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A Heatmap showing correlation coefficients of the relation between frailty and the baseline (unstimulated) phosphorylation of STAT1, STAT3, and STAT5 in monocytes, B cells, and CD4⁺ and CD8⁺ T cells. Every box displays the Spearman’s ρ value based on data of 16 men and 18 women. B Baseline (unstimulated) pSTAT1 expression in monocytes. Solid trendline in (B) indicates that an association was found
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Background
Elderly often show reduced immune functioning and can develop chronic low-grade inflammation. Why some elderly are more prone to become frail is unknown. We investigated whether frailty is associated with altered cytokine signaling through the JAK-STAT pathway in leukocytes of 34 individuals aged 65–74 years. In addition, we investigated...
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Background
Immunosenescence (ISC) describes age-related changes in immune-system composition and function. Multiple sclerosis (MS) is a lifelong inflammatory condition involving effector and regulatory T-cell imbalance, yet little is known about T-cell ISC in MS. We examined age-associated changes in circulating T cells in MS compared to normal con...
Citations
... It is unlikely that the reduced STAT3 phosphorylation in GCA patients is due to a defect in the STAT3 molecule, as pSTAT3 percentages after IL-10 stimulation were robustly increased in GCA patients, and no differences with HCs were seen. Therefore, it is more likely that impaired IL-6 induced pSTAT3 responses observed in our study are the result of chronic stimulation and exhaustion of important components of the JAK/STAT signaling pathway [22]. Moreover, in a similar study in RA by Isomaki et al., a decreased phosphorylation of STAT3 after IL-6 stimulation in CD4 + T cells in RA patients with high plasma IL-6 levels and constitutive STAT3 phosphorylation were reported [23]. ...
... Although some studies have shown a positive association of CRP and ESR levels with relapsing disease in GCA patients [22], other studies failed to confirm the prognostic values of these markers [24]. Therefore, novel diagnostic and prognostic biomarkers are needed to better characterize GCA patients. ...
... One possible reason could be a tolerability of chemotherapy. The previous report showed TILs were negatively associated with frailty [41]. The frailty increased the risk of chemotherapy. ...
Background and Aim
The outcomes of immune checkpoint blockade for colorectal cancer (CRC) treatment are unsatisfactory. Furthermore, the efficacy of immune checkpoint blockade for liver metastasis of various cancer is poor. Here, we investigated the relationship between stromal programmed death-ligand 1 (PD-L1) expression and the prognosis of patients with colorectal cancer liver metastasis (CRLM).
Methods
The present study enrolled 84 CRLM patients who underwent surgery (R0) for CRC. Immunohistochemistry was performed to analyze stromal PD-L1 expression in CRLM.
Results
Stromal PD-L1 was expressed in 52.3% of CRLM samples, which was associated with fewer not optimally resectable metastases ( p = 0.04). Stromal PD-L1 also tended to associate with a lower tumor grade ( p = 0.08). Stromal PD-L1-positive patients had longer overall survival ( p = 0.003). Multivariate analysis identified stromal PD-L1 expression ( p = 0.008) and poorer differentiation ( p < 0.001) as independent prognostic indicators. Furthermore, stromal PD-L1 expression was correlated to a high number of tumor-infiltrating lymphocytes (TILs). Stromal PD-L1– and low TIL groups had shorter OS than stromal PD-L1 + and high TIL groups (46.6% vs. 81.8%, p = 0.05) Stromal PD-L1-positive patients had longer disease-free survival (DFS) ( p = 0.03) and time to surgical failure ( p = 0.001). Interestingly, stromal PD-L1 expression was positively related to the desmoplastic subtype ( p = 0.0002) and inversely related to the replacement subtype of the histological growth pattern ( p = 0.008).
Conclusions
Stromal PD-L1 expression may be a significant prognostic marker for CRLM.
... This suggests a dysfunctional pSTAT response in frail individuals. This highlights the importance of JAK-STAT signaling in healthy aging and identifies cellular pSTAT levels as candidate biomarkers of frailty [34]. Unfortunately, no clear correlation between eosinophilia and frailty has been reported. ...
Observational studies have suggested an association between white blood cells (WBCs) and frailty, but considering the susceptibility to reverse causality and confounding, the causal direction and magnitude of this association remain ambiguous. Our aim was to investigate the causal effect of WBCs on frailty by means of a Mendelian randomization (MR) analysis.
