IL6
Interleukin-6 precursor (IL-6) (B-cell stimulatory factor 2) (BSF-2) (CTL differentiation factor) (CDF) (Hybridoma growth factor) (Interferon beta-2) (IFN-beta-2) [IFNB2]
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REV1/POLζ-dependent mutagenic translesion synthesis (TLS) promotes cell survival after DNA damage but is responsible for most of the resulting mutations. A novel inhibitor of this pathway, JH-RE-06, promotes cisplatin efficacy in cancer cells and mouse xenograft models, but the mechanism underlying this combinatorial effect is not known. We report that, unexpectedly, in two different mouse xenograft models and four human and mouse cell lines we examined in vitro cisplatin/JH-RE-06 treatment does not increase apoptosis. Rather, it increases hallmarks of senescence such as senescence-associated β-galactosidase, increased p21 expression, micronuclei formation, reduced Lamin B1, and increased expression of the immune regulators IL6 and IL8 followed by cell death. Moreover, although p-γ-H2AX foci formation was elevated and ATR expression was low in single agent cisplatin-treated cells, the opposite was true in cells treated with cisplatin/JH-RE-06. These observations suggest that targeting REV1 with JH-RE-06 profoundly affects the nature of the persistent genomic damage after cisplatin treatment and also the resulting physiological responses. These data highlight the potential of REV1/POLζ inhibitors to alter the biological response to DNA-damaging chemotherapy and enhance the efficacy of chemotherapy.
Keywords
- Rev1
- cell death
- chemotherapy
- senescence
- translesion synthesis
The oviduct is essential for reproduction. We previously showed that oviduct epithelial cells (OECs) isolated from aged cows expressed higher levels of inflammatory cytokines, including interleukin (IL) 1A and IL1B. In addition, aging is associated with tissue dysfunction and cellular senescence via a senescence-associated secretory phenotype (SASP) and immune cell accumulation. We investigated whether IL1A or IL1B causes SASP production, cellular senescence, and inflammatory responses in bovine OECs. The OECs were isolated from bovine oviducts from young (mean 50.3 months) and aged cows (mean 157.0 months) and cultured. Treatment with IL1A or IL1B induced SASP production (IL8, IL6, TNFA, and CCL2) and mRNA expression of cell adhesion molecules in bovine OECs, but both IL1s did not induce cellular senescence in OECs and migration of polymorphonuclear neutrophils (PMNs). Cultured medium of OECs treated with IL1s, especially IL1B, dramatically induced PMN migration. Treatment with the CCL2 inhibitor, but not IL8 or its receptor CXCR2 inhibitors, significantly reduced immune cell migration in IL1B-treated OEC-cultured medium. Treatment with IL1B increased PMN adhesion to OECs, resulting in further SASP production in OECs due to a PMN-OEC interaction. We suggest that senescence-associated IL1s cause SASP production in bovine OECs and CCL2 induced by IL1B is essential for the migration of immune cells to OECs. Specifically, IL1B regulates PMN migration and adhesion to bovine OECs, and PMNs accelerate inflammatory cytokine production from bovine OECs via a direct interaction. These phenomena may contribute to chronic oviductal inflammation, resulting in subfertility.
Keywords
- CCL2
- cellular senescence
- inflammaging
- senescence-associated secretory phenotype
COVID-19 pandemia is a major concern for patients and healthcare systems. The fear of infection by patients with concomitant rheumatic diseases (either adult or children) and connective tissue diseases is arising worldwide, because of their immunological background and immunological therapies. Analysing the basic biology of single diseases, the data suggest that there is an "immunological umbrella" that seems to protect against the infection, through IFN type 1 and NK cell function. To date, reports from China, United States and Europe did not reveal an higher risk of infection, either for rheumatoid arthritis, juvenile idiopathic arthritis nor for lupus erythematosus. Antimalarials, anti-IL6-Anti-IL6 receptor, anti-IL1, anti-GM-CSF receptor and JAK1/2/3 inhibitors, are under investigation in COVID-dedicated clinical trials to control the inflammation raised by SARS-CoV-2 infection. Initial reports on the occurrence of autoimmune phenomena in the convalescence phase of SARS-CoV-2 infection suggests that the immunological consequences of the infection need to be strictly understood. Reporting of the study conforms to broad EQUATOR guidelines (Simera et al January 2010 issue of EJCI).
