Telomere Length and CCL11 Levels are Associated With Gray Matter Volume and Episodic Memory Performance in Schizophrenia: Evidence of Pathological Accelerated Aging

Abstract

Schizophrenia (SZ) is associated with increased somatic morbidity and mortality, in addition to cognitive impairments similar to those seen in normal aging, which may suggest that pathological accelerated aging occurs in SZ. Therefore, we aim to evaluate the relationships of age, telomere length (TL), and CCL11 (aging and inflammatory biomarkers, respectively), gray matter (GM) volume and episodic memory performance in individuals with SZ compared to healthy controls (HC). One hundred twelve participants (48 SZ and 64 HC) underwent clinical and memory assessments, structural MRI, and had their peripheral blood drawn for biomarkers analysis. Comparisons of group means and correlations were performed. Participants with SZ had decreased TL and GM volume, increased CCL11, and worse memory performance compared to HC. In SZ, shorter TL was related to increased CCL11, and both biomarkers were related to reduced GM volume, all of which were related to worse memory performance. Older age was only associated with reduced GM, but longer duration of illness was related with all the aforementioned variables. Younger age of disease onset was associated with increased CCL11 levels and worse memory performance. In HC, there were no significant correlations except between memory and GM. Our results are consistent with the hypothesis of accelerated aging in SZ. These results may indicate that it is not age itself, but the impact of the disease associated with a pathological accelerated aging that leads to impaired outcomes in SZ.

Cognitive decline and mortality in a community-based sample of homeless and precariously housed adults: 9-year prospective study

“…8,10 Illnesses associated with premature or accelerated ageing, and found with greater prevalence in marginalised people, include schizophrenia, traumatic brain injury, alcohol dependence and HIV infection. [13][14][15][16] Independent of age-related illnesses, cognitive dysfunction may be a critical marker of diminishing robustness in biological systems associated with premature mortality. 17,18 Identifying vulnerabilities for poor long-term outcomes in homeless people is essential to establish priorities for early interventions.…”

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

“…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 ].…”

“…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 ].…”

“…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 ].…”

Leukocyte Telomere Length Is Unrelated to Cognitive Performance Among Non-Demented and Demented Persons: An Examination of Long Life Family Study Participants

“…Extant literature further demonstrates how shorter LTL may be associated with mortality and several age-related diseases like cancer, cardiovascular disease, type II diabetes, and neurodegenerative disorders such as Parkinson's Disease, Huntington's Disease, and Alzheimer's Disease (AD) (Cai et al, 2013;Degerman et al, 2014;Forero et al, 2016;Herrmann et al, 2018;Honig et al, 2012;Insel, Merkle, Hsiao, & Vidrine, 2012;Ma et al, 2013;Scarabino, Broggio, Gambina, & Corbo, 2017;Wikgren et al, 2014). Some studies have also found relationships between LTL with neuropsychiatric disorders such as depression, anxietyrelated disorders, schizophrenia, and other psychotic disorders, as well as bipolar disorder (Richard, Reitz, Honig, Schupf, & Tamg, 2013;Chang et al, 2018;Czepielewski et al, 2018;Nieratschker et al, 2013, Powell, Dima, Frangou, & Breen, 2018Vasconcelos-Moreno et al, 2017;Wang et al, 2017;Colpo, Leffa, Quevedo, & Carvalho, 2015;Lindqvist et al, 2015). Such aging-, metabolic-, psychiatric-, and inflammation-related conditions have all been associated with cognitive outcomes (Cohen-Manheim et al, 2016).…”