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:

Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response

Molecular Psychiatry volume 17, pages 164–172 (2012)Cite this article

Abstract

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Murray CJ, AD L . Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet 1997; 349: 1436–1442.

    Article  CAS  Google Scholar 

  2. Duman RS, Heninger GR, Nestler EJ . A molecular and cellular theory of depression. Arch gen psychiatry 1997; 54: 597–606.

    Article  CAS  Google Scholar 

  3. Manji HK, Gottesman II, Gould TD . Signal transduction and genes-to-behaviors pathways in psychiatric diseases. Sci STKE 2003; 2003: pe49.

    PubMed  Google Scholar 

  4. 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  Google Scholar 

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

    Article  Google Scholar 

  6. 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  Google Scholar 

  7. 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. 2010 (in review).

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

    Article  Google Scholar 

  9. Blackburn EH . Telomere states and cell fates. Nature 2000; 408: 53–56.

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. Effros RB . Kleemeier Award Lecture 2008--the canary in the coal mine: telomeres and human healthspan. jgerontol 2009; 64: 511–515.

    Google Scholar 

  12. Calado RT, Young NS . Telomere diseases. N Engl J Med 2009; 361: 2353–2365.

    Article  CAS  Google Scholar 

  13. 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: 17312–17315.

    Article  CAS  Google Scholar 

  14. von Zglinicki T, Martin-Ruiz CM . Telomeres as biomarkers for ageing and age-related diseases. Curr mol med 2005; 5: 197–203.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Mattson MP, Fu W, Zhang P . Emerging roles for telomerase in regulating cell differentiation and survival: a neuroscientist′s perspective. Mech ageing dev 2001; 122: 659–671.

    Article  CAS  Google Scholar 

  17. Gorbunova V, Seluanov A . Telomerase as a growth-promoting factor. Cell cycle (Georgetown, TX) 2003; 2: 534–537.

    Article  CAS  Google Scholar 

  18. Zhu H, Fu W, Mattson MP . The catalytic subunit of telomerase protects neurons against amyloid beta-peptide-induced apoptosis. J Neurochem 2000; 75: 117–124.

    Article  CAS  Google Scholar 

  19. Calado RT, Chen J . Telomerase: not just for the elongation of telomeres. Bioessays 2006; 28: 109–112.

    Article  CAS  Google Scholar 

  20. Geserick C, Blasco MA . Novel roles for telomerase in aging. Mech ageing dev 2006; 127: 579–583.

    Article  CAS  Google Scholar 

  21. Sung YH, Choi YS, Cheong C, Lee HW . The pleiotropy of telomerase against cell death. Mol Cells 2005; 19: 303–309.

    CAS  PubMed  Google Scholar 

  22. Kang HJ, Choi YS, Hong SB, Kim KW, Woo RS, Won SJ et al. Ectopic expression of the catalytic subunit of telomerase protects against brain injury resulting from ischemia and NMDA-induced neurotoxicity. J Neurosci 2004; 24: 1280–1287.

    Article  CAS  Google Scholar 

  23. Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE et al. Cell aging in relation to stress arousal and cardiovascular disease risk factors. Psychoneuroendocrinology 2006; 31: 277–287.

    Article  CAS  Google Scholar 

  24. 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  Google Scholar 

  25. Parks CG, Miller DB, McCanlies EC, Cawthon RM, Andrew ME, DeRoo LA et al. Telomere length, current perceived stress, and urinary stress hormones in women. Cancer Epidemiol Biomarkers Prev 2009; 18: 551–560.

    Article  CAS  Google Scholar 

  26. Kotrschal A, Ilmonen P, Penn DJ . Stress impacts telomere dynamics. Biol Lett 2007; 3: 128–130.

    Article  CAS  Google Scholar 

  27. Tyrka AR, Price LH, Kao HT, Porton B, Marsella SA, Carpenter LL . Childhood Maltreatment and Telomere Shortening: Preliminary Support for an Effect of Early Stress on Cellular Aging. Biol psychiatry 2010; 67: 531–534.

    Article  CAS  Google Scholar 

  28. Kananen L, Surakka I, Pirkola S, Suvisaari J, Lonnqvist J, Peltonen L et al. Childhood adversities are associated with shorter telomere length at adult age both in individuals with an anxiety disorder and controls. PloS one 2010; 5: e10826.

