Elsevier

Journal of Psychiatric Research

Volume 85, February 2017, Pages 42-48
Journal of Psychiatric Research

Leukocyte telomere length: Effects of schizophrenia, age, and gender

https://doi.org/10.1016/j.jpsychires.2016.10.015Get rights and content

Abstract

Background

Schizophrenia is linked with early medical comorbidity and mortality. These observations indicate possible “accelerated biological aging” in schizophrenia, although prior findings are mixed, and few such studies have examined the role of gender. One putative marker of biological aging is leukocyte telomere length (LTL), which typically shortens with age.

Methods

We assessed LTL in phenotypically well characterized 134 individuals with schizophrenia (60 women and 74 men) and 123 healthy comparison subjects (HCs) (66 women and 57 men), aged 26 to 65 years.

Results

Overall, LTL was inversely associated with age (t(249) = -6.2, p < 0.001), and a gender effect on the rate of LTL decrease with age was found (t(249) = 2.20, p = 0.029), with men declining more rapidly than women. No significant overall effect of diagnosis on the rate of decline was detected. However, at the average sample age (48 years), there was a significant gender effect in both schizophrenia and HC groups (t(249) = 2.48, p = 0.014), with women having longer LTL than men, and a significant gender X diagnosis effect (t(249) = 2.43, p = 0.016) - at the average sample age, women with schizophrenia had shorter LTL than HC women.

Discussion

Gender, not the diagnosis of schizophrenia, was the major factor involved with LTL shortening across the age range studied. We discuss the constraints of a cross-sectional design and other methodological issues, and indicate future directions. Understanding the impact of schizophrenia on biological aging will require separate evaluations in men and women.

Introduction

Schizophrenia is associated with major medical co-morbidity, a 3- to 5-fold increase in premature death, and an estimated 15–20 years of shortened life span (Dickerson et al., 2014, Kilbourne et al., 2009, Kirkpatrick et al., 2008, Olfson et al., 2015). This has led to a suggestion that schizophrenia is associated with accelerated biological aging (Anthes, 2014, Dawes et al., 2011, Kirkpatrick et al., 2008, Kochunov et al., 2013, Koutsouleris et al., 2014, Lindqvist et al., 2015, Okusaga, 2014, Schnack et al., 2016, Shivakumar et al., 2014). Whereas men have overall higher death rates than women, mortality ratios in schizophrenia (standardized to the general population with respect to age, race/ethnicity and geographic region) are higher in women than in men with schizophrenia, with cardiovascular disease being a leading cause of premature death in both genders (Olfson et al., 2015). The causes of medical co-morbidity and premature mortality in schizophrenia are not fully understood but are likely multifactorial, including lifestyle factors (Chwastiak et al., 2011, Robson and Gray, 2007), antipsychotic drugs, and poor access to health care (McCabe and Leas, 2008) as well as intrinsic biological differences (Ringen et al., 2014). Reasons for possible gender-related differences in mortality ratios in schizophrenia remain obscure.

Whereas chronological age is measured in calendar years, biological age is defined physiologically and is often more closely associated with disease processes (Cawthon et al., 2003, Epel, 2009, Lindqvist et al., 2015). Accelerated biological aging occurs when biological age outpaces chronological age (Lindqvist et al., 2015). One marker of biological age is telomere length (TL), often measured in leukocytes (LTL), since it progressively declines with age and may be inversely related to diseases of aging and mortality (Bojesen, 2013, Cawthon et al., 2003, Mather et al., 2011, Muezzinler et al., 2013, Svensson et al., 2014). However, peak LTL (shortly after birth), the age at which a decline begins, the rate of decline, and when death interrupts the process, vary among individuals (Svensson et al., 2014), suggesting important inter-individual differences in the rates of biological aging (Epel, 2012, Lindqvist et al., 2015, Muezzinler et al., 2013). Variability in telomere length among people of the same chronological age raises the possibility that telomere shortening is potentially modifiable (Bojesen, 2013).

Telomeres are DNA–protein complexes that cap chromosomal DNA ends, protecting chromosomes from damage. When telomeres reach a critically short length, cells undergo replicative senescence or apoptosis or can become genomically unstable (Blackburn, 2005). Telomere length is influenced by genetic factors (Broer et al., 2013), demographic factors and environmental exposure. Telomeres shorten with advancing age (Muezzinler et al., 2013) and are generally shorter in men than in women (Gardner et al., 2014). Telomeres also shorten with repeated mitosis in somatic cells, with replication- and nuclease-associated telomeric DNA damage, and with exposure to oxidative stress, certain cytotoxins, inflammation, and possibly stress hormones (Effros, 2011, Epel et al., 2004, Lindqvist et al., 2015, von Zglinicki, 2002, Wolkowitz et al., 2011). Among the most important lifestyle- and experience-related factors that may impinge on LTL are stress (Epel, 2009, Epel et al., 2004), tobacco use (Babizhayev et al., 2011), exercise (Puterman et al., 2010); and diet (Epel, 2009, Freitas-Simoes et al., 2016), as well certain medical risk factors, such as visceral adiposity (Epel, 2009) (but see (Diaz et al., 2010)), metabolic stress (Epel, 2009) and certain chronic viral infections (e.g., cytomegalovirus) (Effros, 2011). It is unknown if these genetic, lifestyle, and environmental factors also affect LTL in schizophrenia, or if they differ between women and men with schizophrenia.

