Telomerase levels in schizophrenia: A preliminary study

doi:10.1016/j.schres.2008.08.028

Schizophrenia Research

Volume 106, Issues 2–3, December 2008, Pages 242-247

https://doi.org/10.1016/j.schres.2008.08.028 Get rights and content

Abstract

We previously demonstrated that telomere length was markedly reduced in peripheral blood lymphocytes from individuals with schizophrenia. Since reduced telomere length can be caused by decreased telomerase activity, we quantitated basal telomerase activity in peripheral blood lymphocytes derived from individuals with schizophrenia (n = 53), unaffected relatives (n = 31) and unrelated controls (n = 59). Telomerase activity varied greatly among individuals, suggesting that this enzymatic activity is affected by various factors. We observed a nominally significant decrease in telomerase activity among individuals with schizophrenia compared to unaffected individuals (unaffected relatives and unrelated controls). Further studies are needed to investigate the role of telomerase in schizophrenia.

Introduction

In somatic cells, the ends of chromosomes, known as telomeres, progressively shorten with each cell division, a phenomenon resulting from incomplete replication of linear chromosomes by DNA polymerases. Telomerase is a specialized cellular ribonucleoprotein reverse transcriptase that extends telomeres, thereby protecting them and maintaining chromosomal integrity (Blackburn, 2005). In most somatic cells, telomerase is expressed at insufficient levels to completely restore telomeres, and telomeres progressively shorten with each cell division. Telomerase plays a critical role in cellular aging, since maintaining the length of telomeres extends the lifetime of cells (Blackburn, 2005). Thus, telomere length reflects the proliferative history of cells and serves as a mitotic clock of physical aging in many organisms (Blasco, 2005, von Zglinicki and Martin-Ruiz, 2005, Blackburn, 2005).

Abnormal telomere functioning has been implicated in many human diseases associated with aging, including cardiovascular disease (Brouilette et al., 2003, Demissie et al., 2006), neurodegenerative disorders (von Zglinicki et al., 2000, Martin-Ruiz et al., 2006), diabetes (Mitchell and Malone, 2006, Demissie et al., 2006, Jeanclos et al., 1998), and cancer (Blasco, 2005, von Zglinicki and Martin-Ruiz, 2005, Cawthon et al., 2003). These investigations utilized telomere length in peripheral blood cells as a marker for the progression of aging in the whole organism (von Zglinicki and Martin-Ruiz, 2005). Recently, telomere dysfunction in peripheral leukocytes has also been described in psychiatric conditions. Accelerated telomere shortening and decreased telomerase activity has been reported in chronically stressed individuals (Epel et al., 2004) and accelerated telomere shortening has been reported in mood disorders (Simon et al., 2006) and schizophrenia (Kao et al., 2008).

Schizophrenia is not generally conceptualized as an aging disorder since the age of onset usually occurs during adolescence. However, pathological aging may be a component of this disorder, since there are structural brain abnormalities (Buchsbaum and Hazlett, 1997, DeLisi, 1997) and brain hypometabolic patterns (Buchsbaum and Hazlett, 1997, Pettegrew et al., 1993) that mimic findings seen in the elderly. Moreover, individuals with schizophrenia are prone to diseases associated with aging, including diabetes and cardiovascular complications (Hennekens et al., 2005, Mitchell and Malone, 2006), as well as a shorter natural lifespan than the general population (Tsuang and Woolson, 1978). Our recent observation that telomere lengths of peripheral blood lymphocytes is markedly reduced in schizophrenia is consistent with the notion that abnormal aging is present in this disorder (Kao et al., 2008).

Since one mechanism by which telomeres shorten rapidly in cells is reduced telomerase activity, the goal of this study was to quantitate telomerase levels in individuals with schizophrenia and unaffected controls.

Section snippets

Subjects

Subjects were recruited from two departments at the Nathan Kline Institute: cohort A was recruited from the Outpatient Research Department (under the direction of W.M.G.), and cohort B and their unaffected first degree family members were recruited as part of a family study within the Center for Advanced Brain Imaging (under the direction of L.E.D.). Unaffected controls were recruited from both departments at the same institute.