    Article  Google Scholar 

  29. Serrano AL, Andres V . Telomeres and cardiovascular disease: does size matter? Circ res 2004; 94: 575–584.

    Article  CAS  Google Scholar 

  30. Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH . Telomere shortening in atherosclerosis. Lancet 2001; 358: 472–473.

    Article  CAS  Google Scholar 

  31. Huzen J, de Boer RA, van Veldhuisen DJ, van Gilst WH, van der Harst P . The emerging role of telomere biology in cardiovascular disease. Front Biosci 2010; 15: 35–45.

    Article  Google Scholar 

  32. Grodstein F, van Oijen M, Irizarry MC, Rosas HD, Hyman BT, Growdon JH et al. Shorter telomeres may mark early risk of dementia: preliminary analysis of 62 participants from the nurses’ health study. PloS one 2008; 3: e1590.

    Article  Google Scholar 

  33. Fuster JJ, Andres V . Telomere biology and cardiovascular disease. Circ res 2006; 99: 1167–1180.

    Article  CAS  Google Scholar 

  34. Farzaneh-Far R, Cawthon RM, Na B, Browner WS, Schiller NB, Whooley MA . Prognostic value of leukocyte telomere length in patients with stable coronary artery disease: data from the Heart and Soul Study. Arterioscler thromb vasc biol 2008; 28: 1379–1384.

    Article  CAS  Google Scholar 

  35. 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  Google Scholar 

  36. Brouilette SW, Moore JS, McMahon AD, Thompson JR, Ford I, Shepherd J et al. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. Lancet 2007; 369: 107–114.

    Article  CAS  Google Scholar 

  37. Aviv A . Telomeres and human somatic fitness. j gerontol 2006; 61: 871–873.

    Article  Google Scholar 

  38. Adaikalakoteswari A, Balasubramanyam M, Mohan V . Telomere shortening occurs in Asian Indian type 2 diabetic patients. Diabet Med 2005; 22: 1151–1156.

    Article  CAS  Google Scholar 

  39. Valdes AM, Richards JB, Gardner JP, Swaminathan R, Kimura M, Xiaobin L et al. Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis. Osteoporos Int 2007; 18: 1203–1210.

    Article  CAS  Google Scholar 

  40. Epel ES, Merkin SS, Cawthon R, Blackburn EH, Adler NE, Pletcher MJ et al. The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men. Aging 2009 published on line: 12/19/08 1: 81–88.

    Article  CAS  Google Scholar 

  41. Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999; 96: 701–712.

    Article  CAS  Google Scholar 

  42. Effros RB . Telomerase induction in T cells: A cure for aging and disease? Exp gerontol 2007; 42: 416–420.

    Article  CAS  Google Scholar 

  43. 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 2009; 352: 71–80.

    Article  Google Scholar 

  44. Zhang J, Kong Q, Zhang Z, Ge P, Ba D, He W . Telomere dysfunction of lymphocytes in patients with Alzheimer disease. Cogn Behav Neurol 2003; 16: 170–176.

    Article  Google Scholar 

  45. First MB, Spitzer RL, Gibbon M . Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Reserach Version, Patient Edition (SCID-I/P). New York State Psychiatric Institute Biometrics Research: New York, 2002.

    Google Scholar 

  46. Yehuda R . Advances in understanding neuroendocrine alterations in PTSD and their therapeutic implications. Ann N Y Acad Sci 2006; 1071: 137–166.

    Article  CAS  Google Scholar 

  47. Hamilton M . Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6: 278–296.

    Article  CAS  Google Scholar 

  48. Rush AJ, Giles DE, Schlesser MA, Fulton CL, Weissenburger J, Burns C . The inventory for depressive symptomatology (IDS): preliminary findings. Psychiatry res 1986; 18: 65–87.

    Article  CAS  Google Scholar 

  49. Cohen S, Kamarck T, Mermelstein R . A global measure of perceived stress. J Health Soc behav 1983; 24: 385–396.

    Article  CAS  Google Scholar 

  50. Dipietro L, Caspersen CJ, Ostfeld AM, Nadel ER . A survey for assessing physical activity among older adults. Med sci sports exerc 1993; 25: 628–642.