The published literature on LTL in schizophrenia is based on cross-sectional studies. Because concomitants of aging, including changes in LTL with age, are processes taking place within individuals over time, with individual differences in time course, longitudinal studies are ultimately necessary to fully understand these phenomena. However, if the changes over time are generally monotonic (e.g., LTL decreasing within individuals over time), results shown to be age-related in cross-sectional studies are likely to be even more strongly age-related in longitudinal studies, as cross-sectional studies tend to attenuate time effects. Consequently, cross-sectional studies provide clues as to which factors may be considered in the design of such studies. Thus far, cross-sectional studies have reported mixed results. Several investigations found shorter LTL in persons with schizophrenia than in healthy comparison subjects (HCs) (Fernandez-Egea et al., 2009, Kao et al., 2008) or at least in subgroups of individuals with more chronic, severely psychotic, or treatment-resistant illness (Kota et al., 2015, Li et al., 2015, Rao et al., 2016, Yu et al., 2008) (but see (Lin, 2015)), possibly suggesting accelerated biological aging (Jeste et al., 2011, Kirkpatrick et al., 2008). However, one large study reported longer LTL in schizophrenia than in HCs (Nieratschker et al., 2013). Yet other studies have detected no difference in LTL between individuals with schizophrenia and HCs (Li et al., 2015, Malaspina et al., 2014, Mansour et al., 2011). Reasons for discrepancies in findings among these studies are not known, but may include inadequate sample sizes, differing gender distributions, quality of diagnostic evaluations, nature of the comparison sample, chronicity and severity of illness, medical illnesses, medication history, and history of treatment responsiveness, along with demographic and lifestyle factors such as age, diet, body-mass index (BMI), exercise, and tobacco use. Nonetheless, reviews and meta-analyses of these studies of LTL (Darrow et al., 2016, Lindqvist et al., 2015) support decreased LTL in schizophrenia compared to HCs, with an effect size of approximately d = 0.34, with the effect size being larger in subgroups of subjects who were either drug-naïve (d = 0.56) or poor responders to medication (d = 0.97) (Darrow et al., 2016, Lin, 2015, Polho et al., 2015).

The present study, using a relatively large sample size with adequate representation of women and men with schizophrenia and HCs, well matched in age from 26 to 65 years (mean age = 48), was designed to assess the simultaneous association of age, gender, and diagnosis with LTL. We hypothesized that shorter LTL would be associated with older age (Muezzinler et al., 2013), male gender (Gardner et al., 2014) and diagnosis of schizophrenia (Darrow et al., 2016, Lindqvist et al., 2015). Demographics as well as certain factors associated with schizophrenia or aging, such as cigarette consumption, physical exercise, nutrition, stress, psychiatric ratings, antipsychotic medication doses, and physical health, were also explored.

Section snippets

Study participants

This report is based on an analysis of baseline data from an ongoing longitudinal study of biological aging in schizophrenia (NIH R01 MH094151-01 [PI: Dilip V. Jeste]). Although we previously published data on high sensitivity C-reactive protein (hs-CRP) (Joseph et al., 2015), F2-isoprostanes (Lee et al., 2016), as well as cytokines (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) (Lee et al., In Press) and chemokines (Hong et al., In Press) in earlier subsets of

Demographics

We compared persons with schizophrenia and those with schizoaffective disorder, and found no significant between-group differences on socio-demographic, clinical, or lifestyle variables except that individuals with schizophrenia had lower levels of education than those with schizoaffective disorder. We combined those two groups for further analyses. The duration of illness for the men with schizophrenia was 23.6 ± 13.0 years and for women 23.5 ± 11.5 years. The Total antipsychotic dose (DDD)

Discussion

The present results may suggest that gender, not the diagnosis of schizophrenia, is the major factor involved with LTL shortening across the age range studied. Because numerous studies have shown that the onset of schizophrenia tends to be later in life in women than in men (Howard et al., 2000), and the present results indicate that the separation between women with schizophrenia and HC women might differ from that between men with schizophrenia and HC men at various ages, understanding the

Conflicts of interest

Jue Lin is a cofounder and consultant to Telomere Diagnostics, Inc. The company played no role in the current study.

Other authors have no other conflicts of interest to report.

Acknowledgements

This study was supported, in part, by NIH R01MH094151-01 (PI: Dilip V. Jeste, MD); and by the Stein Institute for Research on Aging at the University of California, San Diego.

References (86)

  • J. Joseph et al.

    Associations of high sensitivity C-reactive protein levels in schizophrenia and comparison groups

    Schizophr. Res.

