Aging is associated with an increased incidence of autoimmune diseases, despite the progressive decline of immune responses (immunosenescence). This apparent paradox can be explained by the ...age-related chronic low-grade systemic inflammation (inflammaging) and progressive dysregulation of innate signaling. During cellular aging, there is an accumulation of damaged DNA in the cell's cytoplasm, which serves as ubiquitous danger-associated molecule, promptly recognized by DNA sensors. For instance, the free cytoplasmic DNA can be recognized, by DNA-sensing molecules like cGAS-STING (cyclic GMP-AMP synthase linked to a stimulator of interferon genes), triggering transcriptional factors involved in the secretion of pro-inflammatory mediators. However, the contribution of this pathway to the aging immune system remains largely unknown. Here, we highlight recent advances in understanding the biology of the cGAS-STING pathway, its influence on the senescence-associated secretory phenotype (SASP), and its modulation of the immune system during sterile inflammation. We propose that this important stress sensor of DNA damage is also a trigger of immunosenescence and inflammaging.
Potassium 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-olate (CPBMF65) is a potent inhibitor of the uridine phosphorylase 1 (UPP1) enzyme. Its non-ionized analog has already demonstrated biological ...properties by reducing adverse effects caused by the chemotherapeutic 5-fluorouracil (5-FU). In addition, it has been demonstrated that uridine inhibits inflammation and fibrosis in bleomycin lung injury, decreasing collagen production. The purpose of this study was to investigate the in vitro and in vivo effects of CPBMF65 on activated hepatic stellate cells (HSC) and on carbon tetrachloride-induced liver fibrosis in mice. After incubation with CPBMF65, decreased cell proliferation and phenotype reversion were observed in vitro. In addition, CPBMF65 promoted a protective effect on tetrachloride-induced liver fibrosis in mice, demonstrated by its antifibrotic and anti-inflammatory actions. The results of the present study indicate that the UPP1 inhibitor (CPBMF65) may have potential as a novel therapeutic agent for the treatment of liver fibrosis.
Display omitted
Transplanted individuals in operational tolerance (OT) maintain long-term stable graft function after completely stopping immunosuppression. Understanding the mechanisms involved in OT can provide ...valuable information about pathways to human transplantation tolerance. Here we report that operationally tolerant individuals display quantitative and functional preservation of the B-cell compartment in renal transplantation. OT exhibited normal numbers of circulating total B cells, naive, memory and regulatory B cells (Bregs) as well as preserved B-cell receptor repertoire, similar to healthy individuals. In addition, OT also displayed conserved capacity to activate the cluster of differentiation 40 (CD40)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in Bregs, in contrast, with chronic rejection. Rather than expansion or higher activation, we show that the preservation of the B-cell compartment favors OT.
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.
Display omitted
•Shorter telomere length is associated with accelerated aging in obesity.•Upregulation of regulatory genes associated to telomeres’ length in obesity.•Adaptive antioxidant response were insufficient to counter-act telomere attrition.•TRF1 as a major contributor for telomeres uncapping in the context of obesity.
Different intrauterine exposures are associated with different metabolic profiles
leading to growth and development characteristics in children and also relate to
health and disease patterns in adult ...life. The objective of this work was to
evaluate the impact of four different intrauterine environments on the telomere
length of newborns. This is a longitudinal observational study using a
convenience sample of 222 mothers and their term newborns (>37 weeks of
gestational age) from hospitals in Porto Alegre, Rio Grande do Sul (Brazil),
from September 2011 to January 2016. Sample was divided into four groups:
pregnant women with Gestational Diabetes Mellitus (DM) (n=38), smoking pregnant
women (TOBACCO) (n=52), mothers with small-for-gestational age (SGA) children
due to idiopathic intrauterine growth restriction (n=33), and a control group
(n=99). Maternal and newborn genomic DNA were obtained from epithelial mucosal
cells. Telomere length was assessed by qPCR, with the calculation of the
telomere and single copy gene (T/S ratio). In this sample, there was no
significant difference in telomere length between groups (p>0.05). There was
also no association between childbirth weight and telomere length in children
(p>0.05). For term newborns different intrauterine environments seems not to
influence telomere length at birth.
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.
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‐1β 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.
Abstract
Background:
Growing evidence supports the existence of neurobiological trait abnormalities in individuals at genetic risk for bipolar disorder. The aim of this study was to examine potential ...differences in brain-derived neurotrophic factor, cytokines, oxidative stress, and telomere length markers between patients with bipolar disorder, their siblings, and healthy controls.
Methods:
Thirty-six patients with bipolar disorder type I, 39 siblings, and 44 healthy controls were assessed. Serum levels of brain-derived neurotrophic factor, interleukin-6, interleukin-10, tumor necrosis factor-α, C-C motif chemokine 11, C-C motif chemokine 24, and 3-nitrotyrosine were measured, as were the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Telomere length (T/S ratio) was measured using quantitative polymerase chain reaction.
Results:
Telomere length was different between the 3 groups (P = .041) with both patients and siblings showing a shorter T/S ratio compared with healthy controls. Patients showed increased levels of interleukin-6 (P = .005) and interleukin-10 (P = .002) compared with controls as well as increased levels of interleukin-6 (p = 0.014) and CCL24 (P = .016) compared with their siblings. C-C motif chemokine 11 levels were increased in siblings compared with controls (P = .015), and a similar tendency was found in patients compared with controls (P = .045). Glutathione peroxidase activity was decreased in patients compared with controls (P = .006) and siblings (P = .025). No differences were found for the other markers.
Conclusions:
The present results suggest that unaffected siblings may present accelerated aging features. These neurobiological findings may be considered as endophenotypic traits. Further prospective studies are warranted.
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.
Plant-derived compounds are a reservoir of natural chemicals and can act as drug precursors or prototypes and pharmacological probes. Methoxyeugenol is a natural compound found in plant extracts, ...such as nutmeg (Myristica fragrans), and it presents anthelmintic, antimicrobial, anti-inflammatory activities. Recently, interest in the anticancer activity of plant extracts is increasing and the therapeutic activity of methoxyeugenol against cancer has not yet been explored.
The present study aimed to evaluate the cancer-suppressive role and the molecular signaling pathways of methoxyeugenol in human endometrial cancer (Ishikawa) cell line.
Proliferation, viability, and cell toxicity were assessed by direct counting, MTT assay, and LDH enzyme release assay, respectively. Antiproliferative effect were evaluated by nuclear morphological changes along with the cellular mechanisms of apoptosis and senescence by flow cytometry. The underlying molecular and cellular mechanisms were investigated by RT-qPCR, reactive oxygen species (ROS) levels, mitochondrial dysfunction, and proliferative capacity.
Methoxyeugenol treatment significantly inhibited the proliferation and viability of Ishikawa cells. Probably triggered by the higher ROS levels and mitochondrial dysfunction, the gene expression of p53 and p21 increased and the gene expression of CDK4/6 decreased in response to the methoxyeugenol treatment. The rise in nuclear size and acidic vesicular organelles corroborate with the initial senescence-inducing signals in Ishikawa cells treated with methoxyeugenol. The antiproliferative effect was not related to cytotoxicity and proved to effectively reduce the proliferative capacity of endometrial cancer cells even after treatment withdrawal. These results demonstrated that methoxyeugenol has a promising anticancer effect against endometrial cancer by rising ROS levels, triggering mitochondrial instability, and modulating cell signaling pathways leading to an inhibition of cell proliferation.
Display omitted
PDF