    Article  CAS  Google Scholar 

  51. Mauri MC, Laini V, Cerveri G, Scalvini ME, Volonteri LS, Regispani F et al. Clinical outcome and tolerability of sertraline in major depression: a study with plasma levels. Prog neuropsychopharmacol biol psychiatry 2002; 26: 597–601.

    Article  CAS  Google Scholar 

  52. Akiyama M, Hideshima T, Hayashi T, Tai YT, Mitsiades CS, Mitsiades N et al. Cytokines modulate telomerase activity in a human multiple myeloma cell line. Cancer Res 2002; 62: 3876–3882.

    CAS  Google Scholar 

  53. Kawauchi K, Ihjima K, Yamada O . IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3′-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells. J Immunol 2005; 174: 5261–5269.

    Article  CAS  Google Scholar 

  54. Bettendorf O, Schmidt H, Eltze E, Rody A, Herchenroder F, Jackisch C et al. Quantitative measurement of telomerase activity and localization of its catalytic subunit (hTERT) in chronic inflammation of capsule formation around various model implants and in sarcomas in a rat model. J biomed mater res 2008; 85: 646–650.

    Article  CAS  Google Scholar 

  55. Nishikawa T, Nakajima T, Katagishi T, Okada Y, Jo M, Kagawa K et al. Oxidative stress may enhance the malignant potential of human hepatocellular carcinoma by telomerase activation. Liver Int 2009; 29: 846–856.

    Article  CAS  Google Scholar 

  56. Liu DY, Peng ZH, Qiu GQ, Zhou CZ . Expression of telomerase activity and oxidative stress in human hepatocellular carcinoma with cirrhosis. World J Gastroenterol 2003; 9: 1859–1862.

    Article  CAS  Google Scholar 

  57. Tsirpanlis G, Chatzipanagiotou S, Boufidou F, Kordinas V, Zoga M, Alevyzaki F et al. Serum oxidized low-density lipoprotein is inversely correlated to telomerase activity in peripheral blood mononuclear cells of haemodialysis patients. Nephrology (Carlton) 2006; 11: 506–509.

    Article  CAS  Google Scholar 

  58. Epel ES, Lin J, Dhabhar FS, Wolkowitz OM, Puterman E, Karan L et al. Dynamics of telomerase activity in response to acute psychological stress. Brain behav immun 2010; 24: 531–539.

    Article  CAS  Google Scholar 

  59. Hug N, Lingner J . Telomere length homeostasis. Chromosoma 2006; 115: 413–425.

    Article  CAS  Google Scholar 

  60. Britt-Compton B, Capper R, Rowson J, Baird DM . Short telomeres are preferentially elongated by telomerase in human cells. FEBS letters 2009; 583: 3076–3080.

    Article  CAS  Google Scholar 

  61. Harley CB . Telomerase therapeutics for degenerative diseases. Curr mol med 2005; 5: 205–211.

    Article  CAS  Google Scholar 

  62. Baek S, Bu Y, Kim H, Kim H . Telomerase induction in astrocytes of Sprague-Dawley rat after ischemic brain injury. Neurosci lett 2004; 363: 94–96.

    Article  CAS  Google Scholar 

  63. Zhang P, Dilley C, Mattson MP . DNA damage responses in neural cells: focus on the telomere. Neuroscience 2007; 145: 1439–1448.

    Article  CAS  Google Scholar 

  64. Ornish D, Lin J, Daubenmier J, Weidner G, Epel E, Kemp C et al. Increased telomerase activity and comprehensive lifestyle changes: a pilot study. Lancet Oncol 2008; 9: 1048–1057.

    Article  CAS  Google Scholar 

  65. Werner C, Furster T, Widmann T, Poss J, Roggia C, Hanhoun M et al. Physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall. Circulation 2009; 120: 2438–2447.

    Article  Google Scholar 

  66. Ludlow AT, Zimmerman JB, Witkowski S, Hearn JW, Hatfield BD, Roth SM . Relationship between physical activity level, telomere length, and telomerase activity. Med sci sports exerc 2008; 40: 1764–1771.

    Article  CAS  Google Scholar 

  67. Jacobs TL, Epel ES, Lin J, Blackburn EH, Wolkowitz OM, Bridwell DA et al. Intensive meditation training, immune cell telomerase activity, and psychological mediators. Psychoneuroendocrinology, 2010 (in press).