MeSH Terms
- Adaptive Immunity
- Aged
- Antirheumatic Agents
- COVID-19
- Comorbidity
- Coronavirus Infections
- Disease Outbreaks
- Female
- Humans
- Hydroxychloroquine
- Immunity, Innate
- Immunologic Factors
- Immunosuppressive Agents
- Italy
- Male
- Middle Aged
- Pandemics
- Pneumonia, Viral
- Rheumatic Diseases
- Risk Assessment
- Severe Acute Respiratory Syndrome
Keywords
- COVID-19
- SARS-CoV-2
- geriatrics
- pathophysiology
- pediatrics
- rheumatology
ATM is a kinase involved in DNA damage response (DDR), regulation of response to oxidative stress, autophagy and mitophagy. Mutations in the ATM gene in humans result in ataxi A-Telangiectasia disease (A-T) characterized by a variety of symptoms with neurodegeneration and premature ageing among them. Since brain is one of the most affected organs in A-T, we have focused on senescence of neural progenitor cells (NPCs) derived from A-T reprogrammed fibroblasts. Accordingly, A-T NPCs obtained through neural differentiation of iPSCs in 5% oxygen possessed some features of senescence including increased activity of SA-β-gal and secretion of IL6 and IL8 in comparison to control NPCs. This phenotype of A-T NPC was accompanied by elevated oxidative stress. A-T NPCs exhibited symptoms of impaired autophagy and mitophagy with lack of response to chloroquine treatment. Additional sources of oxidative stress like increased oxygen concentration (20 %) and H O respectively aggravated the phenotype of senescence and additionally disturbed the process of mitophagy. In both cases only A-T NPCs reacted to the treatment. We conclude that oxidative stress may be responsible for the phenotype of senescence and impairment of autophagy in A-T NPCs. Our results point to senescent A-T cells as a potential therapeutic target in this disease.
Keywords
- ATM
- Ataxia-telangiectasia
- Autophagy
- Mitophagy
- Neural progenitors
- Oxidative stress
- Senescence
- hiPSCs
The senescence of vascular smooth muscle cells (VSMCs), characterized by the acquisition of senescence-associated secretory phenotype (SASP), is relevant for VSMCs osteoblastic differentiation and vascular calcification (VC). MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. Herein, we analyzed the relationship between miR-34a and the prototypical SASP component IL6 in in vitro and in vivo models. miR-34a and IL6 levels increased and positively correlated in aortas of 21 months-old male C57BL/6J mice and in human aortic smooth muscle cells (HASMCs) isolated from donors of different age and undergone senescence. Lentiviral overexpression of miR-34a in HASMCs enhanced IL6 secretion. HASMCs senescence and calcification accelerated after exposure to conditioned medium of miR-34a-overexpressing cells. Analysis of miR-34a-induced secretome revealed enhancement of several pro-inflammatory cytokines and chemokines, including IL6, pro-senescent growth factors and matrix-degrading molecules. Moreover, induction of aortas medial calcification and concomitant IL6 expression, with an overdose of vitamin D, was reduced in male C57BL/6J [i]Mir34a [/i] mice. Finally, a positive correlation was observed between circulating miR-34a and IL6 in healthy subjects of 20-90 years. Hence, the vascular age-associated miR-34a promotes VSMCs SASP activation and contributes to arterial inflammation and dysfunctions such as VC.
