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Depressive and anxiety disorders and short leukocyte telomere length: mediating effects of metabolic stress and lifestyle factors

  • D. Révész (a1), J. E. Verhoeven (a1), Y. Milaneschi (a1) and B. W. J. H. Penninx (a1)

Abstract

Background

Depressive and anxiety disorders are associated with shorter leukocyte telomere length (LTL), an indicator of cellular aging. It is, however, unknown which pathways underlie this association. This study examined the extent to which lifestyle factors and physiological changes such as inflammatory or metabolic alterations mediate the relationship.

Method

We applied mediation analysis techniques to data from 2750 participants of the Netherlands Study of Depression and Anxiety. LTL was assessed using quantitative polymerase chain reaction. Independent variables were current depressive (30-item Inventory of Depressive Symptoms – Self Report) and anxiety (21-item Beck's Anxiety Inventory) symptoms and presence of a depressive or anxiety disorder diagnosis based on DSM-IV; mediator variables included physiological stress systems, metabolic syndrome components and lifestyle factors.

Results

Short LTL was associated with higher symptom severity (B = −2.4, p = 0.002) and current psychiatric diagnosis (B = −63.3, p = 0.024). C-reactive protein, interleukin-6, waist circumference, triglycerides, high-density lipoprotein cholesterol and cigarette smoking were significant mediators in the relationship between psychopathology and LTL. When all significant mediators were included in one model, the effect sizes of the relationships between LTL and symptom severity and current diagnosis were reduced by 36.7 and 32.7%, respectively, and the remaining direct effects were no longer significant.

Conclusions

Pro-inflammatory cytokines, metabolic alterations and cigarette smoking are important mediators of the association between depressive and anxiety disorders and LTL. This calls for future research on intervention programs that take into account lifestyle changes in mental health care settings.

Copyright

Corresponding author

*Address for correspondence: J. E. Verhoeven, Department of Psychiatry, VU University Medical Center, A.J. Ernststraat 1187, 1081 HL Amsterdam, The Netherlands. (Email: D.Revesz@vumc.nl) [D.R.] (Email: J.Verhoeven@ggzingeest.nl) [J.E.V.]

