Immunity & Ageing最新文献

{"title":"TBX21, the Master regulator of the type 1 immune response, overexpresses in the leukocytes of peripheral blood in patients with late-onset Alzheimer's disease.","authors":"S R Fatemi Langroudi, M Zeinaly, F Ajamian","doi":"10.1186/s12979-023-00385-1","DOIUrl":"10.1186/s12979-023-00385-1","url":null,"abstract":"<p><strong>Background: </strong>The involvement of the peripheral immune system in the etiology of neurodegenerative diseases has recently been emphasized. Genome-wide association studies (GWAS) have recently identified several candidate immune genes linked to development of both Alzheimer's disease (AD) and depression. TBX21 (T-bet) which drives the Th1 immune response, is linked to the major depressive disorder (MDD) phenotype. This study investigated the association between the TBX21 immune gene and the possibility of late-onset Alzheimer's disease (LOAD) incidence in 194 LOAD and 200 control subjects using the real-time qPCR and the Tetra-ARMS-PCR methods. We also used an in silico approach to analyze the potential effects imparted by TBX21 rs17244587 and rs41515744 polymorphisms in LOAD pathogenesis.</p><p><strong>Results: </strong>We found that the TBX21 \"immune gene\" had significantly elevated mRNA expression levels in the leukocytes of peripheral blood in patients with LOAD (P < 0.0001). We also found an upward trend in TBX21 expression with increasing age in LOAD patients compared to the control group (P < 0.05; CI = 95%). We noticed that the TT genotype of rs41515744 plays a protective role in LOAD incidence, as it attenuates the expression of TBX21 in the control group. We observed that the dominant model of rs41515744 represented a substantial association with LOAD (P = 0.019).</p><p><strong>Conclusions: </strong>Our results show for the first time the likely impact of the TBX21 (T-bet) immune gene in LOAD development and that the elevated TBX21 mRNAs in the WBCs of LOAD patients may represent a new easy diagnostic test for Alzheimer's disease.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10636817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72211874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A genomic perspective of the aging human and mouse lung with a focus on immune response and cellular senescence.","authors":"Meng He, Jürgen Borlak","doi":"10.1186/s12979-023-00373-5","DOIUrl":"10.1186/s12979-023-00373-5","url":null,"abstract":"<p><strong>Background: </strong>The aging lung is a complex process and influenced by various stressors, especially airborne pathogens and xenobiotics. Additionally, a lifetime exposure to antigens results in structural and functional changes of the lung; yet an understanding of the cell type specific responses remains elusive. To gain insight into age-related changes in lung function and inflammaging, we evaluated 89 mouse and 414 individual human lung genomic data sets with a focus on genes mechanistically linked to extracellular matrix (ECM), cellular senescence, immune response and pulmonary surfactant, and we interrogated single cell RNAseq data to fingerprint cell type specific changes.</p><p><strong>Results: </strong>We identified 117 and 68 mouse and human genes linked to ECM remodeling which accounted for 46% and 27%, respectively of all ECM coding genes. Furthermore, we identified 73 and 31 mouse and human genes linked to cellular senescence, and the majority code for the senescence associated secretory phenotype. These cytokines, chemokines and growth factors are primarily secreted by macrophages and fibroblasts. Single-cell RNAseq data confirmed age-related induced expression of marker genes of macrophages, neutrophil, eosinophil, dendritic, NK-, CD4⁺, CD8⁺-T and B cells in the lung of aged mice. This included the highly significant regulation of 20 genes coding for the CD3-T-cell receptor complex. Conversely, for the human lung we primarily observed macrophage and CD4⁺ and CD8⁺ marker genes as changed with age. Additionally, we noted an age-related induced expression of marker genes for mouse basal, ciliated, club and goblet cells, while for the human lung, fibroblasts and myofibroblasts marker genes increased with age. Therefore, we infer a change in cellular activity of these cell types with age. Furthermore, we identified predominantly repressed expression of surfactant coding genes, especially the surfactant transporter Abca3, thus highlighting remodeling of surfactant lipids with implications for the production of inflammatory lipids and immune response.