Keywords
- IL6
- SASP
- VSMCs
- inflammaging
- senescence
- vascular calcification
Changes in innate and adaptive immune responses caused by viral imprinting can have a significant direct or indirect influence on secondary infections and vaccine responses. The purpose of our current study was to investigate the role of immune imprinting by influenza on pneumococcal vaccine effectiveness during [i]Streptococcus pneumoniae[/i] infection in the aged murine lung. Aged adult (18 months) mice were vaccinated with the pneumococcal polyvalent vaccine Pneumovax (5 mg/mouse). Fourteen days post vaccination, mice were instilled with PBS or influenza A/PR8/34 virus (3.5 × 10 PFU). Control and influenza-infected mice were instilled with PBS or [i]S. pneumoniae[/i] (1 × 10 CFU, ATCC 6303) on day 7 of infection and antibacterial immune responses were assessed in the lung. Our results illustrate that, in response to a primary influenza infection, there was diminished bacterial clearance and heightened production of pro-inflammatory cytokines, such as IL6 and IL1β. Vaccination with Pneumovax decreased pro-inflammatory cytokine production by modulating NFҡB expression; however, these responses were significantly diminished after influenza infection. Taken together, the data in our current study illustrate that immune imprinting by influenza diminishes pneumococcal vaccine efficacy and, thereby, may contribute to increased susceptibility of older persons to a secondary infection with [i]S. pneumoniae[/i].
Keywords
- Streptococcus pneumoniae
- aging
- influenza
- vaccine effectiveness
- viral immune imprinting
Senescent fibroblasts are characterized by their inability to proliferate and by a pro-inflammatory and catabolic secretory phenotype, which contributes to age-related pathologies. Furthermore, senescent fibroblasts when cultured under classical conditions in vitro are also characterized by striking morphological changes, i.e. they lose the youthful spindle-like appearance and become enlarged and flattened, while their nuclei from elliptical become oversized and highly lobulated. Knowing the strong relation between cell shape and function, we cultured human senescent fibroblasts on photolithographed Si/poly(vinyl alcohol) (PVA) micro-patterned surfaces in order to restore the classical spindle-like geometry and subsequently to investigate whether the changes in senescent cells' morphology are the cause of their functional alterations. Interestingly, under these conditions senescent cells' nuclei do not revert to the classical elliptical phenotype. Furthermore, enforced spindle-shaped senescent cells retained their deteriorated proliferative ability, and maintained the increased gene expression of the cell cycle inhibitors p16 and p21 . In addition, Si/PVA-patterned-grown senescent fibroblasts preserved their senescence-associated phenotype, as evidenced by the overexpression of inflammatory and catabolic genes such as IL6, IL8, ICAM1 and MMP1 and MMP9 respectively, which was further manifested by an intense downregulation of fibroblasts' most abundant extracellular matrix component Col1A, compared to their young counterparts. These data indicate that the restoration of the spindle-like shape in senescent human fibroblasts is not able to directly alter major functional traits and restore the youthful phenotype.
Keywords
- Cell shape
- Fibroblast
- Lithography
- SASP
- Senescence
Maintaining good cognitive function at older age is important, but our knowledge of patterns and predictors of cognitive aging is still limited. We used Bayesian model-based clustering to group 5064 participants of the Long Life Family Study (ages 49-110 years) into clusters characterized by distinct trajectories of cognitive change in the domains of episodic memory, attention, processing speed, and verbal fluency. For each domain, we identified 4 or 5 large clusters with representative patterns of change ranging from rapid decline to exceptionally slow change. We annotated the clusters by their correlation with genetic and molecular biomarkers, non-genetic risk factors, medical history, and other markers of aging to discover correlates of cognitive changes and neuroprotection. The annotation analysis discovered both predictors of multi-domain cognitive change such as gait speed and predictors of domain-specific cognitive change such as IL6 and NTproBNP that correlate only with change of processing speed or APOE genotypes that correlate only with change of processing speed and logical memory. These patterns also suggest that cognitive decline starts at young age and that maintaining good physical function correlates with slower cognitive decline. To better understand the agreement of cognitive changes across multiple domains, we summarized the results of the cluster analysis into a score of cognitive function change. This score showed that extreme patterns of change affecting multiple cognitive domains simultaneously are rare in this study and that specific signatures of biomarkers of inflammation and metabolic disease predict severity of cognitive changes. The substantial heterogeneity of change patterns within and between cognitive domains and the net of correlations between patterns of cognitive aging and other aging traits emphasizes the importance of measuring a wide range of cognitive functions and the need for studying cognitive aging in concert with other aging traits.