References

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American Diabetes Association (2013). Standards of medical care in diabetes – 2013. Diabetes Care 36 (Suppl. 1), S11S66.
Bakhshaie, J, Zvolensky, MJ, Goodwin, RD (2015). Cigarette smoking and the onset and persistence of depression among adults in the United States: 1994–2005. Comprehensive Psychiatry 60, 142148.
Baylis, D, Ntani, G, Edwards, MH, Syddall, HE, Bartlett, DB, Dennison, EM, Martin-Ruiz, C, Von Zglinicki, T, Kuh, D, Lord, JM, Aihie Sayer, A, Cooper, C (2014). Inflammation, telomere length, and grip strength: a 10-year longitudinal study. Calcified Tissue International 95, 5463.
Beck, AT, Epstein, N, Brown, G, Steer, RA (1988). An inventory for measuring clinical anxiety: psychometric properties. Journal of Consulting and Clinical Psychology 56, 893897.
Boyle, M, Chun, C, Strojny, C, Narayanan, R, Bartholomew, A, Sundivakkam, P, Alapati, S (2014). Chronic inflammation and angiogenic signaling axis impairs differentiation of dental-pulp stem cells. PLOS ONE 9, e113419.
Cawthon, RM (2002). Telomere measurement by quantitative PCR. Nucleic Acids Research 30, e47.
Chan, SRWL, Blackburn, EH (2004). Telomeres and telomerase. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 359, 109121.
Cosci, F, Knuts, IJE, Abrams, K, Griez, EJL, Schruers, KRJ (2010). Cigarette smoking and panic: a critical review of the literature. Journal of Clinical Psychiatry 71, 606615.
Craig, CL, Marshall, AL, Sjostrom, M, Bauman, AE, Booth, ML, Ainsworth, BE, Pratt, M, Ekelund, U, Yngve, A, Sallis, JF, Oja, P (2003). International Physical Activity Questionnaire: 12-country reliability and validity. Medicine and Science in Sports and Exercise 35, 13811395.
Damjanovic, AK, Yang, Y, Glaser, R, Kiecolt-Glaser, JK, Nguyen, H, Laskowski, B, Zou, Y, Beversdorf, DQ, Weng, NP (2007). Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients. Journal of Immunology 179, 42494254.
Daniali, L, Benetos, A, Susser, E, Kark, JD, Labat, C, Kimura, M, Desai, K, Granick, M, Aviv, A (2013). Telomeres shorten at equivalent rates in somatic tissues of adults. Nature Communications 4, 1597.
Dowlati, Y, Herrmann, N, Swardfager, W, Liu, H, Sham, L, Reim, EK, Lanctot, KL (2010). A meta-analysis of cytokines in major depression. Biological Psychiatry 67, 446457.
Epel, ES, Lin, J, Wilhelm, FH, Wolkowitz, OM, Cawthon, R, Adler, NE, Dolbier, C, Mendes, WB, Blackburn, EH (2006). Cell aging in relation to stress arousal and cardiovascular disease risk factors. Psychoneuroendocrinology 31, 277287.
Fisher, AJ, Newman, MG (2013). Heart rate and autonomic response to stress after experimental induction of worry versus relaxation in healthy, high-worry, and generalized anxiety disorder individuals. Biological Psychology 93, 6574.
Gariepy, G, Nitka, D, Schmitz, N (2010). The association between obesity and anxiety disorders in the population: a systematic review and meta-analysis. International Journal of Obesity 34, 407419.
Haycock, PC, Heydon, EE, Kaptoge, S, Butterworth, AS, Thompson, A, Willeit, P (2014). Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. British Medical Journal 349, g4227.
Hayes, AF, Preacher, KJ (2014). Statistical mediation analysis with a multicategorical independent variable. British Journal of Mathematical and Statistical Psychology 67, 451470.
Hoge, EA, Brandstetter, K, Moshier, S, Pollack, MH, Wong, KK, Simon, NM (2009). Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder. Depression and Anxiety 26, 447455.
Howren, MB, Lamkin, DM, Suls, J (2009). Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosomatic Medicine 71, 171186.
Huang, J, Okuka, M, Lu, W, Tsibris, JCM, McLean, MP, Keefe, DL, Lui, L (2013). Telomere shortening and DNA damage of embryonic stem cells induced by cigarette smoke. Reproductive Toxicology 35, 8995.
Huzen, J, Wong, LS, van Veldhuisen, DJ, Samani, NJ, Zwinderman, AH, Codd, V, Cawthon, RM, Benus, GF, van der Horst, IC, Navis, G, Bakker, SJ, Gansevoort, RT, de Jong, PE, Hillege, HL, van Gilst, WH, de Boer, RA, van der Harst, P (2014). Telomere length loss due to smoking and metabolic traits. Journal of Internal Medicine 275, 155163.
