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Review

Early Senescence and Leukocyte Telomere Shortening in SCHIZOPHRENIA: A Role for Cytomegalovirus Infection?

by
Corona Solana
1,*,
Diana Pereira
1 and
Raquel Tarazona
2,*
1
Centro Hospitalar Psiquiatrico de Lisboa, 1700-063 Lisboa, Portugal
2
Immunology Unit, University of Extremadura, 10003 Caceres, Spain
*
Authors to whom correspondence should be addressed.
Brain Sci. 2018, 8(10), 188; https://doi.org/10.3390/brainsci8100188
Submission received: 29 August 2018 / Revised: 9 October 2018 / Accepted: 16 October 2018 / Published: 18 October 2018
(This article belongs to the Special Issue Vulnerability to Schizophrenia and Psychosis)
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Abstract

:
Schizophrenia is a severe, chronic mental disorder characterized by delusions and hallucinations. Several evidences support the link of schizophrenia with accelerated telomeres shortening and accelerated aging. Thus, schizophrenia patients show higher mortality compared to age-matched healthy donors. The etiology of schizophrenia is multifactorial, involving genetic and environmental factors. Telomere erosion has been shown to be accelerated by different factors including environmental factors such as cigarette smoking and chronic alcohol consumption or by psychosocial stress such as childhood maltreatment. In humans, telomere studies have mainly relied on measurements of leukocyte telomere length and it is generally accepted that individuals with short leukocyte telomere length are considered biologically older than those with longer ones. A dysregulation of both innate and adaptive immune systems has been described in schizophrenia patients and other mental diseases supporting the contribution of the immune system to disease symptoms. Thus, it has been suggested that abnormal immune activation with high pro-inflammatory cytokine production in response to still undefined environmental agents such as herpesviruses infections can be involved in the pathogenesis and pathophysiology of schizophrenia. It has been proposed that chronic inflammation and oxidative stress are involved in the course of schizophrenia illness, early onset of cardiovascular disease, accelerated aging, and premature mortality in schizophrenia. Prenatal or neonatal exposures to neurotropic pathogens such as Cytomegalovirus or Toxoplasma gondii have been proposed as environmental risk factors for schizophrenia in individuals with a risk genetic background. Thus, pro-inflammatory cytokines and microglia activation, together with genetic vulnerability, are considered etiological factors for schizophrenia, and support that inflammation status is involved in the course of illness in schizophrenia.

Graphical Abstract

1. Introduction

Schizophrenia is a severe, chronic mental disorder, with a heterogeneous genetic and neurobiological background, characterized by delusions, hallucinations and thought disorder, that causes an important impairment in social and vocational functioning. Current treatment consists largely in the use of antipsychotic drugs combined with psychological and social support, but no cure is currently available, mostly due to the poor understanding of the disease pathogenesis [1,2,3,4]. The etiology of schizophrenia is multifactorial, involving genetic and environmental factors [5].
It has been suggested that several genes can be associated with schizophrenia [6,7,8], including those associated with synaptic function and neurobehavioral phenotypes [9]. Accumulating data using new genomic approaches in combination with extensive neuroimaging collections of brain phenotypes is contributing to the definition of new putative schizophrenia risk genes [10,11] and support the interest of genetically-based patient stratification in patient subgroups sharing deficits in particular biological pathways [12] or the use of common genetic variants to predict endophenotypes such as spatial visualization [13].
In relation with the environmental factors, epidemiological and serological studies in the last decade have highlighted the significance of chronic infections by several pathogens, including viruses (Cytomegalovirus, CMV, and other herpesviruses) and parasites, such as Toxoplasma gondii (T. gondii), in the pathogenesis and clinical evolution of schizophrenia [14,15].
Schizophrenia patients show higher mortality rates than those who died without schizophrenia [16,17,18,19,20]. In a recent meta-analysis, it has been estimated that schizophrenia is associated with 13–15 years of potential life lost and with a life expectancy of 60 years for men and 68 years for women [21]. It has been recently suggested that schizophrenia might be considered as a syndrome of “accelerated aging” [22] or as a “segmental progeroid syndrome” [23].
In this review, we present and discuss recent evidences supporting the role of infection by CMV and other pathogens and inflammation in telomere shortening and accelerated senescence in schizophrenia patients.

2. CMV Is a Major Driver of Immunosenescence

Several biological parameters have been defined as hallmarks of ageing [24]. These hallmarks include the age-associated deterioration of the immune response, also termed immunosenescence, and the existence of age-associated low-grade inflammation usually known as inflamm-ageing [25]. CMV infection is associated with immunosenescence and the accumulation of highly differentiated T cell clones [26,27] characterized by the production of pro-inflammatory cytokine [28,29,30,31,32,33]. One of the major hallmarks of immunosenescence is leukocyte telomere shortening [34].
Telomeres are DNA and protein structures present at the ends of chromosomes to prevent the loss of coding genetic material during cell replication. Telomeres shorten with each cell division and shortened telomeres induce a DNA damage response leading to a growth arrest and, eventually, triggering replicative senescence [35,36,37,38]. Telomerase, which it is normally expressed in pluripotent and adult stem cell, compensates for telomere attrition by the addition of TTAGGG repeats onto chromosome ends [39,40,41,42]. Telomerase-deficient mice show premature aging phenotypes, providing the first evidences that telomere attrition is a determinant of longevity and is at the origin of different age-related pathologies [43,44,45].
Telomere attrition occurs in normal tissues at an estimated rate of 50 to 150 base pairs per cell division, resulting in a gradual decrease in median telomere lengths with increasing age [46]. Circumstances associated with replicative stresses enhance telomere shortening secondary to the increased mitotic activity. Thus, chronic infection by different pathogens, in particular chronic viruses, accelerate leukocyte telomere length (LTL) attrition [47,48]. In addition, the production of reactive oxygen species associated with chronic inflammation, that can also be produced in response to chronic infection, several drugs and toxic products, or radiation exposure, also cause DNA damage and telomere loss [49]. Finally, inheritable gene mutations affecting the telomerase or the telomere protein complex, resulting in decreased telomere lengths (short telomere syndromes, STSs) [50,51]. These syndromes are characterized by severe alterations in hematopoiesis (bone marrow failure) and in organs with high cell turnover, such as skin (dyskeratosis), gastrointestinal tract (esophageal stenosis, enterocolitis, celiac-like enteropathy) and lungs (idiopathic pulmonary fibrosis) [50,51].

2.1. CMV and Leukocyte Telomere Shortening in Healthy Ageing

In humans, telomere studies have mainly relied on measurements of LTL, which reflects telomere length (TL) in other somatic cells. LTL displays high variation across individuals, a phenomenon already observed in newborns and that has been related to different factors such as sex, ethnicity, or parental age at conception (reviewed in [52]). LTL is considered a biomarker of human ageing, and it is generally accepted that individuals with short LTL are biologically older than those with longer ones. However, recent evidences suggest that short telomeres increase the risk of age-related diseases and play a role in the development of these diseases. Although the causes of age-associated frailty are multiple, telomere shortening, immunosenescence and inflamm-ageing have been implicated in its pathophysiology.
Peripheral blood T lymphocytes that have undergone a process of replicative senescence (immunosenescence) are characterized by loss of proliferation, telomere shortening, and by the decreased expression of CD28 and CD27 co-stimulatory molecules and the expression of CD57 [34,53,54,55,56]. These hallmarks of immunosenescence increase with healthy ageing and also in clinical situations associated with chronic activation of the immune response and an accumulation of CD28−CD27−CD57+ T cells occurs during normal aging and chronic-antigen stimulation [25,57,58,59]. Senescence and telomere shortening is observed in particular in CMV infection, characterized by accumulation of cells with a more differentiated state and shorter telomeres than in other virus infections, such as human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), and hepatitis C virus (HCV) [47,48], indicating that CMV is a major driver of immunosenescence.
LTL correlates with lymphocyte telomere length and with the amount of highly differentiated T cells. In addition, telomere shortening is more rapid in CMV-seropositive individuals, indicating that CMV infection induces a strong decrease in T cell telomere length [60]. CMV seropositivity and CMV IgG antibodies correlate not only with LTL but also with telomerase activity [61] The telomere lengths in total and CMV-specific T cells are shorter in old compared to young individuals, although the accumulated end-stage cells are multifunctional T cells and do not have the shortest telomeres [31]. CMV seropositivity and increased total pathogen burden level are significantly associated with shorter telomere length among females [62]. Infection by CMV and other herpes viruses (herpes simplex virus type 1 (HSV1), and human herpesvirus 6) are associated with greater LTL attrition, and higher IgG anti-CMV were also associated with shorter LTL after 3-year follow-up [63]. In a recent longitudinal analysis of healthy individuals (age range 21 to 88 years), with an average follow-up of 13 years (7–19 years) follow-up, age-related telomere attrition, elevated pro-inflammatory cytokines and anti-CMV IgG levels were observed, although no significant correlations among these inflamm-ageing and immunosenescence related parameters were observed, indicating the complexity of the immune aging processes [64].

2.2. CMV Seropositivity and Inflammation

Since the original demonstration that CMV seropositivity was associated with phenotypic and functional alterations of T-cell immunity similar to those found in ageing [27], and that CMV infection induces a strong decrease in T cell telomere length [60], cumulative evidences have extensively documented that CMV infection is characterized by the expansion of CD28/CD27 negative or CD57+ senescent T cells, with short telomeres and high production of pro-inflammatory cytokines [25,26,34,54,60,65,66,67,68,69,70,71,72]. The analysis of CMV in frailty has shown that the frequency of CMV reactivation is associated with aging and ongoing frailty [73], while CMV-seropositivity is not associated with pre-frailty in very old subjects [74].
The possible relationship between CMV infection with psychological stress has been recently highlighted in a recent study showing that early-life adverse and stressful events, such as parental loss or low socioeconomic status, increase the risk of CMV infection. The authors also propose that CMV-driven immunosenescence and inflammation underlie the association between early life adverse and the long-term health consequences such as cardiovascular disease and type 2 diabetes observed in these individuals [75].