Keywords
- Aging
- Biomarker
- Cognition
- Neuropsychology
Ageing is associated with disrupted redox signalling and increased circulating inflammatory cytokines. Skeletal muscle homeostasis depends on the balance between muscle hypertrophy, atrophy and regeneration, however during ageing this balance is disrupted. The molecular pathways underlying the age-related decline in muscle regenerative potential remain elusive. microRNAs are conserved robust gene expression regulators in all tissues including skeletal muscle. Here, we studied satellite cells from adult and old mice to demonstrate that inhibition of miR-21 in satellite cells from old mice improves myogenesis. We determined that increased levels of proinflammatory cytokines, TNFα and IL6, as well as H O , increased miR-21 expression in primary myoblasts, which in turn resulted in their decreased viability and myogenic potential. Inhibition of miR-21 function rescued the decreased size of myotubes following TNFα or IL6 treatment. Moreover, we demonstrated that miR-21 could inhibit myogenesis in vitro via regulating [[IL6R]], PTEN and FOXO3 signalling. In summary, upregulation of miR-21 in satellite cells and muscle during ageing may occur in response to elevated levels of TNFα and IL6, within satellite cells or myofibrillar environment contributing to skeletal muscle ageing and potentially a disease-related decline in potential for muscle regeneration.
Keywords
- IL6
- IL6R
- aging
- cachexia
- miR-21
- microRNA
- muscle
- regeneration
- sarcopenia
The improved effectiveness and safety of the combined antiretroviral therapy (cART) has largely diminished mortality and AIDS-defining morbidity of HIV-patients. Nevertheless, chronic age-related diseases in these individuals are more common and their underlying pathogenic mechanisms of these actions seem to involve accelerated aging and enhanced inflammation. The present study explores markers of these processes in a heterogenous Spanish HIV cohort using peripheral blood samples of HIV-patients and matched uninfected controls. We isolated periheral blood mononuclear cells (PBMCs) and i) compared the expression of a panel of 14 genes related to inflammation and senescence in PBMCs of HIV-patients vs matched uninfected controls, ii) analyzed the expression in HIV-patients in association with a number of demographic, biochemical and immunological parameters and iii) in relation with the current cART they received. PBMCs of HIV-patients displayed significantly increased expression of general inflammatory genes (IL6, IL18 and CXCL10) and this occurs irrespectively of the antiviral therapy they have been receiving. Conversely, levels of senescence-associated genes TP53, SERPINE1andIGFBP3 were slightly but significantly reduced in patients compared to uninfected matched individuals and this effect is related to NNRTI-containing treatments. The expression of the inflammatory markers IL6, IL18, IL1B, TNFA, RELA, CCL2, [[CCL20]] and CXCL10 displayed correlation with certain demographic, morbidity- and HIV infection-related parameters. The levels of TP53 mRNA were positively associated only with plasma LDL. Correlation analysis between the expressions of pairs of genes revealed a different pattern between HIV-patients and controls. The diminished expression of TP53 and SERPINE1 in HIV-patients was also observed at a protein level, and the correlation between the two proteins (p53 and PAI1) in patients and controls showed the opposite trend. In conclusion, HIV-patients show dysregulation of p53 and p53-related mediators, a phenomenon which may be of pathophysiological relevance and could be related to the shorter health- and/or life-span observed in these individuals.
