Up-regulation of leucocytes genes implicated in telomere dysfunction and cellular senescence correlates with depression and anxiety severity scores

Jean-Raymond Teyssier, Jean-Christophe Chauvet-Gelinier, Sylviane Ragot, Bernard Bonin, Jean-Raymond Teyssier, Jean-Christophe Chauvet-Gelinier, Sylviane Ragot, Bernard Bonin

Abstract

Background: Major depressive disorder (MDD) is frequently associated with chronic medical illness responsible of increased disability and mortality. Inflammation and oxidative stress are considered to be the major mediators of the allostatic load, and has been shown to correlate with telomere erosion in the leucocytes of MDD patients, leading to the model of accelerated aging. However, the significance of telomere length as an exclusive biomarker of aging has been questioned on both methodological and biological grounds. Furthermore, telomeres significantly shorten only in patients with long lasting MDD. Sensitive and dynamic functional biomarkers of aging would be clinically useful to evaluate the somatic impact of MDD.

Methodology: To address this issue we have measured in the blood leucocytes of MDD patients (N=17) and controls (N=16) the expression of two genes identified as robust biomarkers of human aging and telomere dysfunction: p16(INK4a) and STMN1. We have also quantified the transcripts of genes involved in the repair of oxidative DNA damage at telomeres (OGG1), telomere regulation and elongation (TERT), and in the response to biopsychological stress (FOS and DUSP1).

Results: The OGG1, p16(INK4a), and STMN1 gene were significantly up-regulated (25 to 100%) in the leucocytes of MDD patients. Expression of p16(INK4a) and STMN1 was directly correlated with anxiety scores in the depression group, and that of p16(INK4a), STMN and TERT with the depression and anxiety scores in the combined sample (MDD plus controls). Furthermore, we identified a unique correlative pattern of gene expression in the leucocytes of MDD subjects.

Conclusions: Expression of p16(INK4) and STMN1 is a promising biomarker for future epidemiological assessment of the somatic impact of depressive and anxious symptoms, at both clinical and subclinical level in both depressive patients and general population.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Adjustment curves of the linear…
Figure 1. Adjustment curves of the linear regression analysis showing the direct correlation between the expression level of p16INK4 (F = 15.68, R2 = 0.51, p = 0.001) and STMN1 (F = 12.54, R2 = 0.45, p = 0.003) and the anxiety scores (HAM-A scale).
Figure 2. Adjustment curves of the linear…
Figure 2. Adjustment curves of the linear regression analysis showing the direct correlation of HAM-A and HAM-D scores with gene expression in the combined sample (depressed plus controls): HAM-D with p16INKa (F = 8.7, R2 = 0.27, p = 0.002), HAM-A with p16INKa (F = 21.3, R2 = 0.43, p = 0.000), HAM-D with STMN1 (F = 15.7, R2 = 0.38, p = 0.001), HAM-A with STMN1 (F = 22.8, R2 = 0.44, p = 0.000), HAM-D with TERT (F = 4.9, R2 = 0.17, p = 0.03), HAM-A with TERT (F = 9.2, R2 = 0.23, p = 0.005).