3. Telomere Length in Age-Associated Diseases

LTL shortening has been proposed to be a primary molecular cause of ageing in healthy individuals [24,42,76,77,78]. Recent evidences provide direct evidences supporting a direct role for inflammation in telomere shortening [64,79]; indirect evidences have clearly shown a strong association between these two parameters in healthy ageing and in different clinical circumstances, including mental diseases (for review see [49]). Telomere erosion has been shown to be accelerated not only by chronic viral infections (see Section 2.1), but also by different factors, including some medical illnesses [50,80,81,82,83], and other environmental factors associated with oxidative stress and chronic inflammation, such as cigarette smoking [84] and chronic alcohol consumption [85] or by psychosocial stress such as childhood maltreatment [86].
In addition, different research groups have reported that many detrimental traits and potentially harmful environmental factors are associated with short telomeres in humans. Accordingly, comparatively short LTL is considered a marker not only of ageing but also of poor health, regardless of the person’s age [87,88,89,90], which predicts all-cause mortality [91]. A significant LTL shortening has also been found across psychiatric disorders [92,93,94].
LTL is a predictor of coronary heart disease events in middle-aged, high-risk men, and reduced LTL is associated with all-cause mortality in patients with stable cardiovascular disease [95,96,97,98,99]. Furthermore, acute myocardial infarction and reperfusion accelerate immunosenescence in cytomegalovirus-seropositive patients [100]. LTL attrition also associates with obesity [101,102] and with the presence and number of diabetic complications in type 2 diabetes patients [103,104,105,106,107,108,109]. It has been recently shown that reducing obesity may reduce the risk of diabetes complications associated with shorter LTL, at least in some Chinese population [110].
Previous studies have shown that many psychiatric illnesses are associated with shortened telomeres [93,94], including major depression [111], chronic mood and anxiety disorders [112] or schizophrenia [113]. In major depressive disorder, LTL is proportional to lifetime exposure to the disease, suggesting that LTL attrition is not related to the origin of this disease but on the contrary it is associated with oxidative stress and inflammation [114], and with accelerated ageing [114,115,116,117]. Further studies are needed to clarify the possible role of TL shortening in the clinical outcome of major depression. The observation that TL shortening is associated with pharmacological treatment [118] and the finding that short LTL is also an index of poor response to selective serotonin reuptake inhibitor (SSRI) treatment [119] might reflect the severity of depression in group of patients with shorter telomeres. Metabolic stress, pro-inflammatory cytokines and metabolic alterations, and lifestyle factors, e.g., cigarette smoking, are also important mediators of the association between depressive and anxiety disorders and LTL [120].
Thus, the traditional view of LTL as a passive biomarker of human ageing is under revision as new evidences suggest that the interplay between evolutionary forces and TL might result in distinct health outcomes. While individuals with short telomeres might have a higher risk of diseases related to restricted cell proliferation and tissue degeneration, including cardiovascular, metabolic or mental diseases, those with long telomeres might have an increased risk of diseases related to increased proliferative growth, including cancer [52].

4. Infection by CMV, T. Gondii and other Pathogens in Schizophrenia

Maternal or neonatal exposure to neurotropic pathogens, such as herpes viruses and T. gondii, has been proposed as an environmental risk factor for schizophrenia in individuals with a risk genetic background (Figure 1). The measurement of pathogen-specific immunoglobulin is a marker of previous contact with each pathogen (IgM for first and IgG for longer term contact), whereas IgG levels are associated with repeated reactivation of the pathogens. Serostatus and titer of IgG against several herpes viruses and T. gondii have been studied in schizophrenia patients, but the results are still inconclusive.
It has been shown that chronic maternal infection with T. gondii or CMV can affect neonatal innate immunity and it has been proposed that chronic infections by these pathogens contribute to increased risk for psychosis [121]. Results from other groups also support that the increase in antibody levels to several viruses is predictive of an 18–34% increase in the risk of developing schizophrenia [122] or that anti-CMV and anti-HSV1 antibody levels are significantly increased in schizophrenia patients [123]. However, others have not found significant differences in antibody titers against the pathogens studied, and therefore do not support the hypothesis that increased exposure to neurotropic pathogens after birth is associated with schizophrenia [124,125]. Other evidences demonstrate that CMV infection is associated to poorer markers in the evolution of schizophrenia. Thus, CMV-seropositive schizophrenia patients show higher negative symptoms scores [125], low California Verbal Learning Test (CVLT) scores, decreased hippocampal volume, and poorer episodic verbal memory [126] than those CMV-seronegative patients. In addition, the risk for suicide in persons with serious mental illness, including schizophrenia, bipolar disorder, or major depression, has been shown to be associated with elevated levels of IgM antibodies to both T. gondii and CMV [127] or with elevated levels of antibodies to CMV [128] indicating that, even if these pathogens are not directly the cause of schizophrenia, they are involved in the pathogenesis, evolution, and complications of the disease.

5. Schizophrenia, Inflammation, and Early Senescence

Schizophrenia and other mental disorders are associated with persistently high rates of morbidity and mortality, despite the widespread use of treatments. Although the causal mechanisms of the early mortality in schizophrenic patients are still poorly understood and require further studies, schizophrenia has been associated with oxidative stress and chronic inflammation, which may be associated with the early onset of inflammatory age-associated syndromes such as cardiovascular disease or type 2 diabetes, accelerated ageing, and premature mortality in schizophrenia [129] (Figure 2).

5.1. Schizophrenia and Inflammation

Cumulative evidences from epidemiological, genetic and peripheral biomarkers in schizophrenia and mood disorder patients point to a dysregulation of innate and adaptive immune systems in the disease, and support that these immune abnormalities contribute to disease symptoms, at least in a subpopulation of patients [130]. It has been suggested that immune activation with a shift to a pro-inflammatory state of the cytokine network in response to still undefined environmental agents, herpesviruses infections, or microbiome, can be involved in the pathogenesis and pathophysiology of this mental illness. An increased level of pro-inflammatory markers in both peripheral and cerebral systems has been consistently documented in schizophrenia, supporting that a concomitant process of inflammatory activity is involved in the progression of schizophrenia [131,132]. The analysis of oxidative and inflammatory markers in psychosis shows that people with schizophrenia have increased pro-inflammatory and pro-oxidative status and the results suggest that greater inflammation and oxidative stress might lead to poorer outcomes in patients with first episodes of early onset psychosis [133,134].

5.2. Leukocyte Telomere Shortening in Schizophrenia

The exact causes and mechanisms involved in early cellular senescence in schizophrenia and its possible significance in the pathogenesis and clinical evolution of the disease are still poorly understood. It has been suggested that LTL shortening is involved in this process. Nevertheless, there are discrepancies among the results of different groups, with studies reporting that LTL in schizophrenia can be shorter [135,136,137,138], similar [139,140], or even longer [141,142] than in controls. Furthermore, a recent study has also reported short telomeres in patients at ultra-high risk for psychosis [143]. There are different reasons that can help to explain these discrepancies, going from the different techniques used to study LTL, to epidemiological parameters (such as age, gender, ethnicity, or style of life) or clinical aspects (such as disease progression, treatment response, or the presence of comorbidities) that affect LTL [94,113,144,145] and could be acting as confounding factors in the different studies. Of particular interest is the finding that telomere length correlates with positive scores using the Positive and Negative Syndrome Scale (PANSS) [142]. However, despite these limitations, most recent studies and meta-analysis support the presence of telomere shortening in schizophrenia patients.
Thus, decreased LTL and increased levels of C-C Motif Chemokine Ligand 11 (CCL11), which crosses the blood-brain barrier and is involved in neuroinflammation, are related with reduced grey matter volume and a longer duration of illness, consistent with the hypothesis that schizophrenia is associated with a pathological accelerated ageing, leading to impaired outcomes in these patients [146]. Telomere shortening also has a detrimental effect on brain size in healthy individuals, but the association between these parameters is significant only for those older than 50 years [147], while in schizophrenia patients this relationship was observed at 36 years [146]. In agreement with these results, another recent study has shown that the diagnosis of schizophrenia, more than other possible confounding parameters such as gender, age, cigarette smoking or alcohol drinking, is the most important condition responsible for LTL shortening in these patients, and that major differences in LTL shortening were mainly observed in patients younger than 50 years, while no significant differences were observed in the group of older subjects [148].
The reasons underlying the phenomenon of telomere shortening in schizophrenia are poorly understood and there is likely a combination of several genetic, environmental, and psychosocial parameters in this process. Although schizophrenia is associated with different genetic alterations, there are no evidences suggesting that they are directly involved in telomere shortening. A significant decrease in telomerase activity among individuals with schizophrenia compared to unaffected individuals has been defined in schizophrenia patients [149]. However, no reports on telomerase alterations, which have been defined in several genetic diseases with disease phenotypes that overlap those normally acquired with ageing [150,151], or in DNA telomere point mutations that accelerate shortening leading to premature ageing [152], have been defined.
On the contrary, infection by CMV, a well-known driver of immunosenescence, (see Section 2), which includes leukocyte telomere shortening and the expansion of T and Natural Killer (NK) cell subsets characterized by the production of pro-inflammatory cytokine, has been postulated to be involved in the pathophysiology and clinical evolution of schizophrenia in genetically susceptible individuals. In a similar way, a pro-inflammatory state has been associated with telomere shortening in different age-associated clinical syndromes such as cardiovascular disease, type 2 diabetes, or neurodegenerative conditions (reviewed in [89]), and also in schizophrenia [146]. The relationship between CMV infection, pro-inflammatory state and telomere shortening in age-associated diseases, that is also observed in schizophrenia, can also be directly or indirectly responsible for the high incidence of comorbidities and premature mortality in schizophrenia patients [22,94].
It has also been suggested that psychological stress plays a role in LTL shortening in schizophrenia. In studies with a small number of patients and controls, significant telomere shortening is observed only in female patients with perceived childhood trauma [153] or in situations of not perceived stress such as in cases of social isolation and loneliness [154], have been postulated to be involved in telomere shortening and accelerated ageing in specific groups of schizophrenia patients. These hypotheses are mutually exclusive. Thus, it has been shown that early-life adverse and stressful events increase the risk of CMV infection [75]. Therefore, the linkage between psychological stress and CMV infection, and the subsequent immunosenescence and inflammation underlie the association between early life adverse and long-term health consequences such as cardiovascular disease and type 2 diabetes observed in these individuals.
Telomere length has been studied in selected brain areas in schizophrenia. This disease is characterized by an initial, rapid rate of grey matter loss that slows in middle life, followed by an appearance of a progressive white matter deterioration [155]. The results show a significant reduction of telomere length in superior temporal gyrus white matter of patients with schizophrenia as compared to controls, with no alterations in telomere length in medial frontal gyrus grey and white matter and in superior temporal gyrus grey matter, supporting cell senescence in white matter temporal brain tissue in these patients [156]. Furthermore, schizophrenia patients show accelerated brain ageing (based on the analysis of grey matter density maps), which occurs mainly during the first year after disease onset [157].
Based on the above observations, it can be suggested that schizophrenia is linked with accelerated cellular ageing [94,157], possibly involving telomere shortening [135,136,137,138,146,148,156].