</p><p><strong>Conclusion: </strong>We report the genomic landscape of the aging lung and provide a rationale for its growing stiffness and age-related inflammation. By comparing the mouse and human pulmonary genome, we identified important differences between the two species and highlight the complex interplay of inflammaging, senescence and the link to ECM remodeling in healthy but aged individuals.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2023-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10626779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71488658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential determinants of antibody responses after vaccination against SARS-CoV-2 in older persons: the Doetinchem Cohort Study.","authors":"Yunus Kuijpers, H Susan J Picavet, Lia de Rond, Mary-Lène de Zeeuw-Brouwer, Ryanne Rutkens, Esther Gijsbers, Irene Slits, Peter Engelfriet, Anne-Marie Buisman, W M Monique Verschuren","doi":"10.1186/s12979-023-00382-4","DOIUrl":"10.1186/s12979-023-00382-4","url":null,"abstract":"<p><strong>Background: </strong>Immune responses to vaccination vary widely between individuals. The aim of this study was to identify health-related variables potentially underlying the antibody responses to SARS-CoV-2 vaccination in older persons. We recruited participants in the long-running Doetinchem Cohort Study (DCS) who underwent vaccination as part of the national COVID-19 program, and measured antibody concentrations to SARS-CoV-2 Spike protein (S1) and Nucleoprotein (N) at baseline (T0), and a month after both the first vaccination (T1), and the second vaccination (T2). Associations between the antibody concentrations and demographic variables, including age, sex, socio-economic status (SES), comorbidities (cardiovascular diseases and immune mediated diseases), various health parameters (cardiometabolic markers, inflammation markers, kidney- and lung function) and a composite measure of frailty ('frailty index', ranging from 0 to 1) were tested using multivariate models.</p><p><strong>Results: </strong>We included 1457 persons aged 50 to 92 years old. Of these persons 1257 were infection naïve after their primary vaccination series. The majority (N = 954) of these individuals were vaccinated with two doses of BNT162b2 (Pfizer) and their data were used for further analysis. A higher frailty index was associated with lower anti-S1 antibody responses at T1 and T2 for both men (R_T1 = -0.095, P_T1 = 0.05; R_T2 = -0.11, P_T2 = 0.02) and women (R_T1 = -0.24, P_T1 < 0.01; R_T2 = -0.15, P_T2 < 0.01). After correcting for age and sex the frailty index was also associated with the relative increase in anti-S1 IgG concentrations between the two vaccinations (β = 1.6, P < 0.01). Within the construct of frailty, history of a cardiac catheterization, diabetes, gastrointestinal disease, a cognitive speed in the lowest decile of the population distribution, and impaired lung function were associated with lower antibody responses after both vaccinations.</p><p><strong>Conclusions: </strong>Components of frailty play a key role in the primary vaccination response to the BNT162b2 vaccine within an ageing population. Older persons with various comorbidities have a lowered immune response after their first vaccination, and while frail and sick older persons see a stronger increase after their second vaccination compared to healthy people, they still have a lower antibody response after their second vaccination.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2023-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10599057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50163715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bifidobacterium bifidum and Lactobacillus paracasei alleviate sarcopenia and cognitive impairment in aged mice by regulating gut microbiota-mediated AKT, NF-κB, and FOXO3a signaling pathways.","authors":"Ji-Su Baek, Yoon-Jung Shin, Xiaoyang Ma, Hee-Seo Park, Yun-Ha Hwang, Dong-Hyun Kim","doi":"10.1186/s12979-023-00381-5","DOIUrl":"10.1186/s12979-023-00381-5","url":null,"abstract":"<p><p>Sarcopenia is closely associated with gut dysbiosis. Probiotics alleviate gut dysbiosis. Therefore, we selected probiotics Lactobacillus paracasei P62 (Lp) and Bifidobacterium bifidum P61 (Bb), which suppressed muscle RING-finger protein-1 (MuRF1) expression and NF-κB activation in C2C12 cells, and examined their effects on muscle mass loss and dysfunction in aged