Eotaxin-1/CCL11 promotes cellular senescence in human-derived fibroblasts through pro-oxidant and pro-inflammatory pathways.

Introduction: Eotaxin-1/CCL11 is a pivotal chemokine crucial for eosinophil homing to the lungs of asthmatic patients. Recent studies also suggest that CCL11 is involved in the aging process, as it is upregulated in elderly, and correlated with shorter telomere length in leukocytes from asthmatic children. Despite its potential pro-aging effects, the precise contribution of CCL11 and the underlying mechanisms involved in the promotion of cellular senescence remains unclear. Therefore, the primary goal of this study was to explore the role of CCL11 on senescence development and the signaling pathways activated by this chemokine in lung fibroblasts. Methods: To investigate the targets potentially modulated by CCL11, we performed an in silico analysis using PseudoCell. We validated in vitro the activation of these targets in the human lung fibroblast cell line MRC-5 following rhCCL11 exposure. Finally, we performed differential gene expression analysis in human airway epithelial cells of asthmatic patients to assess CCL11 signaling and activation of additional senescent markers. Results: Our study revealed that eotaxin-1/CCL11 promote reactive oxygen secretion (ROS) production in lung fibroblasts, accompanied by increased activation of the DNA damage response (DDR) and p-TP53 and γH2AX. These modifications were accompanied by cellular senescence promotion and increased secretion of senescence-associated secretory phenotype inflammatory cytokines IL-6 and IL-8. Furthermore, our data show that airway epithelial lung cells from atopic asthmatic patients overexpress CCL11 along with aging markers such as CDKN2A (p16INK4a) and SERPINE1. Discussion: These findings provide new insights into the mechanisms underlying the pro-aging effects of CCL11 in the lungs of asthmatic patients. Understanding the role of CCL11 on senescence development may have important implications for the treatment of age-related lung diseases, such as asthma.

Telomere length and epigenetic age acceleration in adolescents with anxiety disorders.

Evidence on the relationship between genetics and mental health are flourishing. However, few studies are evaluating early biomarkers that might link genes, environment, and psychopathology. We aimed to study telomere length (TL) and epigenetic age acceleration (AA) in a cohort of adolescents with and without anxiety disorders (N = 234). We evaluated a representative subsample of participants at baseline and after 5 years (n = 76) and categorized them according to their anxiety disorder diagnosis at both time points: (1) control group (no anxiety disorder, n = 18), (2) variable group (anxiety disorder in one evaluation, n = 38), and (3) persistent group (anxiety disorder at both time points, n = 20). We assessed relative mean TL by real-time quantitative PCR and DNA methylation by Infinium HumanMethylation450 BeadChip. We calculated AA using the Horvath age estimation algorithm and analyzed differences among groups using generalized linear mixed models. The persistent group of anxiety disorder did not change TL over time (p = 0.495). The variable group had higher baseline TL (p = 0.003) but no accelerated TL erosion in comparison to the non-anxiety control group (p = 0.053). Furthermore, there were no differences in AA among groups over time. Our findings suggest that adolescents with chronic anxiety did not change telomere length over time, which could be related to a delay in neuronal development in this period of life.

TRF1 as a major contributor for telomeres' shortening in the context of obesity.

Obesity is a prevalent multifactorial chronic disorder characterized by metabolic dysregulation. Sustained pro-oxidative mediators trigger harmful consequences that reflect at systemic level and contribute for the establishment of a premature senescent phenotype associated with macromolecular damage (DNA, protein, and lipids). Telomeres are structures that protect chromosome ends and are associated with a six-protein complex called the shelterin complex and subject to regulation. Under pro-oxidant conditions, telomere attrition and the altered expression of the shelterin proteins are central for the establishment of many pathophysiological conditions such as obesity. Thus, considering that individuals with obesity display a systemic oxidative stress profile that may compromise the telomeres length or its regulation, the aim of this study was to investigate telomere homeostasis in patients with obesity and explore broad/systemic associations with the expression of shelterin genes and the plasma redox state. We performed a cross-sectional study in 39 patients with obesity and 27 eutrophic subjects. Telomere length (T/S ratio) and gene expression of shelterin components were performed in peripheral blood mononuclear cells by qPCR. The oxidative damage (lipid peroxidation and protein carbonylation) and non-enzymatic antioxidant system (total radical-trapping antioxidant potential/reactivity, sulfhydryl and GSH content) were evaluated in plasma. Our results demonstrate that independently of comorbidities, individuals with obesity had significantly shorter telomeres, augmented expression of negative regulators of the shelterin complex, increased lipid peroxidation and higher oxidized protein levels associated with increased non-enzymatic antioxidant defenses. Principal component analysis revealed TRF1 as a major contributor for firstly telomeres shortening. In conclusion, our study is first showing a comprehensive analysis of telomeres in the context of obesity, associated with dysregulation of the shelterin components that was partially explained by TRF1 upregulation that could not be reversed by the observed adaptive non-enzymatic antioxidant response.

Immunosenescence Induced by Plasma from Individuals with Obesity Caused Cell Signaling Dysfunction and Inflammation.

OBJECTIVE: To evaluate the consequences of plasma from individuals with obesity on parameters associated with immunosenescence in unrelated healthy peripheral blood mononuclear cells (PBMC). METHODS: Freshly isolated PBMC were incubated in media supplemented with 10% of plasma from individuals with obesity or control subjects for the first 4 hours of 24 to 120 hours of culture. RESULTS: Plasma from individuals with obesity modulated the phenotype of healthy PBMC, leading to a higher rate of apoptosis, lower amounts of phospho-γH2AX and -p53, and mitochondrial dysfunction. After 120 hours, there was a higher secretion of inflammatory cytokines IL-1ß and IL-8. CD8+ T lymphocytes presented decreased expression of CD28, which is associated with the immunosenescent phenotype. CD14+ macrophages showed increased expression of CD80 and CD206, suggesting a modulation in the activation of macrophages. CONCLUSIONS: These results demonstrate that chronic systemic inflammation observed in obesity induces dysfunctional features in PBMC that are consistent with premature immunosenescence.