Keywords
- Aging
- Antiretroviral drugs
- HIV
- Inflammation
- NNRTI
- Senescence
- p53
Sirtuin 1 (SIRT1) enzyme plays a pivotal role in the regulation of many physiological functions. In particular, it is implicated in ageing-related diseases, such as cardiac hypertrophy, myocardial infarct, and endothelial dysfunction; moreover, its expression decreases with age. Therefore, an effective strategy to extend the lifespan and improve cardiovascular function is the enhancement of the expression/activity of SIRT1 with exogenous agents. The Citrus flavonoid naringenin (NAR) presents structural similarity with the natural SIRT1 activator resveratrol. In this study, we demonstrate through [i]in vitro[/i] assays that NAR significantly activates SIRT1 enzyme and shows antisenescence effects. The binding mode of NAR into SIRT1 was detailed investigated through [i]in silico[/i] studies. Moreover, chronic administration (for six months) of NAR (100 mg/kg/day) to 6-month-old mice leads to an enhancement of SIRT1 expression and a marked reduction of reactive oxygen species production in myocardial tissue. Furthermore, at the end of the treatment, the plasma levels of two well-known markers of cardiovascular inflammation, TNF-[i]α[/i] and IL6, are significantly reduced in 12-month-old mice treated with NAR, as well as the cardiovascular risk (total cholesterol/HDL ratio) compared to control mice. Finally, the age-associated fibrotic remodeling, which is well detected through a Mallory trichrome staining in the vehicle-treated 12-month-old mice, is significantly reduced by the chronic treatment with NAR. Moreover, an improvement of myocardium functionality is highlighted by the enhancement of citrate synthase activity and stabilization of the mitochondrial membrane potential after NAR treatment. Taken together, these results suggest that a nutraceutical approach with NAR may have positive impacts on many critical hallmarks of myocardial senescence, contributing to improve the cardiac performance in aged subjects.
MeSH Terms
- Aging
- Animals
- Antioxidants
- Cell Line
- Cellular Senescence
- Citrus
- Cytoprotection
- Disease Models, Animal
- Flavanones
- Humans
- Interleukin-6
- Mice
- Myocardium
- Protein Binding
- Rats
- Reactive Oxygen Species
- Sirtuin 1
- Tumor Necrosis Factor-alpha
Despite being one of the major causes of infertility in mares, the mechanisms responsible for equine endometrosis are still unclear and controversial. In the last few years, many investigations focused on local immune response modulation. Since it is generally accepted that endometrial fibrosis increases with age, we hypothesize that older mares could show altered local immune modulation, initiating a pro-inflammatory and tissue remodeling cascade of events that could lead to endometrosis. The aim of this study, indeed, is to evaluate and describe the local gene expression of genes involved in acute inflammatory response and fibrosis (COL1A1, COL3A1, TNFA, MMP9, IL6, TGFB1 and TGFBR1), together with others associated to immune modulation (DEFB4B, IDO1 and FOXP3), in uterine specimens from mares of different age. Twenty-five Standardbred mares were involved in the study with age ranging from 7 to 19 years (mean 10.40 ± 4.42). They were divided by age into two groups: G1 (n = 15, less than 10 years old) and G2 (N = 10, greater than 11 years old). Specimens from the uterus' right horn-body junction were collected and processed for histology evaluation and RT-qPCR assay.Gene expression of DEFB4B, MMP9 and TNFA was higher in younger mares, suggesting a balance in immune modulation and tissue remodeling. Interleukin-6 and COL3A1 gene expressions were greater in older animals, probably indicating inflammatory pathways activation and fibrosis increase. Although no differences in fibrosis and inflammation distribution could be found with histological examination among G1 and G2, our results suggest a possible involvement of DEF4BB in regulating the local immune response in younger mare's uterus (G1); age may contribute to the dis-regulation of DEFB4B transcription and, indirectly, influence the extracellular matrix homeostasis. Transcription of IDO1 and FOXP3 genes, instead, does not seem to be age related, or to be involved in local immune-response and tissue remodeling functions. Further investigations are needed in order to clarify the interactions between the expression of DEFB4B, IL6, TNFA, COL3A1 and MMP9 and other local signals of immune-modulation and tissue remodeling, in mares in a prospective study design.