Jurk, D, Wilson, C, Passos, JF, Oakley, F, Correia-Melo, C, Greaves, L, Saretzki, G, Fox, C, Lawless, C, Anderson, R, Hewitt, G, Pender, SL, Fullard, N, Nelson, G, Mann, J, van de Sluis, B, Mann, DA, von Zglinicki, T (2014). Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nature Communications 2, 4172.
Kemp, AH, Quintana, DS, Gray, MA, Felmingham, KL, Brown, K, Gatt, JM (2010). Impact of depression and antidepressant treatment on heart rate variability: a review and meta-analysis. Biological Psychiatry 67, 10671074.
Kroenke, CH, Epel, E, Adler, N, Bush, NR, Obradovic, J, Lin, J, Blackburn, E, Stamperdahl, JL, Boyce, WT (2011). Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children. Psychosomatic Medicine 73, 533540.
Lasser, K, Boyd, JW, Woolhandler, S, Himmelstein, DU, McCormick, D, Bor, DH (2000). Smoking and mental illness: a population-based prevalence study. Journal of the American Medical Association 284, 26062610.
Lee, J, Taneja, V, Vassallo, R (2012). Cigarette smoking and inflammation: cellular and molecular mechanisms. Journal of Dental Research 91, 142149.
Lee, M, Martin, H, Firpo, MA, Demerath, EW (2011). Inverse association between adiposity and telomere length: The Fels Longitudinal Study. American Journal of Human Biology 23, 100106.
Leventhal, AM, Zvolensky, MJ (2015). Anxiety, depression, and cigarette smoking: a transdiagnostic vulnerability framework to understanding emotion–smoking comorbidity. Psychological Bulletin 141, 176212.
Lindqvist, D, Epel, ES, Mellon, SH, Penninx, BW, Revesz, D, Verhoeven, JE, Reus, VI, Lin, J, Mahan, L, Hough, CM, Rosser, R, Bersani, FS, Blackburn, EH, Wolkowitz, OM (2015). Psychiatric disorders and leukocyte telomere length: underlying mechanisms linking mental illness with cellular aging. Neuroscience and Biobehavioral Reviews 55, 333364.
Liu, Y, Kha, H, Ungrin, M, Robinson, MO, Harrington, L (2002). Preferential maintenance of critically short telomeres in mammalian cells heterozygous for mTert. Proceedings of the National Academy of Sciences USA 99, 35973602.
Luger, TM, Suls, J, Vander Weg, MW (2014). How robust is the association between smoking and depression in adults? A meta-analysis using linear mixed-effects models. Addictive Behaviors 39, 14181429.
Luppino, FS, de Wit, LM, Bouvy, PF, Stijnen, T, Cuijpers, P, Penninx, BW, Zitman, FG (2010). Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Archives of General Psychiatry 67, 220229.
Middlekauff, HR, Park, J, Moheimani, RS (2014). Adverse effects of cigarette and noncigarette smoke exposure on the autonomic nervous system: mechanisms and implications for cardiovascular risk. Journal of the American College of Cardiology 64, 17401750.
Monickaraj, F, Gokulakrishnan, K, Prabu, P, Sathishkumar, C, Anjana, RM, Rajkumar, JS, Mohan, V, Balasubramanyam, M (2012). Convergence of adipocyte hypertrophy, telomere shortening and hypoadiponectinemia in obese subjects and in patients with type 2 diabetes. Clinical Biochemistry 45, 14321438.
Muezzinler, A, Zaineddin, AK, Brenner, H (2013). A systematic review of leukocyte telomere length and age in adults. Ageing Research Reviews 12, 509519.
O'Donovan, A, Hughes, BM, Slavich, GM, Lynch, L, Cronin, MT, O'Farrelly, C, Malone, KM (2010). Clinical anxiety, cortisol and interleukin-6: evidence for specificity in emotion–biology relationships. Brain, Behavior, and Immunity 24, 10741077.
Packard, CJ (1998). Overview of fenofibrate. European Heart Journal 19 (Suppl. A), A62A65.
Padmavathi, P, Reddy, VD, Swarnalatha, K, Hymavathi, R, Varadacharyulu, NC (2015). Influence of altered hormonal status on platelet 5-HT and MAO-B activity in cigarette smokers. Indian Journal of Clinical Biochemistry 30, 204209.
Parks, CG, Miller, DB, McCanlies, EC, Cawthon, RM, Andrew, ME, DeRoo, LA, Sandler, DP (2009). Telomere length, current perceived stress, and urinary stress hormones in women. Cancer Epidemiology, Biomarkers and Prevention 18, 551560.