Based on the genome-wide association study (GWAS) summary statistics data provided by the European Bioinformatics Institute (EBI), we carried out a two-sample MR study. We applied the genetically predicted independent WBCs from GWAS as a measure of exposure data. The Rockwood Frailty Index (FI) was used as outcome measure, which was derived from a meta-analysis from GWAS in UK Biobank European ancestry participants and Swedish TwinGene participants. Our study applied inverse variance weighted (IVW), weighted median, Mendelian randomization-Egger (MR-Egger) and outlier test (MR-PRESSO) methods to explore relationships between various WBCs and frailty.
In our study, a possible causal relationship between eosinophil levels and frailty was demonstrated by two-sample MR analysis. Eosinophils were associated with FI (beta:0.0609; 95% CI 0.0382, 0.0836; P = 1.38E–07). Our results suggest that as the level of eosinophils increases, so does the risk of frailty. No meaningful causal relationship between neutrophils, lymphocytes, monocytes or basophils and FI was found in the MR results (P > 0.05).
According to this MR study, higher eosinophil counts are related to an increased risk of frailty. To validate these findings and investigate the mechanisms underlying these connections, future studies are warranted.
... Phosphoflow cytometry has been used to investigate immune cell signaling and function in various peripheral blood mononuclear cell (PBMC) types such as regulatory T cells (Tregs) [9], total T cells [10], and B cells [11]. The method has been applied to various physiologic states, including aging [12], immunodeficiency [13], autoimmune disease [14,15], and cancer, with the first application of this method to evaluate peripheral immune cells of patients with solid tumors published in 2004 by Lesinski et al. [16]. Methods for studying immune cells in cancer patient blood typically involve phenotyping by flow or mass cytometry and functional assays. ...
Tumor biopsy is often not available or difficult to obtain in patients with solid tumors. Investigation of the peripheral immune system allows for in-depth and dynamic profiling of patient immune response prior to and over the course of treatment and disease. Phosphoflow cytometry is a flow cytometry‒based method to detect levels of phosphorylated proteins in single cells. This method can be applied to peripheral immune cells to determine responsiveness of signaling pathways in specific immune subsets to cytokine stimulation, improving on simply defining numbers of populations of cells based on cell surface markers. Here, we review studies using phosphoflow cytometry to (a) investigate signaling pathways in cancer patients’ peripheral immune cells compared with healthy donors, (b) compare immune cell function in peripheral immune cells with the tumor microenvironment, (c) determine the effects of agents on the immune system, and (d) predict cancer patient response to treatment and outcome. In addition, we explore the use and potential of phosphoflow cytometry in preclinical cancer models. We believe this review is the first to provide a comprehensive summary of how phosphoflow cytometry can be applied in the field of cancer immunology, and demonstrates that this approach holds promise in exploring the mechanisms of response or resistance to immunotherapy both prior to and during the course of treatment. Additionally, it can help identify potential therapeutic avenues that can restore normal immune cell function and improve cancer patient outcome.
... Inflammatory reactions to bacterial colonization, immune cells implicated in inflammation, the production of pro-inflammatory mediators, and the activation of innate and adaptive immunity can all be affected by genetic variables (Xu et al. 2019)(AlChalabi et al. 2016 Gene polymorphism refers to variations in DNA sequence among people, groups, or populations. The most prevalent sort of genetic variation that manifests a difference in a single nucleotide is known as SNP (Kozak et al. 2020 (Guo et al. 2020)and (Frick-Cheng et al. 2020) the genetic variant rs2569190 of the CD14 gene (a G-to-A transition, 159 G/A) has been linked to disease severity (Jia et al. 2019) (Samson et al. 2022). ...
... Immunosenescence is correlated with suppressed JAK-STAT signaling in the leukocytes of frail older adults. 37 Biologically, cellular senescence in vital tissues is responsible for the myriad presentations of host aging. Cellular senescence encompasses cytopathologic processes, including telomere attrition, mitochondrial dysfunction, excessive reactive oxygen species (ROS) generation, and stem cell exhaustion. ...