6. Concluding Remarks

The observation that schizophrenia patients show higher mortality rates than people without schizophrenia has evidenced that one of the major complications of this mental illness is premature senescence. The etiology of schizophrenia is multifactorial and involves genetic and environmental factors. Pre- or perinatal infection by pathogens such as CMV and other herpesviruses and T. gondii, and a dysregulation of both innate and adaptive immune systems resulting in immunosenescence and inflammation, have been postulated as environmental factors involved in the pathogenesis of this disease, with a specific effect promoting short LTL shortening and accelerated cellular aging. These factors are also associated with the onset of age-associated diseases such as cardiovascular disease and can be responsible, at least in part, for accelerated ageing and premature mortality in schizophrenia [129]. Although the effect of telomere shortening on the pathogenesis and co-morbidities of human mental disorders should be regarded with caution, further studies to better understand the environmental factors contributing to telomere length attrition will contribute to better understand the pathophysiology of schizophrenia and other mental disorders and to design novel therapy strategies targeting pathogen infection and dysregulated immunological and inflammatory responses in these patients [158].

Author Contributions

C.S. and R.T. designed and wrote the first draft of the manuscript. D.P. discussed the manuscript sections and contributed with updated references. All authors revised and agreed upon the final version of the paper.

Funding

This research was funded by grants SAF2017-87538-R (to RT) from the Ministry of Economy and Competitiveness of Spain, IB16164 and grants to INPATT (CTS040) research group (GR18085) from Junta de Extremadura, co-financed by European Regional Development Funds “Una manera de hacer Europa”.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lieberman, J.A.; First, M.B. Psychotic Disorders. N. Engl. J. Med. 2018, 379, 270–280. [Google Scholar] [CrossRef] [PubMed]
  2. Kahn, R.S.; Sommer, I.E.; Murray, R.M.; Meyer-Lindenberg, A.; Weinberger, D.R.; Cannon, T.D.; O’Donovan, M.; Correll, C.U.; Kane, J.M.; van Os, J.; et al. Schizophrenia. Nat. Rev. Dis. Prim. 2015, 1, 15067. [Google Scholar] [CrossRef] [PubMed]
  3. Edmunds, A.L. Psychotic and Bipolar Disorders: Schizophrenia. FP Essent. 2017, 455, 11–17. [Google Scholar] [PubMed]
  4. Owen, M.J.; Sawa, A.; Mortensen, P.B. Schizophrenia. Lancet 2016, 388, 86–97. [Google Scholar] [CrossRef] [Green Version]
  5. Foley, C.; Corvin, A.; Nakagome, S. Genetics of Schizophrenia: Ready to Translate? Curr. Psychiatry Rep. 2017, 19, 61. [Google Scholar] [CrossRef] [PubMed]
  6. Bustamante, M.L.; Herrera, L.; Gaspar, P.A.; Nieto, R.; Maturana, A.; Villar, M.J.; Salinas, V.; Silva, H. Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2017, 174, 663–670. [Google Scholar] [CrossRef] [PubMed]
  7. Chen, J.; Cao, F.; Liu, L.; Wang, L.; Chen, X. Genetic studies of schizophrenia: An update. Neurosci. Bull. 2015, 31, 87–98. [Google Scholar] [CrossRef] [PubMed]
  8. Gurung, R.; Prata, D.P. What is the impact of genome-wide supported risk variants for schizophrenia and bipolar disorder on brain structure and function? A systematic review. Psychol. Med. 2015, 45, 2461–2480. [Google Scholar] [CrossRef] [PubMed]
  9. Marshall, C.R.; Howrigan, D.P.; Merico, D.; Thiruvahindrapuram, B.; Wu, W.; Greer, D.S.; Antaki, D.; Shetty, A.; Holmans, P.A.; Pinto, D.; et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat. Genet. 2017, 49, 27–35. [Google Scholar] [CrossRef] [PubMed]
  10. Ripke, S.; O’Dushlaine, C.; Chambert, K.; Moran, J.L.; Kähler, A.K.; Akterin, S.; Bergen, S.E.; Collins, A.L.; Crowley, J.J.; Fromer, M.; et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 2013, 45, 1150–1159. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  11. Arslan, A. Imaging genetics of schizophrenia in the post-GWAS era. Prog. Neuropsychopharmacol. Biol. Psychiatry 2018, 80, 155–165. [Google Scholar] [CrossRef] [PubMed]
  12. Matsumoto, M.; Walton, N.M.; Yamada, H.; Kondo, Y.; Marek, G.J.; Tajinda, K. The impact of genetics on future drug discovery in schizophrenia. Expert Opin. Drug Discov. 2017, 12, 673–686. [Google Scholar] [CrossRef] [PubMed]
  13. Ranlund, S.; Calafato, S.; Thygesen, J.H.; Lin, K.; Cahn, W.; Crespo-Facorro, B.; de Zwarte, S.M.C.; Díez, Á.; Di Forti, M.; Iyegbe, C.; et al. A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2018, 177, 21–34. [Google Scholar] [CrossRef] [PubMed]
  14. Hamdani, N.; ban-Huard, C.; Godin, O.; Laouamri, H.; Jamain, S.; Attiba, D.; Delavest, M.; Lépine, J.P.; Le Corvoisier, P.; Houenou, J.; et al. Effects of Cumulative Herpesviridae and Toxoplasma gondii Infections on Cognitive Function in Healthy, Bipolar, and Schizophrenia Subjects. J. Clin. Psychiatry 2017, 78, e18–e27. [Google Scholar] [CrossRef] [PubMed]
  15. Fuglewicz, A.J.; Piotrowski, P.; Stodolak, A. Relationship between toxoplasmosis and schizophrenia: A review. Adv. Clin. Exp. Med. 2017, 26, 1031–1036. [Google Scholar] [CrossRef] [PubMed]
  16. Gatov, E.; Rosella, L.; Chiu, M.; Kurdyak, P.A. Trends in standardized mortality among individuals with schizophrenia, 1993–2012: A population-based, repeated cross-sectional study. CMAJ 2017, 189, E1177–E1187. [Google Scholar] [CrossRef] [PubMed]
  17. Olfson, M.; Gerhard, T.; Huang, C.; Crystal, S.; Stroup, T.S. Premature Mortality among Adults with Schizophrenia in the United States. JAMA Psychiatry 2015, 72, 1172–1181. [Google Scholar] [CrossRef] [PubMed]
  18. Piotrowski, P.; Gondek, T.M.; Krolicka-Deregowska, A.; Misiak, B.; Adamowski, T.; Kiejna, A. Causes of mortality in schizophrenia: An updated review of European studies. Psychiatr. Danub. 2017, 29, 108–120. [Google Scholar] [CrossRef] [PubMed]
  19. Osby, U.; Westman, J.; Hallgren, J.; Gissler, M. Mortality trends in cardiovascular causes in schizophrenia, bipolar and unipolar mood disorder in Sweden 1987–2010. Eur. J. Public Health 2016, 26, 867–871. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. Meesters, P.D.; Comijs, H.C.; Smit, J.H.; Eikelenboom, P.; de Han, L.; Beekman, A.T.; Stek, M.L. Mortality and Its Determinants in Late-Life Schizophrenia: A 5-Year Prospective Study in a Dutch Catchment Area. Am. J. Geriatr. Psychiatry 2016, 24, 272–277. [Google Scholar] [CrossRef] [PubMed]
  21. Hjorthoj, C.; Sturup, A.E.; McGrath, J.J.; Nordentoft, M. Years of potential life lost and life expectancy in schizophrenia: A systematic review and meta-analysis. Lancet Psychiatry 2017, 4, 295–301. [Google Scholar] [CrossRef]
  22. Islam, F.; Mulsant, B.H.; Voineskos, A.N.; Rajji, T.K. Brain-Derived Neurotrophic Factor Expression in Individuals with Schizophrenia and Healthy Aging: Testing the Accelerated Aging Hypothesis of Schizophrenia. Curr. Psychiatry Rep. 2017, 19, 36. [Google Scholar] [CrossRef] [PubMed]
  23. Kirkpatrick, B.; Kennedy, B.K. Accelerated aging in schizophrenia and related disorders: Future research. Schizophr. Res. 2018, 196, 4–8. [Google Scholar] [CrossRef] [PubMed]
  24. Lopez-Otin, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The hallmarks of aging. Cell 2013, 153, 1194–1217. [Google Scholar] [CrossRef] [PubMed]
  25. Solana, R.; Tarazona, R.; Aiello, A.E.; Akbar, A.N.; Appay, V.; Beswick, M.; Bosch, J.A.; Campos, C.; Cantisán, S.; Cicin-Sain, L.; et al. CMV and Immunosenescence: From basics to clinics. Immun. Ageing 2012, 9, 23. [Google Scholar] [CrossRef] [PubMed]