mice. Oral administration of Lp, Bb, or their mix (LB) increased grip strength and treadmill running distance and time. They significantly increased muscle weight in aged mice. They also increased AKT activation, PGC1α, SIRT1, and myosin heavy chain (MyHC) expression, MyHC-positive cell population, and cell size in the gastrocnemius (GA) muscle, while FOXO3a and NF-κB activation, MuRF1, muscle atrophy F-box, and p16 expression, and NF-κB⁺CD11c⁺ cell population decreased. Furthermore, they reduced cognitive impairment-like behavior, IL-6 expression, FOXO3a activation, and NF-κB-positive cell population in the hippocampus, GA, and colon, while hippocampal brain-derived neurotropic factor expression increased. They shifted gut microbiota composition in aged mice: they increased Akkermansiaceae and Bacteroidaceae populations, which were positively correlated with total muscle weight and MyHC expression, and decreased Odoribacteraceae and Deferribacteriaceae populations, which were positively correlated with MuRF1 and IL-6 expression. LB alleviated sarcopenia- and cognitive impairment-like symptoms more potently than Lp or Bb alone. Based on these findings, probiotics, particularly Lp, Bb, and LB, can alleviate aging-dependent sarcopenia and cognitive impairment by regulating gut microbiota-mediated AKT, NF-κB, and/or FOXO3a signaling pathways.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10591382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49693758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of immunology biomarkers associated with hip fracture and fracture risk in older adults.","authors":"Bernardo Abel Cedeno-Veloz, Lucía Lozano-Vicario, Fabricio Zambom-Ferraresi, Joaquín Fernández-Irigoyen, Enrique Santamaría, Alba Rodríguez-García, Roman Romero-Ortuno, Jaime Mondragon-Rubio, Javier Ruiz-Ruiz, Robinson Ramírez-Vélez, Mikel Izquierdo, Nicolás Martínez-Velilla","doi":"10.1186/s12979-023-00379-z","DOIUrl":"10.1186/s12979-023-00379-z","url":null,"abstract":"<p><p>Osteoporosis is a skeletal disease that can increase the risk of fractures, leading to adverse health and socioeconomic consequences. However, current clinical methods have limitations in accurately estimating fracture risk, particularly in older adults. Thus, new technologies are necessary to improve the accuracy of fracture risk estimation. In this observational study, we aimed to explore the association between serum cytokines and hip fracture status in older adults, and their associations with fracture risk using the FRAX reference tool. We investigated the use of a proximity extension assay (PEA) with Olink. We compared the characteristics of the population, functional status and detailed body composition (determined using densitometry) between groups. We enrolled 40 participants, including 20 with hip fracture and 20 without fracture, and studied 46 cytokines in their serum. After conducting a score plot and two unpaired t-tests using the Benjamini-Hochberg method, we found that Interleukin 6 (IL-6), Lymphotoxin-alpha (LT-α), Fms-related tyrosine kinase 3 ligand (FLT3LG), Colony stimulating factor 1 (CSF1), and Chemokine (C-C motif) ligand 7 (CCL7) were significantly different between fracture and non-fracture patients (p < 0.05). IL-6 had a moderate correlation with FRAX (R² = 0.409, p < 0.001), while CSF1 and CCL7 had weak correlations with FRAX. LT-α and FLT3LG exhibited a negative correlation with the risk of fracture. Our results suggest that targeted proteomic tools have the capability to identify differentially regulated proteins and may serve as potential markers for estimating fracture risk. However, longitudinal studies will be necessary to validate these results and determine the temporal patterns of changes in cytokine profiles.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2023-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10583364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49684782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the immune landscape following hip fracture in elderly patients: unveiling temporal dynamics through single-cell RNA sequencing.","authors":"Yining Lu, Yang Luo, Qi Zhang, Wei Chen, Ning Zhang, Ling Wang, Yingze Zhang","doi":"10.1186/s12979-023-00380-6","DOIUrl":"10.1186/s12979-023-00380-6","url":null,"abstract":"<p><strong>Background: </strong>Hip fractures in the elderly have significant consequences, stemming from the initial trauma and subsequent surgeries. Hidden blood loss and stress due to concealed injury sites could impact the whole osteoimmune microenvironment. This study employs scRNA-seq technique to map immune profiles in elderly hip fracture patients from post-trauma to the recovery period, investigating the dynamic changes of immune inflammation regulation subgroups.