Diagnoses were made using DSM-IV criteria. For cohort A, the SCID

Real-time quantification of telomerase activity

Many assays for telomerase activity are semi-quantitative, and antibody-based assays are not available. Here, we utilized a commercial real-time PCR-based assay for the sensitive quantification of telomerase activity (Allied Biotech, Inc.). The assay involves incubating cell extract with an artificial DNA substrate for telomerase (telomerase reaction), followed by real-time PCR quantification of telomeres added to the substrate (Wege et al., 2003). qPCR was monitored with Sybr Green, an

Discussion

Our recent studies demonstrate that significant telomere shortening occurs in individuals with schizophrenia (Kao et al., 2008). To gain a better understanding of telomere biology in this disorder, we examined telomerase levels in the same individuals afflicted with schizophrenia. We observed that telomerase activity was highly variable among individuals. Moreover, no correlation between telomerase activity and telomere length was observed (data not shown). Indeed, previous studies have also

Role of funding source

Funding for this study was provided by grants from the NIH, the Stanley Research Foundation and NARSAD; the NIH, the Stanley Research Foundation and the NARSAD had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Authors Barbara Porton and Hung-Teh Kao designed the study, optimized the telomerase assay, carried out the experimental analyses, and wrote the first draft of the manuscript. Ping Li isolated lymphocytes from blood and carried out many of the telomerase assays that were performed in replicates.

Lynn E. DeLisi provided patient samples (cohort B) for the study and supervised Hilary C. Bertisch. Hilary C. Bertisch obtained consents, history, conducted SCIDs, and procured blood samples for the

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgements

This research was supported by the US National Institutes of Health (R01 MH070898 to B.P.; R01 NS047209 to H.-T.K.; R21 MH071720 to L.E.D.; R01 MH044292 to Jurg Ott), the Stanley Research Medical Foundation (to B.P.), and the National Alliance for Research on Schizophrenia and Depression (NARSAD). We thank Laura Panek, Alexis Moreno, Kyle Brown, and Laurie Nash for assistance in data collection, recruitment of subjects, diagnostic interviewing, and blood collection. We also thank Shelby Sturgis

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It has also been suggested that in schizophrenia, shorter TL was specifically observed in patients reporting childhood abuse (Aas et al., 2019). Furthermore, the classic case-control studies that include subjects in different stages of the disorder might add to the confusion because of the presence in variable proportion or for variable durations of potential confounding factors like medications (Rao et al., 2016; Porton et al., 2008), duration of illness and unhealthy lifestyles (e.g., poor diet, smoking). All these factors may impact upon rates of telomere shortening (Maurya et al., 2017a; Yu et al., 2008) and confound the association between schizophrenia and TL.
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Telomerase levels in schizophrenia: A preliminary study

Abstract

Introduction

Section snippets

Subjects

Real-time quantification of telomerase activity

Discussion

Role of funding source

Contributors

Conflict of interest

Acknowledgements

Anal. Biochem.

FEBS Lett.

Schizophr. Res.

Lancet

Biol. Psych.

Schizophr. Res.

Am. Heart J.

Psychoneuroendocrinology

Immunopharmacology

Exp Cell Res

Biol. Psych.

J. Autoimmun.

Schizophr. Res.

Lab. Invest.

User bulletin #2, ABI PRISM 7700 Sequence detection system. P/N 4303859B

Telomeres and human disease: ageing, cancer and beyond

Nat. Rev., Genet.

White cell telomere length and risk of premature myocardial infarction

Arterioscler. Thromb. Vasc. Biol.

Telomerase regulation during entry into the cell cycle in normal human T cells

Mol. Biol. Cell

Altered T-cell function in schizophrenia: a cellular model to investigate molecular disease mechanisms

PLoS ONE

Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients

J. Immunol.

Haloperidol blood levels and clinical outcome: a meta-analysis of studies relevant to testing the therapeutic window hypothesis

J. Clin. Pharm. Ther.

Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study

Aging Cell