  26. Koch, S.; Larbi, A.; Ozcelik, D.; Solana, R.; Gouttefangeas, C.; Attig, S.; Wikby, A.; Strindhall, J.; Franceschi, C.; Pawelec, G. Cytomegalovirus infection: A driving force in human T cell immunosenescence. Ann. N. Y. Acad. Sci. 2007, 1114, 23–35. [Google Scholar] [CrossRef] [PubMed]
  27. Pawelec, G.; Akbar, A.; Caruso, C.; Solana, R.; Grubeck-Loebenstein, B.; Wikby, A. Human immunosenescence: Is it infectious? Immunol. Rev. 2005, 205, 257–268. [Google Scholar] [CrossRef] [PubMed]
  28. Hassouneh, F.; Lopez-Sejas, N.; Campos, C.; Sanchez-Correa, B.; Tarazona, R.; Pera, A.; Solana, R. Effect of Cytomegalovirus (CMV) and Ageing on T-Bet and Eomes Expression on T-Cell Subsets. Int. J. Mol. Sci. 2017, 18, 1391. [Google Scholar] [CrossRef] [PubMed]
  29. Pera, A.; Vasudev, A.; Tan, C.; Kared, H.; Solana, R.; Larbi, A. CMV induces expansion of highly polyfunctional CD4+ T cell subset coexpressing CD57 and CD154. J. Leukoc. Biol. 2017, 101, 555–566. [Google Scholar] [CrossRef] [PubMed]
  30. Hassouneh, F.; Campos, C.; Lopez-Sejas, N.; Alonso, C.; Tarazona, R.; Solana, R.; Pera, A. Effect of age and latent CMV infection on CD8+ CD56+ T cells (NKT-like) frequency and functionality. Mech. Ageing Dev. 2016, 158, 38–45. [Google Scholar] [CrossRef] [PubMed]
  31. Lopez-Sejas, N.; Campos, C.; Hassouneh, F.; Sanchez-Correa, B.; Tarazona, R.; Pera, A.; Solana, R. Effect of CMV and Aging on the Differential Expression of CD300a, CD161, T-bet, and Eomes on NK Cell Subsets. Front. Immunol. 2016, 7, 476. [Google Scholar] [CrossRef] [PubMed]
  32. Pera, A.; Campos, C.; Corona, A.; Sanchez-Correa, B.; Tarazona, R.; Larbi, A.; Solana, R. CMV latent infection improves CD8+ T response to SEB due to expansion of polyfunctional CD57+ cells in young individuals. PLoS ONE 2014, 9, e88538. [Google Scholar] [CrossRef] [PubMed]
  33. Solana, R.; Campos, C.; Pera, A.; Tarazona, R. Shaping of NK cell subsets by aging. Curr. Opin. Immunol. 2014, 29, 56–61. [Google Scholar] [CrossRef] [PubMed]
  34. Riddell, N.E.; Griffiths, S.J.; Rivino, L.; King, D.C.; Teo, G.H.; Henson, S.M.; Cantisan, S.; Solana, R.; Kemeny, D.M.; MacAry, P.A.; et al. Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults. Immunology 2015, 144, 549–560. [Google Scholar] [CrossRef] [PubMed]
  35. Misri, S.; Pandita, S.; Kumar, R.; Pandita, T.K. Telomeres, histone code, and DNA damage response. Cytogenet. Genome Res. 2008, 122, 297–307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Rossiello, F.; Herbig, U.; Longhese, M.P.; Fumagalli, M.; di Fagagna, F.D. Irreparable telomeric DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence and ageing. Curr. Opin. Genet. Dev. 2014, 26, 89–95. [Google Scholar] [CrossRef] [PubMed]
  37. Fumagalli, M.; Rossiello, F.; Clerici, M.; Barozzi, S.; Cittaro, D.; Kaplunov, J.M.; Bucci, G.; Dobreva, M.; Matti, V.; Beausejour, C.M.; et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 2012, 14, 355–365. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Bielak-Zmijewska, A.; Mosieniak, G.; Sikora, E. Is DNA damage indispensable for stress-induced senescence? Mech. Ageing Dev. 2018, 170, 13–21. [Google Scholar] [CrossRef] [PubMed]
  39. Flores, I.; Benetti, R.; Blasco, M.A. Telomerase regulation and stem cell behaviour. Curr. Opin. Cell Biol. 2006, 18, 254–260. [Google Scholar] [CrossRef] [PubMed]
  40. Flores, I.; Canela, A.; Vera, E.; Tejera, A.; Cotsarelis, G.; Blasco, M.A. The longest telomeres: A general signature of adult stem cell compartments. Genes Dev. 2008, 22, 654–667. [Google Scholar] [CrossRef] [PubMed]
  41. Flores, I.; Blasco, M.A. The role of telomeres and telomerase in stem cell aging. FEBS Lett. 2010, 584, 3826–3830. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Bar, C.; Blasco, M.A. Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases. F1000 Res. 2016, 5. [Google Scholar] [CrossRef] [Green Version]
  43. Blasco, M.A.; Lee, H.W.; Rizen, M.; Hanahan, D.; DePinho, R.; Greider, C.W. Mouse models for the study of telomerase. Ciba Found. Symp. 1997, 211, 160–170. [Google Scholar] [PubMed]
  44. Blasco, M.A. Mouse models to study the role of telomeres in cancer, aging and DNA repair. Eur. J. Cancer 2002, 38, 2222–2228. [Google Scholar] [CrossRef]
  45. Blasco, M.A. Telomerase beyond telomeres. Nat. Rev. Cancer 2002, 2, 627–633. [Google Scholar] [CrossRef] [PubMed]
  46. Wang, J.C.; Warner, J.K.; Erdmann, N.; Lansdorp, P.M.; Harrington, L.; Dick, J.E. Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells. Proc. Natl. Acad. Sci. USA 2005, 102, 14398–14403. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Appay, V.; Dunbar, P.R.; Callan, M.; Klenerman, P.; Gillespie, G.M.; Papagno, L.; Ogg, G.S.; King, A.; Lechner, F.; Spina, C.A.; et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med. 2002, 8, 379–385. [Google Scholar] [CrossRef] [PubMed]
  48. Akbar, A.N.; Beverley, P.C.; Salmon, M. Will telomere erosion lead to a loss of T-cell memory? Nat. Rev. Immunol. 2004, 4, 737–743. [Google Scholar] [CrossRef] [PubMed]
  49. Zhang, J.; Rane, G.; Dai, X.; Shanmugam, M.K.; Arfuso, F.; Samy, R.P.; Lai, M.K.; Kappei, D.; Kumar, A.P.; Sethi, G. Ageing and the telomere connection: An intimate relationship with inflammation. Ageing Res. Rev. 2016, 25, 55–69. [Google Scholar] [CrossRef] [PubMed]
  50. Martinez, P.; Blasco, M.A. Telomere-driven diseases and telomere-targeting therapies. J. Cell Biol. 2017, 216, 875–887. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Mangaonkar, A.A.; Patnaik, M.M. Short Telomere Syndromes in Clinical Practice: Bridging Bench and Bedside. Mayo Clin. Proc. 2018, 93, 904–916. [Google Scholar] [CrossRef]
  52. Aviv, A.; Shay, J.W. Reflections on telomere dynamics and ageing-related diseases in humans. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2018, 373, 20160436. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Hassouneh, F.; Lopez-Sejas, N.; Campos, C.; Sanchez-Correa, B.; Tarazona, R.; Solana, R.; Pera, A. Differential Effect of Cytomegalovirus Infection with Age on the Expression of CD57, CD300a, and CD161 on T-Cell Subpopulations. Front. Immunol. 2017, 8, 649. [Google Scholar] [CrossRef] [PubMed]
  54. Di Benedetto, S.; Derhovanessian, E.; Steinhagen-Thiessen, E.; Goldeck, D.; Muller, L.; Pawelec, G. Impact of age, sex and CMV-infection on peripheral T cell phenotypes: Results from the Berlin BASE-II Study. Biogerontology 2015, 16, 631–643. [Google Scholar] [CrossRef] [PubMed]
  55. Pera, A.; Campos, C.; Lopez, N.; Hassouneh, F.; Alonso, C.; Tarazona, R.; Solana, R. Immunosenescence: Implications for response to infection and vaccination in older people. Maturitas 2015, 82, 50–55. [Google Scholar] [CrossRef]
  56. Pawelec, G. Hallmarks of human “immunosenescence”: Adaptation or dysregulation? Immun. Ageing 2012, 9, 15. [Google Scholar] [CrossRef]
  57. Tarazona, R.; DelaRosa, O.; Alonso, C.; Ostos, B.; Espejo, J.; Pena, J.; Solana, R. Increased expression of NK cell markers on T lymphocytes in aging and chronic activation of the immune system reflects the accumulation of effector/senescent T cells. Mech. Ageing Dev. 2000, 121, 77–88. [Google Scholar] [CrossRef]
  58. Hakim, F.T.; Flomerfelt, F.A.; Boyiadzis, M.; Gress, R.E. Aging, immunity, and cancer. Discov. Med. 2011, 11, 537–550. [Google Scholar] [CrossRef] [PubMed]
  59. Pawelec, G.; Larbi, A.; Derhovanessian, E. Senescence of the human immune system. J. Comp. Pathol. 2010, 142, S39–S44. [Google Scholar] [CrossRef]
  60. Van de Berg, P.J.; Griffiths, S.J.; Yong, S.L.; Macaulay, R.; Bemelman, F.J.; Jackson, S.; Henson, S.M.; ten Berge, I.J.; Akbar, A.N.; van Lier, R.A.; et al. Cytomegalovirus infection reduces telomere length of the circulating T cell pool. J. Immunol. 2010, 184, 3417–3423. [Google Scholar] [CrossRef]