Frailty is the incremental accumulation of minute defects that progressively impair health and performance. Frailty is commonly observed in older adults; however, secondary frailty may also occur in patients with metabolic disorders or major organ failure. In addition to physical frailty, several distinct types of frailty have been identified, including oral, cognitive, and social frailty, each of which is of practical importance. This nomenclature suggests that detailed descriptions of frailty can potentially advance relevant researches. In this narrative review, we first summarize the clinical value and plausible biological origin of frailty, as well as how to appropriately assess it using physical frailty phenotypes and frailty indexes. In the second part, we discuss the issue of vascular tissue as a relatively underappreciated organ whose pathologies contribute to the development of physical frailty. Moreover, when vascular tissue undergoes degeneration, it exhibits vulnerability to subtle injuries and manifests a unique phenotype amenable to clinical assessment prior to or accompanying physical frailty development. Finally, we propose that vascular frailty, based on an extensive set of experimental and clinical evidence, can be considered a new frailty type that requires our attention. We also outline potential methods for the operationalization of vascular frailty. Further studies are required to validate our claim and sharpen the spectrum of this degenerative phenotype.
Increased serum advanced glycation end products (AGEs) are commonly found in the patients with Diabetes mellitus (DM), aging-related diseases, and immune-mediated diseases. These diseases are notorious for vasculopathy, immune dysfunctions, and low-grade inflammation mimicking inflamm-aging. However, the molecular basis of inflamm-aging related to AGEs remains elucidation. In this study, we incubated human serum albumin (HSA) and glucose at 37 °C in 5% CO2 incubator for 0-180 days to generate AGE-HSA. We found the mixture gradually changing the color from transparancy to brown color and increased molecular weight during incubation. The pH value also gradually decreased from 7.2 to 5.4 irrelevant to ionic charge or [Ca2+] concentration, but dependent on gradual glycation of the alkaline amino acids, lysine and arginine. Functionally, 40 μg/mL of AGE-HSA decreased IL-2 production from human Jurkat T cell line via suppressing p-STAT3, p-STAT4, and p-STAT6 with an increased tendency of senescence-associated β-galactosidase (SA-βgal) expression but irrelevant to change of Th1/Th2/Treg subpopulations. In contrast, AGE-HSA enhanced CC motif chemokine ligand 5 (CCL-5), IL-8, macrophage migration inhibitor factor (MIF), and interleukin 1 receptor antagonist (IL-1Ra) but suppressed SA-βgal expression by human macrophage-like THP-1 cells. Interestingly, AGE-HSA abrogated the HSA-induced soluble intercellular adhesion molecules 1 (sICAM-1), sE-selectin and endothelin release from human coronary artery endothelial cells (HCAEC) and enhanced SA-βgal expression. The accelerated and increased HSA glycations by individual inflammation-related cytokine such as IL-2, IL-6, IL-17, TGF-β, or TNF-α in the in vitro study reflect increased serum AGE levels in patients with immune-mediated diseases . In conclusion, AGE-HSA can exert immunosuppresive, inflammatory and vasculopathic effects mimicking inflamm-aging in these patients.
Objective
Inflammation is one of the pathogenesis of frailty, Neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are newly proposed inflammatory indicators. This study aimed to explore the relationship between NLR, PLR and frailty in elderly inpatient with comorbidity.
Methods
Inpatient elderly with comorbidity in our geriatric department from January 2015 to December 2018 were selected, and three groups, which included frailty, pre-frailty and robust, were divided by 5-item FRAIL scale. General data of the patients were collected, and comprehensive geriatric assessment was performed. NLR and PLR were calculated by neutrophil, lymphocyte and platelet in blood. SPSS24.0 software was used for analysis.
Results
1.The neutrophil count, percentage of neutrophil, NLR of the frail group was significantly increased compared with other groups, but not PLR. White blood cell (r = 0.091, P = 0.031), neutrophil (r = 0.110, P = 0.009), neutrophil percentage (r = 0.109, P = 0.010) and NLR (r = 0.122, P = 0.004) was significantly positively correlated with frailty, while percentage of lymphocytes (r = −0.127, P = 0.002) was negatively correlate.
2.With frailty as the dependent variable, multivariate logistic regression analysis showed that NLR was not an independent risk factor for frailty (P>0.05).
Conclusion
Although results from the present study revealed associations between frailty and neutrophil and NLR in elderly inpatient with comorbidity, the potential role of these inflammation indicators on frailty needs further prospective investigation and researches involving larger population to improve its reliability.