  68. Calcagnile O, Gisselsson D . Telomere dysfunction and telomerase activation in cancer--a pathological paradox? Cytogenet genome res 2007; 118: 270–276.

    Article  CAS  Google Scholar 

  69. Saretzki G . Telomerase, mitochondria and oxidative stress. Exp gerontol 2009; 44: 485–492.

    Article  CAS  Google Scholar 

  70. Ahmed S, Passos JF, Birket MJ, Beckmann T, Brings S, Peters H et al. Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J cell sci 2008; 121 (Part 7): 1046–1053.

    Article  CAS  Google Scholar 

  71. Panossian LA, Porter VR, Valenzuela HF, Zhu X, Reback E, Masterman D et al. Telomere shortening in T cells correlates with Alzheimer′s disease status. Neurobiol aging 2003; 24: 77–84.

    Article  CAS  Google Scholar 

  72. Tarkanyi I, Aradi J . Pharmacological intervention strategies for affecting telomerase activity: future prospects to treat cancer and degenerative disease. Biochimie 2008; 90: 156–172.

    Article  CAS  Google Scholar 

  73. Samper E, Flores JM, Blasco MA . Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres. EMBO reports 2001; 2: 800–807.

    Article  CAS  Google Scholar 

  74. Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA et al. A Natural Product Telomerase Activator As Part of a Health Maintenance Program. Rejuvenation research 2010 (e-pub Ahead of print).

  75. Adler N, Epel ES, Castellazzo G, Ickovics JR . Relationship of subjective and objective social status with psychological and physiological functioning: preliminary data in healthy white women. Health Psychol 2000; 19: 586–592.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the assistance of Steven Hamilton, MD, PhD (UCSF), who assisted in evaluating the depressed subjects, of Jean Tillie (Stanford), who performed cytokine assays, of Yali Su, PhD (Kronos) and the lab of Jason Morrow, MD (Vanderbilt), who performed oxidation assays, of Alanie Lazaro and Genevieve Manalo (both UCSF), who assisted in study procedures, laboratory collections and assays, and the nursing and other staff of the UCSF CTSI's Clinical Research Center. This study was funded by an NIMH R01 grant (R01 MH083784), a grant from the O’Shaughnessy Foundation and grants from the UCSF Academic Senate, the UCSF Research Evaluation and Allocation Committee (REAC) and the Bernard and Barbro Osher Foundation. This project was also supported by NIH/ NCRR UCSF-CTSI Grant Number UL1 RR024131. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. None of the granting or funding agencies had a role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review, or approval of the manuscript. The Principal Investigator, Owen Wolkowitz, MD, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosures 1. Drs Elizabeth Blackburn, Elissa Epel and Jue Lin are co-founders of Telome Health Inc., a diagnostics company related to telomere biology, and they own stock in the company.

2. Drs Elizabeth Blackburn, Elissa Epel, Jue Lin, Owen Wolkowitz and Synthia Mellon, on behalf of the Regents of the University of California (who will be assignees of the patent), have applied for a patent covering the use of cell aging markers (including telomerase activity) as a biomarker of depression.

Clinical Trials Registration: Registry name: ClinicalTrials.gov. URL: http://ClinicalTrials.govClinicalTrials.govIdentifier: NCT00285935.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of California, San Francisco (UCSF), School of Medicine, San Francisco, CA, USA

    O M Wolkowitz, V I Reus, R Rosser, M Compagnone & J C Nelson

  2. Department of OB-GYN and Reproductive Sciences, UCSF School of Medicine, San Francisco, CA, USA

    S H Mellon

  3. Department of Psychiatry and Health Psychology Program, UCSF School of Medicine, San Francisco, CA, USA

    E S Epel & H Burke

  4. Department of Biochemistry and Biophysics, UCSF School of Medicine, San Francisco, CA, USA

    J Lin & E H Blackburn

  5. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    F S Dhabhar

Authors
  1. O M Wolkowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S H Mellon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E S Epel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V I Reus
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Rosser
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Burke
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Compagnone
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J C Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F S Dhabhar
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. E H Blackburn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O M Wolkowitz.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wolkowitz, O., Mellon, S., Epel, E. et al. Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response. Mol Psychiatry 17, 164–172 (2012). https://doi.org/10.1038/mp.2010.133

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2010.133

Keywords

This article is cited by

Search

Advanced search

Quick links