Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Major depressive disorder and accelerated cellular aging: results from a large psychiatric cohort study

Abstract

Patients with major depressive disorder (MDD) have an increased onset risk of aging-related somatic diseases such as heart disease, diabetes, obesity and cancer. This suggests mechanisms of accelerated biological aging among the depressed, which can be indicated by a shorter length of telomeres. We examine whether MDD is associated with accelerated biological aging, and whether depression characteristics such as severity, duration, and psychoactive medication do further impact on biological aging. Data are from the Netherlands Study of Depression and Anxiety, including 1095 current MDD patients, 802 remitted MDD patients and 510 control subjects. Telomere length (TL) was assessed as the telomere sequence copy number (T) compared to a single-copy gene copy number (S) using quantitative polymerase chain reaction. This resulted in a T/S ratio and was converted to base pairs (bp). MDD diagnosis and MDD characteristics were determined by self-report questionnaires and structured psychiatric interviews. Compared with control subjects (mean bp=5541), sociodemographic-adjusted TL was shorter among remitted MDD patients (mean bp=5459; P=0.014) and current MDD patients (mean bp=5461; P=0.012). Adjustment for health and lifestyle variables did not reduce the associations. Within the current MDD patients, separate analyses showed that both higher depression severity (P<0.01) and longer symptom duration in the past 4 years (P=0.01) were associated with shorter TL. Our results demonstrate that depressed patients show accelerated cellular aging according to a ‘dose–response’ gradient: those with the most severe and chronic MDD showed the shortest TL. We also confirmed the imprint of past exposure to depression, as those with remitted MDD had shorter TL than controls.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Nicholson A, Kuper H, Hemingway H . Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. Eur Heart J 2006; 27: 2763–2774.

    Article  PubMed  Google Scholar 

  2. Mezuk B, Eaton WW, Albrecht S, Golden SH . Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 2008; 31: 2383–2390.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BW et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry 2010; 67: 220–229.

    Article  PubMed  Google Scholar 

  4. Gao y, Huang C, Zhao K, Ma L, Qiu X, Zhang L et al. Depression as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Int J Geriatr Psychiatry 2012; 28: 441–449.

    Article  PubMed  Google Scholar 

  5. Chida Y, Hamer M, Wardle J, Steptoe A . Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat Clin Pract Oncol 2008; 5: 466–475.

    Article  PubMed  Google Scholar 

  6. Penninx BW, Guralnik JM, Ferrucci L, Simonsick EM, Deeg DJ, Wallace RB . Depressive symptoms and physical decline in community-dwelling older persons. JAMA 1998; 279: 1720–1726.

    Article  CAS  PubMed  Google Scholar 

  7. Schulz R, Beach SR, Ives DG, Martire LM, Ariyo AA, Kop WJ . Association between depression and mortality in older adults: the Cardiovascular Health Study. Arch Intern Med 2000; 160: 1761–1768.

    Article  CAS  PubMed  Google Scholar 

  8. Cuijpers P, Smit F . Excess mortality in depression: a meta-analysis of community studies. J Affect Disord 2002; 72: 227–236.

    Article  PubMed  Google Scholar 

  9. Wolkowitz OM, Epel ES, Reus VI, Mellon SH . Depression gets old fast: do stress and depression accelerate cell aging? Depress Anxiety 2010; 27: 327–338.

    Article  CAS  PubMed  Google Scholar 

  10. Wolkowitz OM, Reus VI, Mellon SH . Of sound mind and body: depression, disease, and accelerated aging. Dialogues Clin Neurosci 2011; 13: 25–39.

    PubMed  Google Scholar 

  11. Blackburn EH . Switching and signaling at the telomere. Cell 2001; 106: 661–673.

    Article  CAS  PubMed  Google Scholar 

  12. Epel ES . Psychological and metabolic stress: a recipe for accelerated cellular aging? Hormones (Athens) 2009; 8: 7–22.