Pavanello, S, Hoxha, M, Dioni, L, Bertazzi, PA, Snenghi, R, Nalesso, A, Ferrara, SD, Montisci, M, Baccarelli, A (2011). Shortened telomeres in individuals with abuse in alcohol consumption. International Journal of Cancer 129, 983992.
Penninx, BWJH, Beekman, ATF, Smit, JH, Zitman, FG, Nolen, WA, Spinhoven, P, Cuijpers, P, de Jong, PJ, Van Marwijk, HWJ, Assendelft, WJJ, van der Meer, K, Verhaak, P, Wensing, M, de Graaf, R, Hoogendijk, WJ, Ormel, J, Van Dyck, R (2008). The Netherlands Study of Depression and Anxiety (NESDA): rationale, objectives and methods. International Journal of Methods in Psychiatric Research 17, 121140.
Penninx, BWJH, Milaneschi, Y, Lamers, F, Vogelzangs, N (2013). Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Medicine 11, 129.
Picard, M, Turnbull, DM (2013). Linking the metabolic state and mitochondrial DNA in chronic disease, health, and aging. Diabetes 62, 672678.
Pruessner, JC, Kirschbaum, C, Meinlschmid, G, Hellhammer, DH (2003). Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology 28, 916931.
Puterman, E, Lin, J, Blackburn, E, O'Donovan, A, Adler, N, Epel, E (2010). The power of exercise: buffering the effect of chronic stress on telomere length. PLoS ONE 5, e10837.
Puterman, E, Lin, J, Krauss, J, Blackburn, E, Epel, E (2014). Determinants of telomere attrition over 1 year in healthy older women: stress and health behaviors matter. Molecular Psychiatry 20, 529–35.
Révész, D, Milaneschi, Y, Verhoeven, JE, Lin, J, Penninx, BWJH (2015). Longitudinal associations between metabolic syndrome components and telomere shortening. Journal of Clinical Endocrinology and Metabolism 100, 30503059.
Révész, D, Milaneschi, Y, Verhoeven, JE, Penninx, B (2014 a). Telomere length as a marker of cellular ageing is associated with prevalence and progression of metabolic syndrome. Journal of Clinical Endocrinology and Metabolism 99, 46074615.
Révész, D, Verhoeven, JE, Milaneschi, Y, de Geus, EJ, Wolkowitz, OM, Penninx, BWJH (2014 b). Dysregulated physiological stress systems and accelerated cellular aging. Neurobiology of Aging 35, 14221430.
Rush, AJ, Gullion, CM, Basco, MR, Jarrett, RB, Trivedi, MH (1996). The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychological Medicine 26, 477486.
Sahakyan, K, Somers, V, Rodriguez-Escudero, J, Hodge, D, Carter, R, Sochor, O, Coutinho, T, Jensen, M, Roger, V, Singh, P, Lopez-Jimenez, F (2015). Normal-weight central obesity: implications for total and cardiovascular mortality. Annals of Internal Medicine 163, 827835.
Schutte, NS, Malouff, JM (2015). The association between depression and leukocyte telomere length: a meta-analysis. Depression and Anxiety 32, 229238.
Stetler, C, Miller, GE (2011). Depression and hypothalamic–pituitary–adrenal activation: a quantitative summary of four decades of research. Psychosomatic Medicine 73, 114126.
Strine, TW, Mokdad, AH, Balluz, LS, Gonzalez, O, Crider, R, Berry, JT, Kroenke, K (2008). Depression and anxiety in the United States: findings from the 2006 Behavioral Risk Factor Surveillance System. Psychiatric Services 59, 13831390.
Tomiyama, AJ, O'Donovan, A, Lin, J, Puterman, E, Lazaro, A, Chan, J, Dhabhar, FS, Wolkowitz, O, Kirschbaum, C, Blackburn, E, Epel, E (2012). Does cellular aging relate to patterns of allostasis? An examination of basal and stress reactive HPA axis activity and telomere length. Physiology and Behavior 106, 4045.
Valdes, AM, Andrew, T, Gardner, JP, Kimura, M, Oelsner, E, Cherkas, LF, Aviv, A, Spector, TD (2005). Obesity, cigarette smoking, and telomere length in women. Lancet 366, 662664.
Van Gool, CH, Kempen, GIJM, Bosma, H, van Boxtel, MPJ, Jolles, J, van Eijk, JTM (2007). Associations between lifestyle and depressed mood: longitudinal results from the Maastricht Aging Study. American Journal of Public Health 97, 887894.
Van Reedt Dortland, AK, Giltay, EJ, van, VT, Zitman, FG, Penninx, BW (2010). Metabolic syndrome abnormalities are associated with severity of anxiety and depression and with tricyclic antidepressant use. Acta Psychiatrica Scandinavica 122, 3039.