  61. Dowd, J.B.; Bosch, J.A.; Steptoe, A.; Blackburn, E.H.; Lin, J.; Rees-Clayton, E.; Aiello, A.E. Cytomegalovirus is associated with reduced telomerase activity in the Whitehall II cohort. Exp. Gerontol. 2013, 48, 385–390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Aiello, A.E.; Jayabalasingham, B.; Simanek, A.M.; ez-Roux, A.; Feinstein, L.; Meier, H.C.S.; Needham, B.L.; Dowd, J.B. The impact of pathogen burden on leukocyte telomere length in the Multi-Ethnic Study of Atherosclerosis. Epidemiol. Infect. 2017, 145, 3076–3084. [Google Scholar] [CrossRef]
  63. Dowd, J.B.; Bosch, J.A.; Steptoe, A.; Jayabalasingham, B.; Lin, J.; Yolken, R.; Aiello, A.E. Persistent Herpesvirus Infections and Telomere Attrition Over 3 Years in the Whitehall II Cohort. J. Infect. Dis. 2017, 216, 565–572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Lustig, A.; Liu, H.B.; Metter, E.J.; Macaulay, R.; Bemelman, F.J.; Jackson, S.; Henson, S.M.; ten Berge, I.J.; Akbar, A.N.; van Lier, R.A. Telomere Shortening, Inflammatory Cytokines, and Anti-Cytomegalovirus Antibody Follow Distinct Age-Associated Trajectories in Humans. Front. Immunol. 2017, 8, 1027. [Google Scholar] [CrossRef] [PubMed]
  65. Chou, J.P.; Effros, R.B. T cell replicative senescence in human aging. Curr. Pharm. Des. 2013, 19, 1680–1698. [Google Scholar] [PubMed]
  66. Collerton, J.; Martin-Ruiz, C.; Davies, K.; Hilkens, C.M.; Isaacs, J.; Kolenda, C.; Parker, C.; Dunn, M.; Catt, M.; Jagger, C.; et al. Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: Cross-sectional findings from the Newcastle 85+ Study. Mech. Ageing Dev. 2012, 133, 456–466. [Google Scholar] [CrossRef] [PubMed]
  67. Effros, R.B. Telomere/telomerase dynamics within the human immune system: Effect of chronic infection and stress. Exp. Gerontol. 2011, 46, 135–140. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Fletcher, J.M.; Vukmanovic-Stejic, M.; Dunne, P.J.; Birch, K.E.; Cook, J.E.; Jackson, S.E.; Salmon, M.; Rustin, M.H.; Akbar, A.N. Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J. Immunol. 2005, 175, 8218–8225. [Google Scholar] [CrossRef] [PubMed]
  69. Pawelec, G. Immunosenenescence: Role of cytomegalovirus. Exp. Gerontol. 2014, 54, 1–5. [Google Scholar] [CrossRef] [PubMed]
  70. Fulop, T.; Larbi, A.; Pawelec, G. Human T cell aging and the impact of persistent viral infections. Front. Immunol. 2013, 4, 271. [Google Scholar] [CrossRef] [PubMed]
  71. McElhaney, J.E.; Zhou, X.; Talbot, H.K.; Soethout, E.; Bleackley, R.C.; Granville, D.J.; Pawelec, G. The unmet need in the elderly: How immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines. Vaccine 2012, 30, 2060–2067. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Pawelec, G.; Derhovanessian, E. Role of CMV in immune senescence. Virus Res. 2011, 157, 175–179. [Google Scholar] [CrossRef] [PubMed]
  73. Thomasini, R.L.; Pereira, D.S.; Pereira, F.S.M.; Mateo, E.C.; Mota, T.N.; Guimarães, G.G.; Pereira, L.S.M.; Lima, C.X.; Teixeira, M.M.; Teixeira, A.L. Junior. Aged-associated cytomegalovirus and Epstein-Barr virus reactivation and cytomegalovirus relationship with the frailty syndrome in older women. PLoS ONE 2017, 12, e0180841. [Google Scholar] [CrossRef] [PubMed]
  74. Cao-Dinh, H.; Bautmans, I.; Beyer, I.; Mets, T.; Onyema, O.O.; Forti, L.N.; Renmans, W.; Vander Meeren, S.; Jochmans, K.; Vermeiren, S.; et al. Association between Immunosenescence Phenotypes and pre-frailty in Older Subjects: Does Cytomegalovirus Play a Role? J. Gerontol. A Biol. Sci. Med. Sci. 2018. [Google Scholar] [CrossRef] [PubMed]
  75. Elwenspoek, M.M.C.; Sias, K.; Hengesch, X.; Schaan, V.K.; Leenen, F.A.D.; Adams, P.; Mériaux, S.B.; Schmitz, S.; Bonnemberger, F.; Ewen, A.; et al. T Cell Immunosenescence after Early Life Adversity: Association with Cytomegalovirus Infection. Front. Immunol. 2017, 8, 1263. [Google Scholar] [CrossRef] [PubMed]
  76. SBakaysa, L.; Mucci, L.A.; Slagboom, P.E.; Boomsma, D.I.; McClearn, G.E.; Johansson, B.; Pedersen, N.L. Telomere length predicts survival independent of genetic influences. Aging Cell 2007, 6, 769–774. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Fernandez-Alvira, J.M.; Fuster, V.; Dorado, B.; Soberón, N.; Flores, I.; Gallardo, M.; Pocock, S.; Blasco, M.A.; Andrés, V. Short Telomere Load, Telomere Length, and Subclinical Atherosclerosis: The PESA Study. J. Am. Coll. Cardiol. 2016, 67, 2467–2476. [Google Scholar] [CrossRef] [PubMed]
  78. Needham, B.L.; Rehkopf, D.; Adler, N.; Gregorich, S.; Lin, J.; Blackburn, E.H.; Epel, E.S. Leukocyte telomere length and mortality in the National Health and Nutrition Examination Survey, 1999–2002. Epidemiology 2015, 26, 528–535. [Google Scholar] [CrossRef] [PubMed]
  79. Lin, J.; Sun, J.; Wang, S.; Milush, J.M.; Baker, C.A.R.; Coccia, M.; Effros, R.B.; Puterman, E.; Blackburn, E.; Prather, A.A.; et al. In vitro proinflammatory gene expression predicts in vivo telomere shortening: A preliminary study. Psychoneuroendocrinology 2018, 96, 179–187. [Google Scholar] [CrossRef] [PubMed]
  80. Zhu, H.; Belcher, M.; Van Der Harst, P. Healthy aging and disease: Role for telomere biology? Clin. Sci. 2011, 120, 427–440. [Google Scholar] [CrossRef] [PubMed]
  81. Harari, Y.; Kupiec, M. Do long telomeres affect cellular fitness? Curr. Genet. 2018, 64, 173–176. [Google Scholar] [CrossRef] [PubMed]
  82. Opresko, P.L.; Shay, J.W. Telomere-associated aging disorders. Ageing Res. Rev. 2017, 33, 52–66. [Google Scholar] [CrossRef] [PubMed]
  83. Blackburn, E.H.; Epel, E.S.; Lin, J. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science 2015, 350, 1193–1198. [Google Scholar] [CrossRef] [PubMed]
  84. Astuti, Y.; Wardhana, A.; Watkins, J.; Wulaningsih, W. Cigarette smoking and telomere length: A systematic review of 84 studies and meta-analysis. Environ. Res. 2017, 158, 480–489. [Google Scholar] [CrossRef] [PubMed]
  85. Wang, H.; Kim, H.; Baik, I. Associations of alcohol consumption and alcohol flush reaction with leukocyte telomere length in Korean adults. Nutr. Res. Pract. 2017, 11, 334–339. [Google Scholar] [CrossRef] [PubMed]
  86. Kang, J.I.; Hwang, S.S.; Choi, J.R.; Lee, S.T.; Kim, J.; Hwang, I.S.; Kim, H.W.; Kim, C.H.; Kim, S.J. Telomere length in alcohol dependence: A role for impulsive choice and childhood maltreatment. Psychoneuroendocrinology 2017, 83, 72–78. [Google Scholar] [CrossRef] [PubMed]
  87. De Meyer, T.; Nawrot, T.; Bekaert, S.; De Buyzere, M.L.; Rietzschel, E.R.; Andrés, V. Telomere Length as Cardiovascular Aging Biomarker: JACC Review Topic of the Week. J. Am. Coll. Cardiol. 2018, 72, 805–813. [Google Scholar] [CrossRef] [PubMed]
  88. Herrmann, M.; Pusceddu, I.; Marz, W.; Herrmann, W. Telomere biology and age-related diseases. Clin. Chem. Lab. Med. 2018, 56, 1210–1222. [Google Scholar] [CrossRef] [PubMed]
  89. Fougere, B.; Boulanger, E.; Nourhashemi, F.; Guyonnet, S.; Cesari, M. Chronic Inflammation: Accelerator of Biological Aging. J. Gerontol. A Biol. Sci. Med. Sci. 2017, 72, 1218–1225. [Google Scholar] [CrossRef] [PubMed]
  90. Yeh, J.K.; Wang, C.Y. Telomeres and Telomerase in Cardiovascular Diseases. Genes 2016, 7, 58. [Google Scholar] [CrossRef] [PubMed]
  91. Mons, U.; Muezzinler, A.; Schottker, B.; Dieffenbach, A.K.; Butterbach, K.; Schick, M.; Peasey, A.; De Vivo, I.; Trichopoulou, A.; Boffetta, P.; et al. Leukocyte Telomere Length and All-Cause, Cardiovascular Disease, and Cancer Mortality: Results from Individual-Participant-Data Meta-Analysis of 2 Large Prospective Cohort Studies. Am. J. Epidemiol. 2017, 185, 1317–1326. [Google Scholar] [CrossRef] [PubMed]