    Article  Google Scholar 

  13. Olovnikov AM . Telomeres, telomerase, and aging: origin of the theory. Exp Gerontol 1996; 31: 443–448.

    Article  CAS  PubMed  Google Scholar 

  14. Blackburn EH, Greider CW, Szostak JW . Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 2006; 12: 1133–1138.

    Article  CAS  PubMed  Google Scholar 

  15. Fitzpatrick AL, Kronmal RA, Gardner JP, Psaty BM, Jenny NS, Tracy RP et al. Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am J Epidemiol 2007; 165: 14–21.

    Article  PubMed  Google Scholar 

  16. Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF et al. Obesity, cigarette smoking, and telomere length in women. Lancet 2005; 366: 662–664.

    Article  CAS  PubMed  Google Scholar 

  17. Sampson MJ, Winterbone MS, Hughes JC, Dozio N, Hughes DA . Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diabetes Care 2006; 29: 283–289.

    Article  CAS  PubMed  Google Scholar 

  18. Willeit P, Willeit J, Mayr A, Weger S, Oberhollenzer F, Brandstätter A et al. Telomere length and risk of incident cancer and cancer mortality. JAMA 2010; 304: 69–75.

    Article  CAS  PubMed  Google Scholar 

  19. Martin-Ruiz C, Dickinson HO, Keys B, Rowan E, Kenny RA, von Zglinicki T . Telomere length predicts poststroke mortality, dementia, and cognitive decline. Ann Neurol 2006; 60: 174–180.

    Article  PubMed  Google Scholar 

  20. Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA . Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003; 361: 393–395.

    Article  CAS  PubMed  Google Scholar 

  21. Simon NM, Smoller JW, McNamara KL, Maser RS, Zalta AK, Pollack MH et al. Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol Psychiatry 2006; 60: 432–435.

    Article  CAS  PubMed  Google Scholar 

  22. Lung FW, Chen NC, Shu BC . Genetic pathway of major depressive disorder in shortening telomeric length. Psychiatr Genet 2007; 17: 195–199.

    Article  PubMed  Google Scholar 

  23. Hartmann N, Boehner M, Groenen F, Kalb R . Telomere length of patients with major depression is shortened but independent from therapy and severity of the disease. Depress Anxiety 2010; 27: 1111–1116.

    Article  CAS  PubMed  Google Scholar 

  24. Hoen PW, de Jonge P, Na BY, Farzaneh-Far R, Epel E, Lin J et al. Depression and leukocyte telomere length in patients with coronary heart disease: data from the Heart and Soul Study. Psychosom Med 2011; 73: 541–547.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wolkowitz OM, Mellon SH, Epel ES, Lin J, Dhabhar FS, Su Y et al. Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress—preliminary findings. PLoS One 2011; 6: e17837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wikgren M, Maripuu M, Karlsson T, Nordfjäll K, Bergdahl J, Hultdin J et al. Short telomeres in depression and the general population are associated with a hypocortisolemic state. Biol Psychiatry 2012; 71: 294–300.

    Article  CAS  PubMed  Google Scholar 

  27. Penninx BWJH, Beekman ATF, Smit JH, Zitman FG, Nolen WA, Spinhoven P et al. The Netherlands Study of Depression and Anxiety (NESDA): rationale, objectives and methods. Int J Methods Psychiatr Res 2008; 17: 121–140.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH . The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 1996; 26: 477–486.

    Article  CAS  PubMed  Google Scholar 

  29. Cawthon RM . Telomere measurement by quantitative PCR. Nucleic Acids Res 2002; 30: e47.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Aviv A, Hunt SC, Lin J, Cao X, Kimura M, Blackburn E . Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR. Nucleic Acids Res 2011; 39: e134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lin J, Epel E, Cheon J, Kroenke C, Sinclair E, Bigos M et al. Analyses and comparisons of telomerase activity and telomere length in human T and B cells: insights for epidemiology of telomere maintenance. J Immunol Methods 2010; 352: 71–80.

    Article  CAS  PubMed  Google Scholar 

  32. Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN et al. The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry 2003; 54: 573–583.

    Article  PubMed  Google Scholar 

  33. Lyketsos CG, Nestadt G, Cwi J, Heithoff K . The life-chart interview: a standardized method to describe the course of psychopathology. Int J Meth Psychiatr Res 1994; 4: 143–155.