</p><p><strong>Methods: </strong>We collected peripheral blood samples from four elderly hip fracture patients (two males and two females, all > 75 years of age) at three different time points (24 h post-trauma, 24 h post-operation, and day 7 post-operation) and applied scRNA-seq technique to analyze the cellular heterogeneity and identify differentially expressed genes in peripheral blood individual immune cells from elderly hip fracture patients.</p><p><strong>Results: </strong>In this study, we analyzed the composition and gene expression profiles of peripheral blood mononuclear cells (PBMCs) from elderly hip fracture patients by scRNA-seq and further identified new CD14 monocyte subpopulations based on marker genes and transcriptional profiles. Distinct gene expression changes were observed in various cell subpopulations at different time points. C-Mono2 monocyte mitochondria-related genes were up-regulated and interferon-related and chemokine-related genes were down-regulated within 24 h post-operation. Further analysis of gene expression profiles at day 7 post-operation showed that C-Mono2 monocytes showed downregulation of inflammation-related genes and osteoblast differentiation-related genes. However, the expression of these genes in cytotoxic T cells, Treg cells, and B cell subsets exhibited a contrasting trend. GZMK⁺CD8⁺ cytotoxic T cells showed downregulation of chemokine-related genes, and Treg cells showed upregulation of genes related to the JAK/STAT signaling pathway. Furthermore, we examined interactions among diverse immune cell subsets, pinpointing specific ligand-receptor pairs. These findings imply cross-talk and communication between various cell types in the post-traumatic immune response.</p><p><strong>Conclusions: </strong>Our study elucidates the notable alterations in immune cell subpopulations during different stages of hip fracture in elderly patients, both in terms of proportions and differential gene expressions. These changes provide significant clinical implications for tissue repair, infection prevention, and fracture healing in clinic.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10580557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41240790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of autologous serum on TREM2 and APOE in a personalized monocyte-derived macrophage assay of late-onset Alzheimer's patients.","authors":"Neriman Eren, Susanna Gerike, Berk Üsekes, Oliver Peters, Nicoleta-Carmen Cosma, Julian Hellmann-Regen","doi":"10.1186/s12979-023-00376-2","DOIUrl":"10.1186/s12979-023-00376-2","url":null,"abstract":"<p><strong>Background: </strong>Age-associated deterioration of the immune system contributes to a chronic low-grade inflammatory state known as \"inflammaging\" and is implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD). Whether changes in the tissue environment caused by circulatory factors associated with aging may alter the innate immune response is unknown. Monocyte-derived macrophages (Mo-MФs) infiltrating the brain alongside microglia are postulated to play a modulatory role in LOAD and both express triggering receptor expressed on myeloid cells 2 (TREM2). Apolipoprotein E (APOE) acts as a ligand for TREM2, and their role in amyloid beta (Aβ) clearance highlights their importance in LOAD. However, the influence of the patient's own milieu (autologous serum) on the synthesis of TREM2 and APOE in infiltrating macrophages remains unknown.</p><p><strong>Objectives: </strong>To functionally assess patient-specific TREM2 and APOE synthesis, we designed a personalized assay based on Mo-MФs using monocytes from LOAD patients and matched controls (CO). We assessed the influence of each participant's own milieu, by examining the effect of short- (1 day) and long- (10 days) term differentiation of the cells in the presence of the donor´s autologous serum (AS) into M1-, M2- or M0-macrophages. Additionally, sex differences and Aβ-uptake ability in short- and long-term differentiated Mo-MФs were assessed.