MeSH Terms
- Aging
- Animals
- Breeding
- Defensins
- Endometrium
- Female
- Fibrosis
- Gene Expression
- Horses
- Inflammation
- Reverse Transcriptase Polymerase Chain Reaction
Keywords
- Defensin-β
- Endometrium
- Gene expression
- Immune-modulation
- Mare
Whether disruption of iron metabolism is implicated in human muscle aging is presently unclear. We explored the relationship among iron metabolism, muscle mitochondrial homeostasis, inflammation, and physical function in older adults and young controls. Eleven young and 23 older men and women were included. Older adults were classified into high-functioning (HF) and low-functioning (LF) groups according to their Short Physical Performance Battery score. Vastus lateralis muscle biopsies were assayed for total iron content, expression of 8-oxoguanine and DNA glycosylase (OGG1), 3-nitrotyrosine (3-NT) levels, and mitochondrial DNA (mtDNA) content and damage. Circulating ferritin and hepcidin levels were also quantified. Muscle iron levels were greater in the old group. Protein expression of transferrin receptor 1, Zrt-Irt-like protein (ZIP) 8, and ZIP14 were lower in old participants. Circulating levels of ferritin, hepcidin, interleukin 6 (IL6), and C-reactive protein were higher in the old group. Old participants showed lower mtDNA content and greater mtDNA damage. OGG1 protein expression declined with age, whereas 3-NT levels were greater in old participants. Finally, a negative correlation was determined between ZIP14 expression and circulating IL6 levels in LF older adults. None of assayed parameters differed between HF and LF participants. Our findings suggest that muscle iron homeostasis is altered in old age, which might contribute to loss of mtDNA stability. Muscle iron metabolism may therefore represent a target for interventions against muscle aging.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- DNA, Mitochondrial
- Female
- Homeostasis
- Humans
- Inflammation
- Iron
- Male
- Mitochondria, Muscle
- Quadriceps Muscle
- Young Adult
Keywords
- ZIP
- ferritin
- hepcidin
- inflammation
- iron overload
- mitochondrial dysfunction
- mtDNA
- muscle aging
- physical performance
- transferrin
Human biliary tree stem/progenitor cells (hBTSCs), reside in peribiliary glands, are mainly stimulated by primary sclerosing cholangitis (PSC) and cholangiocarcinoma. In these pathologies, hBTSCs displayed epithelial-to-mesenchymal transition (EMT), senescence characteristics, and impaired differentiation. Here, we investigated the effects of cholest-4,6-dien-3-one, an oxysterol involved in cholangiopathies, on hBTSCs biology. hBTSCs were isolated from donor organs, cultured in self-renewal control conditions, differentiated in mature cholangiocytes by specifically tailored medium, or exposed for 10 days to concentration of cholest-4,6-dien-3-one (0.14 mM). Viability, proliferation, senescence, [i]EMT[/i] genes expression, telomerase activity, interleukin 6 (IL6) secretion, differentiation capacity, and [i]HDAC6[/i] gene expression were analyzed. Although the effect of cholest-4,6-dien-3-one was not detected on hBTSCs viability, we found a significant increase in cell proliferation, senescence, and IL6 secretion. Interestingly, cholest-4.6-dien-3-one impaired differentiation in mature cholangiocytes and, simultaneously, induced the EMT markers, significantly reduced the telomerase activity, and induced [i]HDAC6[/i] gene expression. Moreover, cholest-4,6-dien-3-one enhanced bone morphogenic protein 4 (Bmp-4) and sonic hedgehog (Shh) pathways in hBTSCs. The same pathways activated by human recombinant proteins induced the expression of EMT markers in hBTSCs. In conclusion, we demonstrated that chronic exposition of cholest-4,6-dien-3-one induced cell proliferation, EMT markers, and senescence in hBTSC, and also impaired the differentiation in mature cholangiocytes.