    Google Scholar 

  34. de Graaf R, Bijl RV, Smit F, Vollebergh WAM, Spijker J . Risk factors for 12-month comorbidity of mood, anxiety, and substance use disorders: findings from the Netherlands Mental Health Survey and Incidence Study. Am J Psychiatry 2002; 159: 620–629.

    Article  PubMed  Google Scholar 

  35. Hovens JG, Wiersma JE, Giltay EJ, van Oppen P, Spinhoven P, Penninx BW et al. Childhood life events and childhood trauma in adult patients with depressive, anxiety and comorbid disorders vs. controls. Acta Psychiatr Scand 2010; 122: 66–74.

    Article  CAS  PubMed  Google Scholar 

  36. Wiersma JE, Hovens JG, van OP, Giltay EJ, van Schaik DJ, Beekman AT et al. The importance of childhood trauma and childhood life events for chronicity of depression in adults. J Clin Psychiatry 2009; 70: 983–989.

    Article  PubMed  Google Scholar 

  37. Spinhoven P, Elzinga BM, Hovens JG, Roelofs K, Zitman FG, van Oppen P et al. The specificity of childhood adversities and negative life events across the life span to anxiety and depressive disorders. J Affect Disord 2010; 126: 103–112.

    Article  PubMed  Google Scholar 

  38. World Health Organization Collaboration Centre for Drug Statistics Methodology. Anatomical Therapeutic Chemical (ATC) Classification System. World Health Organization Collaboration Centre for Drug Statistics Methodology: Oslo, Norway, 2007.

  39. Craig CL, Marshall AL, Sjostrom M, Bauman AE, Booth ML, Ainsworth BE et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc 2003; 35: 1381–1395.

    Article  PubMed  Google Scholar 

  40. Ainsworth BE, Haskell WL, Herrmann SD, Meckes N, Bassett DR Jr, Tudor-Locke C et al. 2011 Compendium of physical activities: a second update of codes and MET values. Med Sci Sports Exerc 2011; 43: 1575–1581.

    Article  PubMed  Google Scholar 

  41. Howren MB, Lamkin DM, Suls J . Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71: 171–186.

    Article  CAS  PubMed  Google Scholar 

  42. Molendijk M, Bus B, Oude Voshaar R, Spinhoven P, Penninx BW, Elzinga B . Serum levels of brain-derived neurotrophic factor in major depressive disorder: state—trait issues, clinical features, and pharmacological treatment. Mol Psychiatry 2010; 16: 1088–1095.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Vreeburg SA, Hoogendijk WJ, van PJ, Derijk RH, Verhagen JC, van Dyck R et al. Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch Gen Psychiatry 2009; 66: 617–626.

    Article  CAS  PubMed  Google Scholar 

  44. Price LH, Kao HT, Burgers DE, Carpenter LL, Tyrka AR . Telomeres and early-life stress: an overview. Biol Psychiatry 2013; 73: 15–23.

    Article  CAS  PubMed  Google Scholar 

  45. Penninx BW, Beekman AT, Bandinelli S, Corsi AM, Bremmer M, Hoogendijk WJ et al. Late-life depressive symptoms are associated with both hyperactivity and hypoactivity of the hypothalamo-pituitary-adrenal axis. Am J Geriatr Psychiatry 2007; 15: 522–529.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67: 446–457.

    Article  CAS  PubMed  Google Scholar 

  47. Vogelzangs N, Duivis HE, Beekman ATF, Kluft C, Neuteboom J, Hoogendijk W et al. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Transl Psychiatry 2012; 2: e79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rottenberg J . Cardiac vagal control in depression: a critical analysis. Biol Psychol 2007; 74: 200–211.

    Article  PubMed  Google Scholar 

  49. Licht CM, de Geus EJ, Zitman FG, Hoogendijk WJ, van DR, Penninx BW . Association between major depressive disorder and heart rate variability in the Netherlands Study of Depression and Anxiety (NESDA). Arch Gen Psychiatry 2008; 65: 1358–1367.