  92. Bersani, F.S.; Lindqvist, D.; Mellon, S.H.; Epel, E.S.; Yehuda, R.; Flory, J.; Henn-Hasse, C.; Bierer, L.M.; Makotkine, I.; Abu-Amara, D.; et al. Association of dimensional psychological health measures with telomere length in male war veterans. J. Affect. Disord. 2016, 190, 537–542. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Darrow, S.M.; Verhoeven, J.E.; Revesz, D.; Lindqvist, D.; Penninx, B.W.; Delucchi, K.L.; Wolkowitz, O.M.; Mathews, C.A. The Association between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons. Psychosom. Med. 2016, 78, 776–787. [Google Scholar] [CrossRef] [PubMed]
  94. Lindqvist, D.; Epel, E.S.; Mellon, S.H.; Penninx, B.W.; Révész, D.; Verhoeven, J.E.; Reus, V.I.; Lin, J.; Mahan, L.; Hough, C.M.; et al. Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging. Neurosci. Biobehav. Rev. 2015, 55, 333–364. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Brouilette, S.W.; Moore, J.S.; McMahon, A.D.; Thompson, J.R.; Ford, I.; Shepherd, J.; Packard, C.J.; Samani, N.J. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: A nested case-control study. Lancet 2007, 369, 107–114. [Google Scholar] [CrossRef]
  96. Farzaneh-Far, R.; Cawthon, R.M.; Na, B.; Browner, W.S.; Schiller, N.B.; Whooley, M.A. Prognostic value of leukocyte telomere length in patients with stable coronary artery disease: Data from the Heart and Soul Study. Arterioscler. Thromb. Vasc. Biol. 2008, 28, 1379–1384. [Google Scholar] [CrossRef] [PubMed]
  97. Spyridopoulos, I.; von Zglinicki, T. Telomere length predicts cardiovascular disease. BMJ 2014, 349, g4373. [Google Scholar] [CrossRef] [PubMed]
  98. Chen, S.; Lin, J.; Matsuguchi, T.; Blackburn, E.; Yeh, F.; Best, L.G.; Devereux, R.B.; Lee, E.T.; Howard, B.V.; Roman, M.J.; et al. Short leukocyte telomere length predicts incidence and progression of carotid atherosclerosis in American Indians: The Strong Heart Family Study. Aging 2014, 6, 414–427. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Goglin, S.E.; Farzaneh-Far, R.; Epel, E.S.; Lin, J.; Blackburn, E.H.; Whooley, M.A. Change in Leukocyte Telomere Length Predicts Mortality in Patients with Stable Coronary Heart Disease from the Heart and Soul Study. PLoS ONE 2016, 11, e0160748. [Google Scholar]
  100. Hoffmann, J.; Shmeleva, E.V.; Boag, S.E.; Fiser, K.; Bagnall, A.; Murali, S.; Dimmick, I.; Pircher, H.; Martin-Ruiz, C.; Egred, M.; et al. Myocardial ischemia and reperfusion leads to transient CD8 immune deficiency and accelerated immunosenescence in CMV-seropositive patients. Circ. Res. 2015, 116, 87–98. [Google Scholar] [CrossRef] [PubMed]
  101. Chen, S.; Yeh, F.; Lin, J.; Matsuguchi, T.; Blackburn, E.; Lee, E.T.; Howard, B.V.; Zhao, J. Short leukocyte telomere length is associated with obesity in American Indians: The Strong Heart Family study. Aging 2014, 6, 380–389. [Google Scholar] [CrossRef] [PubMed]
  102. Zhao, J.; Zhu, Y.; Uppal, K.; Tran, V.T.; Yu, T.; Lin, J.; Matsuguchi, T.; Blackburn, E.; Jones, D.; Lee, E.T.; et al. Metabolic profiles of biological aging in American Indians: The Strong Heart Family Study. Aging 2014, 6, 176–186. [Google Scholar] [CrossRef] [PubMed]
  103. Testa, R.; Olivieri, F.; Sirolla, C.; Spazzafumo, L.; Rippo, M.R.; Marra, M.; Bonfigli, A.R.; Ceriello, A.; Antonicelli, R.; Franceschi, C.; et al. Leukocyte telomere length is associated with complications of type 2 diabetes mellitus. Diabet. Med. 2011, 28, 1388–1394. [Google Scholar] [CrossRef] [PubMed]
  104. Gurung, R.L.; Yiamunaa, M.; Liu, S.; Liu, J.J.; Lim, S.C. Short Leukocyte Telomere Length Predicts Albuminuria Progression in Individuals with Type 2 Diabetes. Kidney Int. Rep. 2018, 3, 592–601. [Google Scholar] [CrossRef] [PubMed]
  105. Rosa, E.C.C.C.; Santos, R.R.C.D.; Fernandes, L.F.A.; Neves, F.A.R.; Coelho, M.S.; Amato, A.A. Leukocyte telomere length correlates with glucose control in adults with recently diagnosed type 2 diabetes. Diabetes Res. Clin. Pract. 2018, 135, 30–36. [Google Scholar] [CrossRef] [PubMed]
  106. Sethi, I.; Bhat, G.R.; Singh, V.; Kumar, R.; Bhanwer, A.J.; Bamezai, R.N.; Sharma, S.; Rai, E. Role of telomeres and associated maintenance genes in Type 2 Diabetes Mellitus: A review. Diabetes Res. Clin. Pract. 2016, 122, 92–100. [Google Scholar] [CrossRef] [PubMed]
  107. Bonfigli, A.R.; Spazzafumo, L.; Prattichizzo, F.; Bonafè, M.; Mensà, E.; Micolucci, L.; Giuliani, A.; Fabbietti, P.; Testa, R.; Boemi, M.; et al. Leukocyte telomere length and mortality risk in patients with type 2 diabetes. Oncotarget 2016, 7, 50835–50844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  108. Spigoni, V.; Aldigeri, R.; Picconi, A.; Derlindati, E.; Franzini, L.; Haddoub, S.; Prampolini, G.; Vigna, G.B.; Zavaroni, I.; Bonadonna, R.C.; et al. Telomere length is independently associated with subclinical atherosclerosis in subjects with type 2 diabetes: A cross-sectional study. Acta Diabetol. 2016, 53, 661–667. [Google Scholar] [CrossRef] [PubMed]
  109. Tamura, Y.; Takubo, K.; Aida, J.; Araki, A.; Ito, H. Telomere attrition and diabetes mellitus. Geriatr. Gerontol. Int. 2016, 16, 66–74. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Gurung, R.L.; Yiamunaa, M.; Liu, S.; Liu, J.J.; Chan, S.M.; Moh, M.C.; Ang, K.; Tang, W.E.; Sum, C.F.; Subramaniam, T.; et al. Ethnic disparities in relationship of obesity indices and telomere length in Asians with type 2 diabetes. J. Diabetes 2018. [Google Scholar] [CrossRef] [PubMed]
  111. Verhoeven, J.E.; Revesz, D.; Epel, E.S.; Lin, J.; Wolkowitz, O.M.; Penninx, B.W. Major depressive disorder and accelerated cellular aging: Results from a large psychiatric cohort study. Mol. Psychiatry 2014, 19, 895–901. [Google Scholar] [CrossRef] [PubMed]
  112. Verhoeven, J.E.; Revesz, D.; van Oppen, P.; Epel, E.S.; Wolkowitz, O.M.; Penninx, B.W. Anxiety disorders and accelerated cellular ageing. Br. J. Psychiatry 2015, 206, 371–378. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Wolkowitz, O.M.; Jeste, D.V.; Martin, A.S.; Lin, J.; Daly, R.E.; Reuter, C.; Kraemer, H. Leukocyte telomere length: Effects of schizophrenia, age, and gender. J. Psychiatr. Res. 2017, 85, 42–48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Wolkowitz, O.M.; Mellon, S.H.; Epel, E.S.; Lin, J.; Dhabhar, F.S.; Su, Y.; Reus, V.I.; Rosser, R.; Burke, H.M.; Kupferman, E.; et al. Leukocyte telomere length in major depression: Correlations with chronicity, inflammation and oxidative stress—Preliminary findings. PLoS ONE 2011, 6, e17837. [Google Scholar] [CrossRef] [PubMed]
  115. Ridout, K.K.; Ridout, S.J.; Price, L.H.; Sen, S.; Tyrka, A.R. Depression and telomere length: A meta-analysis. J. Affect. Disord. 2016, 191, 237–247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Wium-Andersen, M.K.; Orsted, D.D.; Rode, L.; Bojesen, S.E.; Nordestgaard, B.G. Telomere length and depression: Prospective cohort study and Mendelian randomisation study in 67 306 individuals. Br. J. Psychiatry 2017, 210, 31–38. [Google Scholar] [CrossRef] [PubMed]
  117. Vance, M.C.; Bui, E.; Hoeppner, S.S.; Kovachy, B.; Prescott, J.; Mischoulon, D.; Walton, Z.E.; Dong, M.; Nadal, M.F.; Worthington, J.J.; et al. Prospective association between major depressive disorder and leukocyte telomere length over two years. Psychoneuroendocrinology 2018, 90, 157–164. [Google Scholar] [CrossRef] [PubMed]
  118. Needham, B.L.; Mezuk, B.; Bareis, N.; Lin, J.; Blackburn, E.H.; Epel, E.S. Depression, anxiety and telomere length in young adults: Evidence from the National Health and Nutrition Examination Survey. Mol. Psychiatry 2015, 20, 520–528. [Google Scholar] [CrossRef] [PubMed]
  119. Hough, C.M.; Bersani, F.S.; Mellon, S.H.; Epel, E.S.; Reus, V.I.; Lindqvist, D.; Lin, J.; Mahan, L.; Rosser, R.; Burke, H.; et al. Leukocyte telomere length predicts SSRI response in major depressive disorder: A preliminary report. Mol. Neuropsychiatry 2016, 2, 88–96. [Google Scholar] [CrossRef] [PubMed]