MeSH Terms
- Biliary Tract
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- Cholestenones
- Epithelial-Mesenchymal Transition
- Histone Deacetylase 6
- Humans
- Interleukin-6
- Signal Transduction
- Stem Cells
- Tissue Donors
Keywords
- BMP pathway
- SHH pathway
- biliary tree stem/progenitor cells (BTSCs)
- epithelial-to-mesenchymal transition (EMT)
- primary sclerosing cholangitis (PSC)
- senescence
- telomerase
Prolonging the ovarian lifespan is attractive and challenging. An optimal clinical strategy must be safe, long-acting, simple, and economical. Allotransplantation of brown adipose tissue (BAT), which is most abundant and robust in infants, has been utilized to treat various mouse models of human disease. Could we use BAT to prolong the ovarian lifespan of aging mice? Could we try BAT xenotransplantation to alleviate the clinical need for allogeneic BAT due to the lack of voluntary infant donors? In the current study, we found that a single rat-to-mouse (RTM) BAT xenotransplantation did not cause systemic immune rejection but did significantly increase the fertility of mice and was effective for more than 5 months (equivalent to 10 years in humans). Next, we did a series of analysis including follicle counting; AMH level; estrous cycle; mTOR activity; GDF9, BMP15, LHR, Sirt1, and Cyp19a level; ROS and annexin V level; IL6 and adiponectin level; biochemical blood indices; body temperature; transcriptome; and DNA methylation studies. From these, we proposed that rat BAT xenotransplantation rescued multiple indices indicative of follicle and oocyte quality; rat BAT also improved the metabolism and general health of the aging mice; and transcriptional and epigenetic (DNA methylation) improvement in F0 mice could benefit F1 mice; and multiple KEGG pathways and GO classified biological processes the differentially expressed genes (DEGs) or differentially methylated regions (DMRs) involved were identical between F0 and F1. This study could be a helpful reference for clinical BAT xenotransplantation from close human relatives to the woman.
MeSH Terms
- Adipose Tissue, Brown
- Animals
- Cellular Senescence
- Female
- Longevity
- Male
- Mice
- Ovarian Follicle
- Ovary
- Rats
- Rats, Sprague-Dawley
- Transplantation, Heterologous
Keywords
- aging
- brown adipose tissue (BAT)
- lifespan
- mice
- ovary
- rat
- xenotransplant
Heavy ion radiation, prevalent in outer space and relevant for radiotherapy, is densely ionizing and poses risk to stem cells that are key to intestinal homeostasis. Currently, the molecular spectrum of heavy ion radiation-induced perturbations in intestinal stem cells (ISCs), that could trigger intestinal pathologies, remains largely unexplored. The Lgr5-EGFP-IRES-creERT mice were exposed to 50 cGy of iron radiation. Mice were euthanized 60 d after exposure and ISCs were sorted using fluorescence activated cell sorting. Reactive oxygen species (ROS) and mitochondrial superoxide were measured using fluorescent probes. Since DNA damage is linked to senescence and senescent cells acquire senescence-associated secretory phenotype (SASP), we stained ISCs for both senescence markers p16, p21, and p19 as well as SASP markers IL6, IL8, and VEGF. Due to potential positive effects of SASP on proliferation, we also stained for PCNA. Data show increased ROS and ongoing DNA damage, by staining for γH2AX, and 53BP1, along with accumulation of senescence markers. Results also showed increased SASP markers in senescent cells. Collectively, our data suggest that heavy-ion-induced chronic stress and ongoing DNA damage is promoting SASP in a fraction of the ISCs, which has implications for gastrointestinal function, inflammation, and carcinogenesis in astronauts and patients.