    Article  PubMed  Google Scholar 

  50. Michel TM, Pulschen D, Thome J . The role of oxidative stress in depressive disorders. Curr Pharm Des 2012; 18: 5890–5899.

    Article  CAS  PubMed  Google Scholar 

  51. Choi J, Fauce SR, Effros RB . Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun 2008; 22: 600–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. von Zglinicki T . Oxidative stress shortens telomeres. Trends Biochem Sci 2002; 27: 339–344.

    Article  CAS  PubMed  Google Scholar 

  53. Damjanovic AK, Yang Y, Glaser R, Kiecolt-Glaser JK, Nguyen H, Laskowski B et al. Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients. J Immunol 2007; 179: 4249–4254.

    Article  CAS  PubMed  Google Scholar 

  54. Aviv A, Chen W, Gardner JP, Kimura M, Brimacombe M, Cao X et al. Leukocyte telomere dynamics: longitudinal findings among young adults in the Bogalusa Heart Study. Am J Epidemiol 2009; 169: 323–329.

    Article  PubMed  Google Scholar 

  55. Nordfjall K, Svenson U, Norrback KF, Adolfsson R, Lenner P, Roos G . The individual blood cell telomere attrition rate is telomere length dependent. PLoS Genet 2009; 5: e1000375.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Shalev I, Moffitt T, Sugden K, Williams B, Houts RM, Danese A et al. Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study. Mol Psychiatry 2012; 18: 576–581.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Teyssier JR, Ragot S, Donzel A, Chauvet-Gelinier JC . [Telomeres in the brain cortex of depressive patients]. Encephale 2010; 36: 491–494.

    Article  PubMed  Google Scholar 

  58. Zhang D, Cheng L, Craig DW, Redman M, Liu C . Cerebellar telomere length and psychiatric disorders. Behav Genet 2010; 40: 250–254.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Zhou QG, Hu Y, Wu DL, Zhu LJ, Chen C, Jin X et al. Hippocampal telomerase is involved in the modulation of depressive behaviors. J Neurosci 2011; 31: 12258–12269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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 USA 2004; 101: 17312–17315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wolkowitz OM, Mellon SH, Epel ES, Lin J, Reus VI, Rosser R et al. Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response. Mol Psychiatry 2012; 17: 164–172.

    Article  CAS  PubMed  Google Scholar 

  62. Puterman E, Lin J, Blackburn E, O'Donovan A, Adler N, Epel E . The power of exercise: buffering the effect of chronic stress on telomere length. PLoS One 2010; 5: e10837.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Du M, Prescott J, Kraft P, Han J, Giovannucci E, Hankinson SE et al. Physical activity, sedentary behavior, and leukocyte telomere length in women. Am J Epidemiol 2012; 175: 414–422.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Lin J, Epel E, Blackburn E . Telomeres and lifestyle factors: roles in cellular aging. Mutat Res 2012; 730: 85–89.

    Article  CAS  PubMed  Google Scholar 

  65. Osthus IB, Sgura A, Berardinelli F, Alsnes IV, Brønstad E, Rehn T et al. Telomere length and long-term endurance exercise: does exercise training affect biological age? A pilot study. PLoS One 2012; 7: e52769.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities and mental health-care organizations (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Institute for Quality of Health Care (IQ Healthcare), Netherlands Institute for Health Services Research (NIVEL) and Netherlands Institute of Mental Health and Addiction (Trimbos)). BP, JV, DR and telomere length assaying were supported through a NWO-VICI grant (number 91811602).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J E Verhoeven.

Ethics declarations

Competing interests

EE is a co-founder of Telome Health, Inc, a telomere measurement company. JL is an Associate Research Biochemist in the Department of Biochemistry and Biophysics at UCSF. The other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verhoeven, J., Révész, D., Epel, E. et al. Major depressive disorder and accelerated cellular aging: results from a large psychiatric cohort study. Mol Psychiatry 19, 895–901 (2014). https://doi.org/10.1038/mp.2013.151

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2013.151

Keywords

This article is cited by

Search

Quick links