</p><p><strong>Results: </strong>We showed a time-dependent increase in TREM2 and APOE protein levels in LOAD- and CO-derived cells. While AS did not differentially modulate TREM2 compared to standard fetal calf serum (FCS), AS decreased APOE levels in M2 macrophages but increased levels in M1 macrophages. Interestingly, higher levels of TREM2 and lower levels of APOE were detected in female- than in male- LOAD patients. Finally, we report decreased Aβ-uptake in long-term differentiated CO- and LOAD-derived cells, particularly in APOEε4(+) carriers.</p><p><strong>Conclusions: </strong>We demonstrate for the first time the suitability of a personalized Mo-MФ cell culture-based assay for studying functional TREM2 and APOE synthesis in a patient's own aged milieu. Our strategy may thus provide a useful tool for future research on diagnostic and therapeutic aspects of personalized medicine.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2023-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia preserve visual function loss in the aging retina by supporting retinal pigment epithelial health.","authors":"Margarete M Karg, May Moorefield, Emma Hoffmann, Hannah Philipose, Drenushe Krasniqi, Cindy Hoppe, Daisy Y Shu, Shintaro Shirahama, Bruce R Ksander, Magali Saint-Geniez","doi":"10.1186/s12979-023-00358-4","DOIUrl":"10.1186/s12979-023-00358-4","url":null,"abstract":"<p><strong>Background: </strong>Increased age is a risk factor for the development and progression of retinal diseases including age-related macular degeneration (AMD). Understanding the changes that occur in the eye due to aging is important in enhancing our understanding of AMD pathogenesis and the development of novel AMD therapies. Microglia, the resident brain and retinal immune cells are associated with both maintaining homeostasis and protection of neurons and loss of microglia homeostasis could be a significant player in age related neurodegeneration. One important characteristic of retinal aging is the migration of microglia from the inner to outer retina where they reside in the subretinal space (SRS) in contact with the retinal pigment epithelial (RPE) cells. The role of aged subretinal microglia is unknown. Here, we depleted microglia in aged C57/BL6 mice fed for 6 weeks with a chow containing PLX5622, a small molecule inhibitor of colony-stimulating factor-1 receptor (Csf1r) required for microglial survival.</p><p><strong>Results: </strong>The subretinal P2RY12 + microglia in aged mice displayed a highly amoeboid and activated morphology and were filled with autofluorescence droplets reminiscent of lipofuscin. TEM indicates that subretinal microglia actively phagocytize shed photoreceptor outer segments, one of the main functions of retinal pigmented epithelial cells. PLX5622 treatment depleted up to 90% of the retinal microglia and was associated with significant loss in visual function. Mice on the microglia depletion diet showed reduced contrast sensitivity and significantly lower electroretinogram for the c-wave, a measurement of RPE functionality, compared to age-matched controls. The loss of c-wave coincided with a loss of RPE cells and increased RPE swelling in the absence of microglia.</p><p><strong>Conclusions: </strong>We conclude that microglia preserve visual function in aged mice and support RPE cell function, by phagocytosing shed photoreceptor outer segments and lipids, therefore compensating for the known age-related decline of RPE phagocytosis.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2023-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obesity drives adipose-derived stem cells into a senescent and dysfunctional phenotype associated with P38MAPK/NF-KB axis.","authors":"L K Grun, R M Maurmann, J N Scholl, M E Fogaça, C R R Schmitz, C K Dias, J Gasparotto, A V Padoin, C C Mottin, F Klamt, F Figueiró, M H Jones, E C Filippi-Chiela, F C R Guma, F M Barbé-Tuana","doi":"10.1186/s12979-023-00378-0","DOIUrl":"10.1186/s12979-023-00378-0","url":null,"abstract":"<p><strong>Background: </strong>Adipose-derived stem cells (ADSC) are multipotent cells implicated in tissue homeostasis. Obesity represents a chronic inflammatory disease associated with metabolic dysfunction and age-related mechanisms, with progressive accumulation of senescent cells and compromised ADSC function. In this study, we aimed to explore mechanisms associated with the inflammatory environment present in obesity in modulating ADSC to a senescent phenotype. We evaluated phenotypic and functional alterations through 18 days of treatment. ADSC were cultivated with a conditioned medium supplemented with a pool of plasma from eutrophic individuals (PE, n = 15) or with obesity (PO, n = 14), and compared to the control.