., Vagg P.R., Jacobs G.A. Consulting Psychological Press; Palo Alto, CA: 1983. Manual for the State-Trait Anxiety Inventory.

Suarez A., Lahti J., Czamara D., Lahti-Pulkkinen M., Girchenko P., Andersson S. The epigenetic clock and pubertal, neuroendocrine, psychiatric, and cognitive outcomes in adolescents. Clin. Epigenetics. 2018;10:96. PubMed PMC

Binder A.M., Corvalan C., Mericq V., Pereira A., Santos J.L., Horvath S. Faster ticking rate of the epigenetic clock is associated with faster pubertal development in girls. Epigenetics. 2018;13:85–94. PubMed PMC

Simpkin A.J., Hemani G., Suderman M., Gaunt T.R., Lyttleton O., McArdle W.L. Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies. Hum. Mol. Genet. 2016;25:191–201. PubMed PMC

Javed R., Chen W., Lin F., Liang H. Infant's DNA methylation age at birth and epigenetic aging accelerators. Biomed Res. Int. 2016;2016:4515928. PubMed PMC

Lee K.W., Richmond R., Hu P., French L., Shin J., Bourdon C. Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environ. Health Perspect. 2015;123:193–199. PubMed PMC

Houseman E.A., Accomando W.P., Koestler D.C., Christensen B.C., Marsit C.J., Nelson H.H. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinf. 2012;13:86. PubMed PMC

Lucas C.P., Zhang H., Fisher P.W., Shaffer D., Regier D.A., Narrow W.E. The DISC Predictive Scales (DPS): efficiently screening for diagnoses. J. Am. Acad. Child Adolesc. Psychiatry. 2001;40:443–449. PubMed

Horvath S., Gurven M., Levine M.E., Trumble B.C., Kaplan H., Allayee H. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol. 2016;17:171. PubMed PMC

Case A., Paxson C. Sex differences in morbidity and mortality. Demography. 2005;42:189–214. PubMed

Oksuzyan A., Juel K., Vaupel J.W., Christensen K. Men: good health and high mortality. Sex differences in health and aging. Aging Clin. Exp. Res. 2008;20:91–102. PubMed PMC

Levine M.E., Lu A.T., Chen B.H., Hernandez D.G., Singleton A.B., Ferrucci L. Menopause accelerates biological aging. Proc. Natl. Acad. Sci. USA. 2016;113:9327–9332. PubMed PMC

Wierenga L.M., Langen M., Oranje B., Durston S. Unique developmental trajectories of cortical thickness and surface area. Neuroimage. 2014;87:120–126. PubMed

Wang T., Li M., Xu S., Liu B., Wu T., Lu F. Relations between trait anxiety and depression: a mediated moderation model. J. Affect. Disord. 2019;244:217–222. PubMed

Weger M., Sandi C. High anxiety trait: a vulnerable phenotype for stress-induced depression. Neurosci. Biobehav. Rev. 2018;87:27–37. PubMed

Simons R.L., Lei M.K., Beach S.R., Philibert R.A., Cutrona C.E., Gibbons F.X. Economic hardship and biological weathering: the epigenetics of aging in a U.S. sample of black women. Soc. Sci. Med. 2016;150:192–200. PubMed PMC

Hughes A., Smart M., Gorrie-Stone T., Hannon E., Mill J., Bao Y. Socioeconomic position and DNA methylation age acceleration across the life course. Am. J. Epidemiol. 2018;187:2346–2354. PubMed PMC

Boes A.D., McCormick L.M., Coryell W.H., Nopoulos P. Rostral anterior cingulate cortex volume correlates with depressed mood in normal healthy children. Biol. Psychiatry. 2008;63:391–397. PubMed PMC

Fallucca E., MacMaster F.P., Haddad J., Easter P., Dick R., May G. Distinguishing between major depressive disorder and obsessive-compulsive disorder in children by measuring regional cortical thickness. Arch. Gen. Psychiatry. 2011;68:527–533. PubMed PMC

Shad M.U., Muddasani S., Rao U. Gray matter differences between healthy and depressed adolescents: a voxel-based morphometry study. J. Child Adolesc. Psychopharmacol. 2012;22:190–197. PubMed PMC

Reynolds S., Carrey N., Jaworska N., Langevin L.M., Yang X.R., Macmaster F.P. Cortical thickness in youth with major depressive disorder. BMC Psychiatry. 2014;14:83. PubMed PMC

Whittle S., Lichter R., Dennison M., Vijayakumar N., Schwartz O., Byrne M.L. Structural brain development and depression onset during adolescence: a prospective longitudinal study. Am. J. Psychiatry. 2014;171:564–571. PubMed

Mitochondrial DNA variants and their impact on epigenetic and biological aging in young adulthood

Longitudinal study of epigenetic aging and its relationship with brain aging and cognitive skills in young adulthood