  120. Revesz, D.; Verhoeven, J.E.; Milaneschi, Y.; Penninx, B.W. Depressive and anxiety disorders and short leukocyte telomere length: Mediating effects of metabolic stress and lifestyle factors. Psychol. Med. 2016, 46, 2337–2349. [Google Scholar] [CrossRef] [PubMed]
  121. Blomstrom, A.; Gardner, R.M.; Dalman, C.; Yolken, R.H.; Karlsson, H. Influence of maternal infections on neonatal acute phase proteins and their interaction in the development of non-affective psychosis. Transl. Psychiatry 2015, 5, e502. [Google Scholar] [CrossRef] [PubMed]
  122. Li, Y.; Weber, N.S.; Fisher, J.A.; Yolken, R.H.; Cowan, D.N.; Larsen, R.A.; Niebuhr, D.W. Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel. Schizophr. Res. 2013, 151, 36–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Mohagheghi, M.; Eftekharian, M.M.; Taheri, M.; Alikhani, M.Y. Determining the IgM and IgG antibodies titer against HSV1, HSV2 and CMV in the serum of schizophrenia patients. Hum. Antibodies 2018, 26, 87–93. [Google Scholar] [CrossRef] [PubMed]
  124. De Witte, L.D.; van Mierlo, H.C.; Litjens, M.; Klein, H.C.; Bahn, S.; Osterhaus, A.D. The association between antibodies to neurotropic pathogens and schizophrenia: A case-control study. NPJ Schizophr. 2015, 1, 15041. [Google Scholar] [CrossRef] [PubMed]
  125. Bolu, A.; Oznur, T.; Tok, D.; Balikci, A.; Sener, K.; Celik, C.; Gulsun, M. Seropositivity of neurotropic infectious agents in first-episode schizophrenia patients and the relationship with positive and negative symptoms. Psychiatr. Danub. 2016, 28, 132–138. [Google Scholar] [PubMed]
  126. Houenou, J.; d’Albis, M.A.; Daban, C.; Hamdani, N.; Delavest, M.; Lepine, J.P.; Vederine, F.E.; Carde, S.; Lajnef, M.; Cabon, C.; et al. Cytomegalovirus seropositivity and serointensity are associated with hippocampal volume and verbal memory in schizophrenia and bipolar disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 2014, 48, 142–148. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Dickerson, F.; Wilcox, H.C.; Adamos, M.; Katsafanas, E.; Khushalani, S.; Origoni, A.; Savage, C.; Schweinfurth, L.; Stallings, C.; Sweeney, K.; et al. Suicide attempts and markers of immune response in individuals with serious mental illness. J. Psychiatr. Res. 2017, 87, 37–43. [Google Scholar] [CrossRef] [PubMed]
  128. Dickerson, F.; Origoni, A.; Schweinfurth, L.A.B.; Stallings, C.; Savage, C.L.G.; Sweeney, K.; Katsafanas, E.; Wilcox, H.C.; Khushalani, S.; Yolken, R. Clinical and Serological Predictors of Suicide in Schizophrenia and Major Mood Disorders. J. Nerv. Ment. Dis. 2018, 206, 173–178. [Google Scholar] [CrossRef] [PubMed]
  129. Okusaga, O.O. Accelerated aging in schizophrenia patients: The potential role of oxidative stress. Aging Dis. 2014, 5, 256–262. [Google Scholar] [PubMed]
  130. Horvath, S.; Mirnics, K. Immune system disturbances in schizophrenia. Biol. Psychiatry 2014, 75, 316–323. [Google Scholar] [CrossRef] [PubMed]
  131. Rodrigues-Amorim, D.; Rivera-Baltanas, T.; Spuch, C.; Caruncho, H.J.; Gonzalez-Fernandez, A.; Olivares, J.M.; Agis-Balboa, R.C. Cytokines dysregulation in schizophrenia: A systematic review of psychoneuroimmune relationship. Schizophr. Res. 2017, 197, 19–33. [Google Scholar] [CrossRef] [PubMed]
  132. Na, K.S.; Jung, H.Y.; Kim, Y.K. The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2014, 48, 277–286. [Google Scholar] [CrossRef] [PubMed]
  133. Schiavone, S.; Trabace, L. Inflammation, Stress Response, and Redox Dysregulation Biomarkers: Clinical Outcomes and Pharmacological Implications for Psychosis. Front Psychiatry 2017, 8, 203. [Google Scholar] [CrossRef] [PubMed]
  134. Fraguas, D.; az-Caneja, C.M.; Rodriguez-Quiroga, A.; Arango, C. Oxidative Stress and Inflammation in Early Onset First Episode Psychosis: A Systematic Review and Meta-Analysis. Int. J. Neuropsychopharmacol. 2017, 20, 435–444. [Google Scholar] [CrossRef] [PubMed]
  135. Polho, G.B.; De-Paula, V.J.; Cardillo, G.; dos Santos, B.; Kerr, D.S. Leukocyte telomere length in patients with schizophrenia: A meta-analysis. Schizophr. Res. 2015, 165, 195–200. [Google Scholar] [CrossRef] [PubMed]
  136. Rao, S.; Kota, L.N.; Li, Z.; Yao, Y.; Tang, J.; Mao, C.; Jain, S.; Xu, Y.; Xu, Q. Accelerated leukocyte telomere erosion in schizophrenia: Evidence from the present study and a meta-analysis. J. Psychiatr. Res. 2016, 79, 50–56. [Google Scholar] [CrossRef] [PubMed]
  137. Rao, S.; Ye, N.; Hu, H.; Shen, Y.; Xu, Q. Variants in TERT influencing telomere length are associated with paranoid schizophrenia risk. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016, 171, 317–324. [Google Scholar] [CrossRef] [PubMed]
  138. Galletly, C.; Dhillon, V.S.; Liu, D.; Balzan, R.P.; Hahn, L.A.; Fenech, M.F. Shorter telomere length in people with schizophrenia: A preliminary study from Australia. Schizophr. Res. 2017, 190, 46–51. [Google Scholar] [CrossRef] [PubMed]
  139. Vaez-Azizi, L.M.; Ruby, E.; Dracxler, R.; Rothman, K.; Perrin, M.; Walsh-Messinger, J.; Antonius, D.; Goetz, R.R.; Goetz, D.M.; Keefe, D.L.; et al. Telomere length variability is related to symptoms and cognition in schizophrenia. Schizophr. Res. 2015, 164, 268–269. [Google Scholar] [CrossRef] [PubMed]
  140. Mansour, H.; Chowdari, K.; Fathi, W.; Elassy, M.; Ibrahim, I.; Wood, J.; Bamne, M.; Tobar, S.; Yassin, A.; Salah, H.; et al. Does telomere length mediate associations between inbreeding and increased risk for bipolar I disorder and schizophrenia? Psychiatry Res. 2011, 188, 129–132. [Google Scholar] [CrossRef] [PubMed]
  141. Nieratschker, V.; Lahtinen, J.; Meier, S.; Strohmaier, J.; Frank, J.; Heinrich, A.; Breuer, R.; Witt, S.H.; Nöthen, M.M.; Rietschel, M.; et al. Longer telomere length in pattiens with schizophrenia. Schizophr. Res. 2013, 149, 116–120. [Google Scholar] [CrossRef] [PubMed]
  142. Maurya, P.K.; Rizzo, L.B.; Xavier, G.; Tempaku, P.F.; Ota, V.K.; Santoro, M.L.; Spíndola, L.M.; Moretti, P.S.; Mazzotti, D.R.; Gadelha, A.; et al. Leukocyte telomere length variation in different stages of schizophrenia. J. Psychiatr. Res. 2018, 96, 218–223. [Google Scholar] [CrossRef] [PubMed]
  143. Maurya, P.K.; Rizzo, L.B.; Xavier, G.; Tempaku, P.F.; Zeni-Graiff, M.; Santoro, M.L.; Mazzotti, D.R.; Zugman, A.; Pan, P.; Noto, C.; et al. Shorter leukocyte telomere length in patients at ultra high risk for psychosis. Eur. Neuropsychopharmacol. 2017, 27, 538–542. [Google Scholar] [CrossRef] [PubMed]
  144. Malaspina, D.; Walsh-Messinger, J.; Antonius, D.; Dracxler, R.; Rothman, K.; Puthota, J.; Gilman, C.; Feuerstein, J.L.; Keefe, D.; Goetz, D.; et al. Parental age effects on odor sensitivity in healthy subjects and schizophrenia patients. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016, 171, 513–520. [Google Scholar] [CrossRef] [PubMed]
  145. Hansen, M.E.; Hunt, S.C.; Stone, R.C.; Horvath, K.; Herbig, U.; Ranciaro, A.; Hirbo, J.; Beggs, W.; Reiner, A.P.; Wilson, J.G.; et al. Shorter telomere length in Europeans than in Africans due to polygenetic adaptation. Hum. Mol. Genet. 2016, 25, 2324–2330. [Google Scholar] [CrossRef] [PubMed]
  146. Czepielewski, L.S.; Massuda, R.; Panizzutti, B.; Grun, L.K.; Barbe-Tuana, F.M.; Teixeira, A.L.; Barch, D.M.; Gama, C.S. Telomere Length and CCL11 Levels are Associated with Gray Matter Volume and Episodic Memory Performance in Schizophrenia: Evidence of Pathological Accelerated Aging. Schizophr. Bull. 2018, 44, 158–167. [Google Scholar] [CrossRef] [PubMed]
  147. King, K.S.; Kozlitina, J.; Rosenberg, R.N.; Peshock, R.M.; McColl, R.W.; Garcia, C.K. Effect of leukocyte telomere length on total and regional brain volumes in a large population-based cohort. JAMA Neurol. 2014, 71, 1247–1254. [Google Scholar] [CrossRef] [PubMed]