</p><p><strong>Results: </strong>Our results showed that PO-treated ADSC exhibited decreased proliferative capacity with G2/M cycle arrest and CDKN1A (p21^WAF1/Cip1) up-regulation. We also observed increased senescence-associated β-galactosidase (SA-β-gal) activity, which was positively correlated with TRF1 protein expression. After 18 days, ADSC treated with PO showed augmented CDKN2A (p16^INK4A) expression, which was accompanied by a cumulative nuclear enlargement. After 10 days, ADSC treated with PO showed an increase in NF-κB phosphorylation, while PE and PO showed an increase in p38MAPK activation. PE and PO treatment also induced an increase in senescence-associated secretory phenotype (SASP) cytokines IL-6 and IL-8. PO-treated cells exhibited decreased metabolic activity, reduced oxygen consumption related to basal respiration, increased mitochondrial depolarization and biomass, and mitochondrial network remodeling, with no superoxide overproduction. Finally, we observed an accumulation of lipid droplets in PO-treated ADSC, implying an adaptive cellular mechanism induced by the obesogenic stimuli.</p><p><strong>Conclusions: </strong>Taken together, our data suggest that the inflammatory environment observed in obesity induces a senescent phenotype associated with p38MAPK/NF-κB axis, which stimulates and amplifies the SASP and is associated with impaired mitochondrial homeostasis.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2023-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10566105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional characteristics and functional validation of three monocyte subsets during aging.","authors":"Chen Wang, Yating Cheng, Boyu Li, Xueping Qiu, Hui Hu, Xiaokang Zhang, Zhibing Lu, Fang Zheng","doi":"10.1186/s12979-023-00377-1","DOIUrl":"10.1186/s12979-023-00377-1","url":null,"abstract":"<p><strong>Background: </strong>Age-associated changes in immunity are inextricably linked to chronic inflammation and age-related diseases, the impact of aging on monocyte subsets is poorly understood.</p><p><strong>Methods: </strong>Flow cytometry was applied to distinguish three monocyte subsets between 120 young and 103 aged individuals. We then analyzed the expression profiles of three monocyte subsets from 9 young and 9 older donors and CD14⁺ monocytes from 1202 individuals between 44 and 83 years old. Flow cytometry was used to measure β-galactosidase activities, ROS levels, mitochondrial contents, mitochondrial membrane potentials (MMPs) and intracellular IL-6 levels in three monocyte subsets of young and elderly individuals, and plasma IL-6 levels were detected by electrochemiluminescence immunoassay. Mitochondrial stress and glycolytic rate of CD14⁺ monocytes from young and aged individuals were measured by Seahorse XFe24 Analyzer.</p><p><strong>Results: </strong>Compared with young individuals, the percentage of classical subset in aged persons significantly decreased, while the proportion of nonclassical subset increased. Age-related differential genes were obviously enriched in cellular senescence, ROS, oxidative phosphorylation, mitochondrial respiratory chain, IL-6 and ribosome-related pathways. Compared with young individuals, the β-galactosidase activities, ROS contents, intracellular IL-6 levels of three monocyte subsets, and plasma IL-6 levels in aged individuals were significantly elevated, while the MMPs apparently declined with age and the mitochondrial contents were only increased in intermediate and nonclassical subsets. CD14⁺ monocytes from elderly adults had conspicuously lower basal and spare respiratory capacity and higher basal glycolysis than those from young individuals.</p><p><strong>Conclusions: </strong>During aging, monocytes exhibited senescence-associated secretory phenotype, mitochondrial dysfunction, decreased oxidative phosphorylation and increased glycolysis and the nonclassical subset displayed the clearest features of aging. Our study comprehensively investigated age-related transcriptional alterations of three monocyte subsets and identified the pivotal pathways of monocyte senescence, which may have significant implications for tactics to alleviate age-related conditions.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2023-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10523626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41156783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}