Leukocyte telomere length: Effects of schizophrenia, age, and gender
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)
- et al.
A depression rating scale for schizophrenics
Schizophr. Res.
(1990) - et al.
Educational attainment and late life telomere length in the health, aging and body composition study
Brain Behav. Immun.
(2013 Jan) Telomeres and telomerase: their mechanisms of action and the effects of altering their functions
FEBS Lett.
(2005)- et al.
Association between telomere length in blood and mortality in people aged 60 years or older
Lancet
(2003) - et al.
Association of psychiatric illness and obesity, physical inactivity, and smoking among a national sample of veterans
Psychosomatics
(2011) Telomere/telomerase dynamics within the human immune system: effect of chronic infection and stress
Exp. Gerontol.
(2011)- et al.
Validation of a physical activity assessment tool for individuals with schizophrenia
Schizophr. Res.
(2006) - et al.
Nutrients, foods, dietary patterns and telomere length: update of epidemiological studies and randomized trials
Metabolism
(2016) - et al.
Age and neuropsychologic function in schizophrenia: a decline in executive abilities beyond that observed in healthy volunteers
Biol. Psychiatry
(2000) - et al.
Gender and telomere length: systematic review and meta-analysis
Exp. Gerontol.
(2014)
Associations of high sensitivity C-reactive protein levels in schizophrenia and comparison groups
Schizophr. Res.
Excess heart-disease-related mortality in a national study of patients with mental disorders: identifying modifiable risk factors
Gen. Hosp. Psychiatry
Testing the hypothesis of accelerated cerebral white matter aging in schizophrenia and major depression
Biol. Psychiatry
Elevated plasma F2-isoprostane levels in schizophrenia
Schizophr. Res.
Analyses and comparisons of telomerase activity and telomere length in human T and B cells: insights for epidemiology of telomere maintenance
J. Immunol. Methods.
Shortened leukocyte telomere length in patients with schizophrenia is related to disease status
Schizophr. Res.
Psychiatric disorders and leukocyte telomere length: underlying mechanisms linking mental illness with cellular aging
Neurosci. Biobehav Rev.
Explaining discrepancies between longitudinal and cross-sectional models
J. Chronic Dis.
Does telomere length mediate associations between inbreeding and increased risk for bipolar I disorder and schizophrenia?
Psychiatry Res.
A systematic review of leukocyte telomere length and age in adults
Ageing Res. Rev.
Longer telomere length in patients with schizophrenia
Schizophr. Res.
Leukocyte telomere length in patients with schizophrenia: a meta-analysis
Schizophr. Res.
Telomeres and early-life stress: an overview
Biol. Psychiatry.
Serious mental illness and physical health problems: a discussion paper
Int. J. Nurs. Stud.
Do schizophrenia patients age early?
Asian J. Psychiatr.
Leukocyte telomere length is not associated with mortality in older men
Exp. Gerontol.
Evaluation of Defined Daily Dose, percentage of British National Formulary maximum and chlorpromazine equivalents in antipsychotic drug utilization
Saudi Pharm. J.
Oxidative stress shortens telomeres
Trends Biochem. Sci.
Mortality associated with incident mental health disorders after stroke
Aust. N. Z. J. Psychiatry
Symptoms of schizophrenia. Methods, meanings, and mechanisms
Arch. Gen. Psychiatry
Negative v positive schizophrenia. Definition and validation
Arch. Gen. Psychiatry
Ageing: live faster, die younger
Nature
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.
Telomeres and human health
J. Intern Med.
Meta-analysis of telomere length in 19,713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect
Eur. J. Hum. Genet.
Telomere measurement by quantitative PCR
Nucleic Acids Res.
The effects of social status on biological aging as measured by white-blood-cell telomere length
Aging Cell
T cell replicative senescence in human aging
Curr. Pharm. Des.
A global measure of perceived stress
J. Health Soc. Behav.
International physical activity questionnaire: 12-country reliability and validity
Med. Sci. Sports Exerc
Are psychiatric disorders associated with shorter telomeres? A meta-analysis involving 14,827 Persons
Psychosom. Med.
Cognitive profiles in persons with chronic schizophrenia
J. Clin. Exp. Neuropsychol.
Delis-Kaplan Executive Function Scale (D-KEFS): Examiner's Manual
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2021, Journal of AutoimmunityCitation Excerpt :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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