    (2015)
  • A.M. Kilbourne et al.

    Excess heart-disease-related mortality in a national study of patients with mental disorders: identifying modifiable risk factors

    Gen. Hosp. Psychiatry

    (2009)
  • P. Kochunov et al.

    Testing the hypothesis of accelerated cerebral white matter aging in schizophrenia and major depression

    Biol. Psychiatry

    (2013)
  • E.E. Lee et al.

    Elevated plasma F2-isoprostane levels in schizophrenia

    Schizophr. Res.

    (2016 Oct)
  • J. Lin 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 Jan 31)
  • P.Y. Lin

    Shortened leukocyte telomere length in patients with schizophrenia is related to disease status

    Schizophr. Res.

    (2015)
  • D. Lindqvist et al.

    Psychiatric disorders and leukocyte telomere length: underlying mechanisms linking mental illness with cellular aging

    Neurosci. Biobehav Rev.

    (2015)
  • T.A. Louis et al.

    Explaining discrepancies between longitudinal and cross-sectional models

    J. Chronic Dis.

    (1986)
  • H. Mansour et al.

    Does telomere length mediate associations between inbreeding and increased risk for bipolar I disorder and schizophrenia?

    Psychiatry Res.

    (2011)
  • A. Muezzinler et al.

    A systematic review of leukocyte telomere length and age in adults

    Ageing Res. Rev.

    (2013)
  • V. Nieratschker et al.

    Longer telomere length in patients with schizophrenia

    Schizophr. Res.

    (2013)
  • G.B. Polho et al.

    Leukocyte telomere length in patients with schizophrenia: a meta-analysis

    Schizophr. Res.

    (2015)
  • L.H. Price et al.

    Telomeres and early-life stress: an overview

    Biol. Psychiatry.

    (2013 Jan 1)
  • D. Robson et al.

    Serious mental illness and physical health problems: a discussion paper

    Int. J. Nurs. Stud.

    (2007)
  • V. Shivakumar et al.

    Do schizophrenia patients age early?

    Asian J. Psychiatr.

    (2014)
  • J. Svensson et al.

    Leukocyte telomere length is not associated with mortality in older men

    Exp. Gerontol.

    (2014)
  • W.M. Sweileh et al.

    Evaluation of Defined Daily Dose, percentage of British National Formulary maximum and chlorpromazine equivalents in antipsychotic drug utilization

    Saudi Pharm. J.

    (2014)
  • T. von Zglinicki

    Oxidative stress shortens telomeres

    Trends Biochem. Sci.

    (2002)
  • O.P. Almeida et al.

    Mortality associated with incident mental health disorders after stroke

    Aust. N. Z. J. Psychiatry

    (2007)
  • N.C. Andreasen et al.

    Symptoms of schizophrenia. Methods, meanings, and mechanisms

    Arch. Gen. Psychiatry

    (1995)
  • N.C. Andreasen et al.

    Negative v positive schizophrenia. Definition and validation

    Arch. Gen. Psychiatry

    (1982)
  • E. Anthes

    Ageing: live faster, die younger

    Nature

    (2014)
  • M.A. Babizhayev et al.

    Telomere length is a biomarker of cumulative oxidative stress, biologic age, and an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior

    Am. J. Ther.

    (2011)
  • S.E. Bojesen

    Telomeres and human health

    J. Intern Med.

    (2013)
  • L. Broer et al.

    Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

    Eur. J. Hum. Genet.

    (2013)
  • R.M. Cawthon

    Telomere measurement by quantitative PCR

    Nucleic Acids Res.

    (2002)
  • L.F. Cherkas et al.

    The effects of social status on biological aging as measured by white-blood-cell telomere length

    Aging Cell

    (2006)
  • J.P. Chou et al.

    T cell replicative senescence in human aging

    Curr. Pharm. Des.

    (2013)
  • S. Cohen et al.

    A global measure of perceived stress

    J. Health Soc. Behav.

    (1983)
  • C.L. Craig et al.

    International physical activity questionnaire: 12-country reliability and validity

    Med. Sci. Sports Exerc

    (2003)
  • S. Darrow et al.

    Are psychiatric disorders associated with shorter telomeres? A meta-analysis involving 14,827 Persons

    Psychosom. Med.

    (2016 Sep)
  • S.E. Dawes et al.

    Cognitive profiles in persons with chronic schizophrenia

    J. Clin. Exp. Neuropsychol.

    (2011)
  • D. Delis et al.

    Delis-Kaplan Executive Function Scale (D-KEFS): Examiner's Manual

    (2001)
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      Telomere length (TL) has been associated to the pace of ageing and to the onset/severity of ageing-related diseases [3]. At the time of birth, TL is highly variable in mammals, specifically humans [3–5], and appears to be associated with parental TL [6–19], gender [16,17,20–29] and ethnicity [25,26,29–32]. From this starting point, telomere attrition accompanies normal ageing.

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