Vera, E, Bernardes de, JB, Foronda, M, Flores, JM, Blasco, MA (2013). Telomerase reverse transcriptase synergizes with calorie restriction to increase health span and extend mouse longevity. PLOS ONE 8, e53760.
Verde, Z, Reinoso-Barbero, L, Chicharro, L, Garatachea, N, Resano, P, Sanchez-Hernandez, I, Rodriguez Gonzalez-Moro, JM, Bandres, F, Santiago, C, Gomez-Gallego, F (2015). Effects of cigarette smoking and nicotine metabolite ratio on leukocyte telomere length. Environmental Research 140, 488494.
Verhoeven, J, Révész, D, Epel, E, Lin, J, Wolkowitz, O, Penninx, B (2014 a). Major depressive disorder and accelerated cellular aging: results from a large psychiatric cohort study. Molecular Psychiatry 19, 895901.
Verhoeven, JE, Révész, D, Van Oppen, P, Epel, ES, Wolkowitz, O, Penninx, BWJH (2014 b). Anxiety disorders and accelerated cellular aging. British Journal of Psychiatry 206, 371378.
Verhoeven, JE, Révész, D, Wolkowitz, OM, Penninx, BW (2014 c). Cellular aging in depression: permanent imprint or reversible process?: An overview of the current evidence, mechanistic pathways, and targets for interventions. BioEssays 36, 968978.
Vogelzangs, N, Beekman, ATF, de Jonge, P, Penninx, BWJH (2013). Anxiety disorders and inflammation in a large adult cohort. Translational Psychiatry 3, e249.
Vreeburg, SA, Kruijtzer, BP, van Pelt, J, van Dyck, R, DeRijk, RH, Hoogendijk, WJ, Smit, JH, Zitman, FG, Penninx, BW (2009). Associations between sociodemographic, sampling and health factors and various salivary cortisol indicators in a large sample without psychopathology. Psychoneuroendocrinology 34, 11091120.
Ward, MC, White, DT, Druss, BG (2015). A meta-review of lifestyle interventions for cardiovascular risk factors in the general medical population: lessons for individuals with serious mental illness. Journal of Clinical Psychiatry 76, e477e486.
Weischer, M, Bojesen, SE, Nordestgaard, BG (2014). Telomere shortening unrelated to smoking, body weight, physical activity, and alcohol intake: 4,576 general population individuals with repeat measurements 10 years apart. PLoS Genetics 10, e1004191.
Wikgren, M, Maripuu, M, Karlsson, T, Nordfjall, K, Bergdahl, J, Hultdin, J, Del-Favero, J, Roos, G, Nilsson, LG, Adolfsson, R, Norrback, KF (2012). Short telomeres in depression and the general population are associated with a hypocortisolemic state. Biological Psychiatry 71, 294300.
Willeit, P, Raschenberger, J, Heydon, EE, Tsimikas, S, Haun, M, Mayr, A, Weger, S, Witztum, JL, Butterworth, AS, Willeit, J, Kronenberg, F, Kiechl, S (2014). Leucocyte telomere length and risk of type 2 diabetes mellitus: new prospective cohort study and literature-based meta-analysis. PLOS ONE 9, e112483.
Wong, JYY, De Vivo, I, Lin, X, Fang, SC, Christiani, DC (2014). The relationship between inflammatory biomarkers and telomere length in an occupational prospective cohort study. PLOS ONE 9, e87348.
World Health Organization (1997). The Composite Interview Diagnostic Instrument. WHO: Geneva.
Zhou, S, Wright, JL, Liu, J, Sin, DD, Churg, A (2013). Aging does not enhance experimental cigarette smoke-induced COPD in the mouse. PLOS ONE 8, e71410.
Ziedonis, D, Hitsman, B, Beckham, JC, Zvolensky, M, Adler, LE, Audrain-McGovern, J, Breslau, N, Brown, RA, George, TP, Williams, J, Calhoun, PS, Riley, WT (2008). Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report. Nicotine and Tobacco Research 10, 16911715.
Zvolensky, MJ, Taha, F, Bono, A, Goodwin, RD (2015). Big five personality factors and cigarette smoking: a 10-year study among US adults. Journal of Psychiatric Research 63, 9196.

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Depressive and anxiety disorders and short leukocyte telomere length: mediating effects of metabolic stress and lifestyle factors

  • D. Révész (a1), J. E. Verhoeven (a1), Y. Milaneschi (a1) and B. W. J. H. Penninx (a1)

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