References

    1. Kupfer DJ, Frank E, Phillips ML (2012) Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet 379: 1045–1055.
    1. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, et al. (2007) Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet 370: 851–858.
    1. Patten SB, Williams JVA, Lavorato DH, Modgill G, Jetté N, Eliasziw M (2008) Major depression as a risk factor for chronic disease incidence: longitudinal analyses in a general population cohort. Gen Hosp Psychiatry 30: 407–413.
    1. Murphy JM, Burke Jr JD, Monson RR, Horton NJ, Laird NM, et al. (2008) Mortality associated with depression. Soc Psychiatry Epidemiol 45: 594–601.
    1. McIntyre RS, Soczynska JK, Konarski JZ, Woldeyohannes HO, Law CWY, et al. (2007) Should depressive syndrome be reclassified as “etabolic syndrome Type II”? Ann Clin Psychiatry 4: 257–264.
    1. Krishnadas R, Cavanagh J (2012) Depression: an inflammatory illness? J Neurol Neurosurg Psychiatry 83: 495–502.
    1. Capuron L, Su S, Miller AH, Bremmer JD, Goldberg J, et al. (2088) Depressive symtoms and metabolic syndrome: is inflammation the underlying link? Biol Psychiatry 64: 896–900.
    1. Maes M, Galecki P, Chang YS, Berk M (2011) A review on the oxidative and nitrosative stress (O§NS) pathways in major depression and their possible contribution to the (neuro) degenerative process in that illness. Prog Neuropsychopharmacol Biol Psychiatry 35: 676–692.
    1. McEven BS (2003) Mood disorders and allostatic load. Biol Psychiatry 54: 200–207.
    1. Zhu H, Belcher M, van der Harst P (2011) Healthy aging and disease: role for telomere biology? Clinical Science 120: 427–440.
    1. Bakaysa SL, Mucci LA, Slagboom PE, Boomsma DI, McClearn GE, et al. (2007) Telomere length predicts survival independent of genetic influences. Aging Cell 6: 769–774.
    1. Houben JMJ, Moonen HJJ, van Schooten FJ, Hageman GJ (2008) Telomere length assessment: biomarker of chronic oxidative stress? Free Radic Biol Med 44: 235–246.
    1. Wolkowitz OM, Mellon SH, Epel ES, Lin J, Dhabhar FS, et al. (2011) Leucocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress – preliminary findings. PloS One 6: e17837.
    1. Wolkowitz OM, Reus VI, Mellon SH (2011) Of sound mind and body: depression, disease, and accelerated aging. Dial Clin Neurosci 13: 25–39.
    1. Aviv A, Valdes AM, Spector TD (2006) Human telomere biology: pitfalls of moving from the laboratory to epidemiology. Int J Epidemiol 35: 1424–1429.
    1. Shiels PG (2010) Improving precision in investigating aging: why telomeres can cause problems? J Gerontol A Biol Sci Med Sci 65: 789–791.
    1. Mather KA, Jorm AF, Parslow RA, Christensen H (2011) Is telomere length a biomarker of aging? A review. J Gerontol A Biol Sci Med Sci 66: 202–213.
    1. Herbig U, Sedivy JM (2006) Regulation of growth in senescence: telomere damage is not the end of the story. Mech Ageing Dev 127: 16–24.
    1. Kariseder J, Smogorzewska A, de Lange T (2002) Senescence induced by altered telomere state, not telomere loss. Science 295: 2446–2449.
    1. Takai H, Smogorzewska A, de Lange T (2003) DNA damage foci at dysfunctional telomeres. Cur Biol 13: 1549–1556.
    1. Kaul Z, Cesare AJ, Huschtscha LI, Neumann AA, Reddel RR (2012) Five dysfunctional telomeres predict onset of senescence in human cells. EMBO reports 13: 52–59.
    1. Jiang H, Schiffer E, Song Z, Wang J, Zürbig P, et al. (2008) Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease. Proc Natl Acad Sci USA 105: 11299–11304.
    1. Rayess H, Wang MB, Srivatsan ES (2012) Cellular senescence and tumor suppressor gene p16. Int J Cancer 130: 1715–1725.
    1. Herbig U, Jobling WA, Chen BPC, Chen DJ, Sedivy JM (2004) Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21cip1, but not p16INK4a . Mol Cell 14: 501–513.
    1. Jacobs JJL, de Lange T (2005) p16INK4a as a second effector of the telomere damage pathway. Cell Cycle 4: 1364–1368.
    1. Zhang X, Wu X, Tang W, Luo Y (2012) Loss of p16INK4a function recues cellular senescence induced by telomere dysfunction. Int J Mol Sci 13: 5866–5877.
    1. Le-Niculescu H, Case NJ, Hulvershorn L, Patel SD, Bowker D, et al. (2011) Convergent functional genomic studies of omega-3 fatty acids in stress reactivity, bipolar disorder and alcoholism. Transl Psychiatry 1: e4.
    1. Rusyn I, Asakura S, Pachkowski B, Bradford BU, Denissenko MF, et al. (2004) Expression of base excision repair genes is a sensitive biomarker for in vivo detection of chemical-induced chronic oxidative stress: identification of the molecular source of radicals responsible for DNA damage by peroxisome proliferators. Cancer Res 64: 1050–1057.
    1. Lu J, Liu Y (2010) Deletion of Ogg1 DNA glycosylase results in telomere base damage and length alteration in yeast. Embo J 29: 398–409.
    1. Howren MB, Lamkin DM, Suls J (2009) Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 71: 171–186.
    1. Johson TE (2006) Recent results: biomarkers of aging. Exp Gerontol 41: 1243–1246.
    1. Wolkowitz OM, Mellon SH, Epel ES, Lin J, Reus VI, et al. (2012) Resting leucocyte telomerase activity is elevated in major depression and predicts treatment response. Mol Psychiatry 17: 164–172.
    1. Cifuentes-Rojas C, Shippen DE (2012) Telomerase regulation. Mut Res 730: 20–27.
    1. Saliques S, Teyssier JR, Vergely C, Lorgis L, Lorin J, et al. (2011) Circulating leukocyte telomere length and oxidative stress: a new target for statin therapy. Atherosclerosis 219: 753–760.