  148. Russo, P.; Prinzi, G.; Proietti, S.; Lamonaca, P.; Frustaci, A.; Boccia, S.; Amore, R.; Lorenzi, M.; Onder, G.; Marzetti, E.; et al. Shorter telomere length in schizophrenia: Evidence from a real-world population and meta-analysis of most recent literature. Schizophr. Res. 2018, in press. [Google Scholar] [CrossRef] [PubMed]
  149. Porton, B.; Delisi, L.E.; Bertisch, H.C.; Ji, F.; Gordon, D.; Li, P.; Benedict, M.M.; Greenberg, W.M.; Kao, H.T. Telomerase levels in schizophrenia: A preliminary study. Schizophr. Res. 2008, 106, 242–247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  150. Alder, J.K.; Parry, E.M.; Yegnasubramanian, S.; Wagner, C.L.; Lieblich, L.M.; Auerbach, R.; Auerbach, A.D.; Wheelan, S.J.; Armanios, M. Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene. Hum. Mutat. 2013, 34, 1481–1485. [Google Scholar] [CrossRef] [PubMed]
  151. Stanley, S.E.; Armanios, M. The short and long telomere syndromes: Paired paradigms for molecular medicine. Curr. Opin. Genet. Dev. 2015, 33, 1–9. [Google Scholar] [CrossRef] [PubMed]
  152. Fyhrquist, F.; Saijonmaa, O. Telomere length and cardiovascular aging. Ann. Med. 2012, 44 (Suppl. 1), S138–S142. [Google Scholar] [CrossRef] [PubMed]
  153. Riley, G.; Perrin, M.; Vaez-Azizi, L.M.; Ruby, E.; Goetz, R.R.; Dracxler, R.; Walsh-Messinger, J.; Keefe, D.L.; Buckley, P.F.; Szeszko, P.R.; et al. Telomere length and early trauma in schizophrenia. Schizophr. Res. 2018, 199, 426–430. [Google Scholar] [CrossRef] [PubMed]
  154. Balzan, R.P.; Dhillon, V.S.; Liu, D.; Hahn, L.; Fenech, M.F.; Galletly, C. Shorter telomere length in people with schizophrenia who live alone? Schizophr. Res. 2018, 199, 426–430. [Google Scholar] [CrossRef] [PubMed]
  155. Cropley, V.L.; Klauser, P.; Lenroot, R.K.; Bruggemann, J.; Sundram, S.; Bousman, C.; Pereira, A.; Di Biase, M.A.; Weickert, T.W.; Weickert, C.S.; et al. Accelerated Gray and White Matter Deterioration with Age in Schizophrenia. Am. J. Psychiatry 2017, 174, 286–295. [Google Scholar] [CrossRef] [PubMed]
  156. Van Mierlo, H.C.; Wichers, C.G.K.; He, Y.; Sneeboer, M.A.M.; Radstake, T.R.D.J.; Kahn, R.S.; Broen, J.C.A.; de Witte, L.D. Telomere quantification in frontal and temporal brain tissue of patients with schizophrenia. J. Psychiatr. Res. 2017, 95, 231–234. [Google Scholar] [CrossRef] [PubMed]
  157. Schnack, H.G.; van Haren, N.E.; Nieuwenhuis, M.; Pol, H.E.H.; Cahn, W.; Kahn, R.S. Accelerated Brain Aging in Schizophrenia: A Longitudinal Pattern Recognition Study. Am. J. Psychiatry 2016, 173, 607–616. [Google Scholar] [CrossRef] [PubMed]
  158. Drexhage, R.C.; Weigelt, K.; van Beveren, N.; Cohen, D.; Versnel, M.A.; Nolen, W.A.; Drexhage, H.A. Immune and neuroimmune alterations in mood disorders and schizophrenia. Int. Rev. Neurobiol. 2011, 101, 169–201. [Google Scholar] [PubMed]
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Figure 1. Schematic representation of the possible role of prenatal infections in schizophrenia pathophysiology. Exposure to neurotropic pathogens such as cytomegalovirus (CMV), other herpes viruses or T. gondii, or early adverse or stressful events has been proposed as environmental risk factors for schizophrenia in individuals with genetic susceptibility. Thus, maternal immune response to infection during pregnancy induce the production of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-1, tumor necrosis factor (TNF)-α and interferon (IFN)-γ, which activate placenta, fetal blood vessel and meninges. Inflammation may transiently alter brain development that, in the absence of genetic susceptibility, recovers in a short period of time. However, in the presence of genetic susceptibility to schizophrenia, the fetal meninges and blood vessels are hyper-responsive to these cytokines by secreting more cytokines and chemokines, the compensatory mechanisms (e.g., gene expression changes induced by IFN-γ) are exhausted and finally results in chronic inflammatory responses interfering with brain development. The inflammation status also influences postnatal brain development and the course of illness that after a prodrome phase finally results in schizophrenia. (Brain icon was obtained from: https://www.wpclipart.com/medical/anatomy/brain/brain_icon.png.html).
Figure 1. Schematic representation of the possible role of prenatal infections in schizophrenia pathophysiology. Exposure to neurotropic pathogens such as cytomegalovirus (CMV), other herpes viruses or T. gondii, or early adverse or stressful events has been proposed as environmental risk factors for schizophrenia in individuals with genetic susceptibility. Thus, maternal immune response to infection during pregnancy induce the production of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-1, tumor necrosis factor (TNF)-α and interferon (IFN)-γ, which activate placenta, fetal blood vessel and meninges. Inflammation may transiently alter brain development that, in the absence of genetic susceptibility, recovers in a short period of time. However, in the presence of genetic susceptibility to schizophrenia, the fetal meninges and blood vessels are hyper-responsive to these cytokines by secreting more cytokines and chemokines, the compensatory mechanisms (e.g., gene expression changes induced by IFN-γ) are exhausted and finally results in chronic inflammatory responses interfering with brain development. The inflammation status also influences postnatal brain development and the course of illness that after a prodrome phase finally results in schizophrenia. (Brain icon was obtained from: https://www.wpclipart.com/medical/anatomy/brain/brain_icon.png.html).
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Figure 2. Possible mechanisms involved in schizophrenia associated early ageing. Reactivation of pathogens, such as Cytomegalovirus (CMV), involved in chronic inflammation together with other stressful events and genetic vulnerability can be considered etiological factors for schizophrenia and other mental diseases. Chronic inflammation induces telomere shortening that is related to increased cardiovascular risk and cognitive impairment altogether involved in early mortality in schizophrenia patients.
Figure 2. Possible mechanisms involved in schizophrenia associated early ageing. Reactivation of pathogens, such as Cytomegalovirus (CMV), involved in chronic inflammation together with other stressful events and genetic vulnerability can be considered etiological factors for schizophrenia and other mental diseases. Chronic inflammation induces telomere shortening that is related to increased cardiovascular risk and cognitive impairment altogether involved in early mortality in schizophrenia patients.
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MDPI and ACS Style

Solana, C.; Pereira, D.; Tarazona, R. Early Senescence and Leukocyte Telomere Shortening in SCHIZOPHRENIA: A Role for Cytomegalovirus Infection? Brain Sci. 2018, 8, 188. https://doi.org/10.3390/brainsci8100188

AMA Style

Solana C, Pereira D, Tarazona R. Early Senescence and Leukocyte Telomere Shortening in SCHIZOPHRENIA: A Role for Cytomegalovirus Infection? Brain Sciences. 2018; 8(10):188. https://doi.org/10.3390/brainsci8100188

Chicago/Turabian Style

Solana, Corona, Diana Pereira, and Raquel Tarazona. 2018. "Early Senescence and Leukocyte Telomere Shortening in SCHIZOPHRENIA: A Role for Cytomegalovirus Infection?" Brain Sciences 8, no. 10: 188. https://doi.org/10.3390/brainsci8100188

APA Style

Solana, C., Pereira, D., & Tarazona, R. (2018). Early Senescence and Leukocyte Telomere Shortening in SCHIZOPHRENIA: A Role for Cytomegalovirus Infection? Brain Sciences, 8(10), 188. https://doi.org/10.3390/brainsci8100188

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