    1. Saliques S, Teyssier JR, Vergely C, Lorgis L, Lorin J, et al. (2011) Smoking and FOS expression from blood leukocyte transcripts in patients with coronary artery disease. Atherosclerosis 219: 931–936.
    1. Vandesompele J, De Peter K, Pattyn F, Poppe B, Van Roy N, et al. (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3: 0034.1–0034.11.
    1. Cawthon RM. Telomere measurement by quantitative PCR (2002) Nucleic Acids Res. 30: e47.
    1. Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30: e36.
    1. Song Z, von Figura G, Liu Y, Kraus JM, Torrice C, et al. (2010) Lifestyle impacts on the aging-associated expression of biomarkers of DNA damage and telomere dysfunction in human blood. Aging Cell 9: 607–615.
    1. Curmi PA, Gavet O, Charbaut E, Ozon S, Lachkar-Colmerauer S, et al. (1999) Stathmin and its phosphoprotein family: general properties, biochemical and functional interaction with tubulin. Cell Struct Funct 24: 345–357.
    1. Gil J, Peters G (2006) Regulation of the INK4b-ARF-INK4a tumor suppressor locus: all for one or one for all. Nat Rev Mol Biol 7: 667–677.
    1. Melzer D, Frayling TM, Murray A, Hurst AJ, Harries LW, et al. (2007) A common variant of the p16(INK4a) genetic region is associated with physical function in older people. Mec Aging Dev 128: 370–377.
    1. The Welcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common disease and 3,000 shared controls. Nature 447: 661–678.
    1. Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, et al. (2006) p16INK4a is a robust in vivo biomarker of cellular aging in human skin. Aging Cell 5: 379–389.
    1. Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, et al. (2004) INK4a/Arf expression is a biomarker of aging. J Clin Invest 114: 1299–1307.
    1. Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM (2006) Cellular senescence in aging primates. Science 311: 1257.
    1. Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, et al. (2009) Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell 8: 439–448.
    1. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, et al. (2011) Clearance of p16INK4a–positive senescent cells delays ageing-associated disorders. Nature 479: 232–236.
    1. David SS, O'Shea VL, Kundu S (2007) Base-excision repair of oxidative DNA damage. Nature 447: 941–950.
    1. Wang Z, Rhee DB, Lu J, Bohr CT, Zhou F, et al. (2010) Characterization of oxidative guanine damage and repair in mammalian telomeres. PloS Genet 6: e1000951.
    1. Forlenza MJ, Miller GE (2006) Increased serum level of 8-hydroxy-2′-deoxyguanosine in clinical depression. Psychosom Med 68: 1–7.
    1. Xu G, Herzig M, Rotrekl, Walter CA (2008) Base excision repair, aging and health span. Mech Aging Dev 129: 366–382.
    1. Iossifov I, Zheng T, Baron M, Gillian TC, Rzhetsky A (2008) Genetic-linkage mapping of complex hereditary disorders to a whole-genome molecular-interaction network. Genome Res 18: 1150–1162.
    1. Simon NM, Smoller JW, McNamara KL, Maser RS, zalta AK, et al. (2006) Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol Psychiary 60: 432–435.
    1. Hartmann N, Boehner M, Groenen F, Kalb R (2010) Telomere length of patients with major depression is shortened but independent from therapy and severity of the disease. Depress Anxiety 27: 1111–1116.
    1. Wikgren M, Maripuu M, Karlsson T, Nordfjäll K, Bergdahl J, et al. (2012) Short telomeres in depression and the general population are associated with a hypocortisolemic state. Biol Psychiatry 71: 294–300.
    1. O'Donovan A, Pantell MS, Puterman E, Dhabhar FS, Blackburn EH, et al. (2001) Cumulative inflammatory load is associated with short leucocyte telomere length in the Health, Aging, and Body Composition Study. PloS ONE 6: e19687.
    1. O'Donnell A, Odrowaz Z, Sharrocks AD (2012) Immediate-early gene activation by the MAPK pathways: what do and don't we know? Biochem Soc Trans 40: 58–66.
    1. Wancket LM, Frazier WJ, Liu Y (2012) Mitogen-activated protein kinase phosphatase (MKP)-1 in immunology, physiology and disease. Life Sciences 90: 237–248.
    1. Patini WD, Mian OY, Kang JG, Matoba S, Barlett LD, et al. (2005) Circulating transcriptome reveals markers of atherosclerosis. Proc Natl Acad Sci USA 102: 3423–3428.
    1. Mukherjee S, Firpo EJ, Wang Y, Roberts JM (2011) Separation of telomerase functions by reverse genetics. Proc Natl Acad Sci USA 108: E1363–E1371.
    1. Teyssier JR, Ragot S, Chauvet-Gelinier JC, Trojak B, Bonin B (2011) Expression of oxidative stress-response genes is not activated in the prefrontal cortex of patients with depressive disorder. Psychiatry Res 186: 244–247.
    1. Lu T, Pan Y, Kao SY, Li C, Kohane I, et al. (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429: 883–891.
    1. Shumyatsky GP, Malleret G, Shin RM, Takizawa S, Tully K, et al. (2005) stathmin, a gene enriched in the amygdala, controls both learned and innate fear. Cell 123: 697–709.
    1. Brocke B, Lesch KP, Armbruster D, Moser DA, Müller A, et al. (2009) stahtmin, a gene regulating neural plasticity, affects fear and anxiety processing in humans. Am J Med Genet Part B 153B: 243–251.
    1. Ehlis AC, Bauernschmitt K, Dresler T, Hahn T, Hermann MJ, et al. (2011) Influence of a genetic variant of the neuronal growth associated protein stathmin-1 on cognitive and affective control processes: an event-related potential study. Am J Med Genet Part B 156B: 291–302.

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