MeSH Terms
- Animals
- Cellular Senescence
- DNA Damage
- Epithelial Cells
- Flow Cytometry
- Green Fluorescent Proteins
- Heavy Ions
- Humans
- Intestinal Mucosa
- Iron
- Male
- Mice
- Reactive Oxygen Species
- Receptors, G-Protein-Coupled
- Stem Cells
Keywords
- SASP
- heavy ion radiation
- intestinal stem cell
- premature aging
- radiotherapy
- senescence
- space radiation
Sexual hormone deficiency has been associated with metabolic changes, oxidative stress and subclinical inflammation in postmenopausal women. Hormone replacement therapies are effective in many instances, even though some patients either do not respond or are not eligible. The aim of this study was to evaluate the impact of short- (15 days) versus long-term (60 days) sexual hormone depletion and whether antioxidant supplementation with N-acetylcysteine (NAC) and alpha-lipoic acid (LA) improves oxidative stress, metabolic, and inflammatory parameters in ovariectomized (OVX) rats. Short-term OVX rapidly depleted circulating estrogen, causing uterine atrophy and body weight gain without affecting oxidative damage, inflammatory and lipid metabolism markers. In contrast, long-term OVX augmented oxidative damage in serum and peripheral tissues as well as increased serum total cholesterol, TNF-α and IL6 levels. Triglycerides, glucose and HDL cholesterol were not altered. Long-term OVX-induced oxidative stress was associated with depletion of GSH and total non-enzymatic antioxidants as well as decreased activity of Glutathione Peroxidase (GPx) and Glutathione Reductase (GR), but not Superoxide Dismutase (SOD) and Catalase (CAT). NAC and LA supplementation prevented GSH and total non-enzymatic antioxidants depletion as well as restored GPx and GR activities, TNF-α, IL6 and cholesterol in OVX rats. NAC and LA effects appear to be independent on NRF2 activation and estrogen-like activity, since NAC/LA did not promote NRF2 activation and were not able to emulate estrogen effects in OVX rats and estrogen-receptor-positive cells. The herein presented data suggest that NAC and LA may improve some deleterious effects of sexual hormone depletion via estrogen-independent mechanisms.
MeSH Terms
- Acetylcysteine
- Animals
- Antioxidants
- Cytokines
- Dietary Supplements
- Estrogens
- Female
- Glutathione
- Inflammation
- Lipids
- NF-E2-Related Factor 2
- Ovariectomy
- Oxidative Stress
- Rats, Wistar
- Thioctic Acid
Keywords
- Aging
- Antioxidants
- Cytokines
- Estrogen
- Menopause
The present study aimed to evaluate and clarify how the age at which the intake of a high-fat and high-fructose diet begins can affect animals' livers. Thirty-eight male wistar rats aged 6 and 12 weeks were fed a high-fat and high-fructose diet for 13 weeks. Inflammatory cytokines, hepatic glycogen, serum and hepatic triacylglycerol and pAkt protein content in the liver were assessed. Percentage of weight gained, and visceral adiposity were also evaluated. Young animal presented increased hepatic triacylglycerol and decreased glycogen, while adult animals had no significant alterations regarding its contents. IL6 and IL10 to IL6 ratio were also altered in young animals exposed to HFHF, while adult animals fed with HFHF had only increases in TNF-α. Both groups which received HFHF had increased serum triacylglycerol and visceral adiposity. However, only young animals gained more relative weight and had greater final body weight, gains which were related to alterations found in hepatic triacylglycerol and glycogen. Age of which consumption begins interferes in how the liver deals with an excess of nutrient and subsequent proinflammatory stimulation, leading to different phenotypes.
MeSH Terms
- Aging
- Animals
- Cytokines
- Diet, High-Fat
- Dietary Sugars
- Fructose
- Glycogen
- Liver
- Male
- Rats, Wistar
- Triglycerides
Keywords
- Age-dependent
- Hepatic glycogen
- Hepatic triacylglycerol
- IL6
- Inflammation
- TNF-α
The effects of pollution on health have received increasing attention in recent years. Extrinsic skin aging occurs via multiple processes, and pollution is now recognized as a major component, causing increased pigmentation and wrinkles via oxidative mechanisms. We tested the antipollution efficacy of a cosmetic facial cream (FC) by assessing its effects on carbon particle adhesion to skin and on oxidative and inflammatory pathways in the skin. In an in vivo study, FC was applied once to the forearms of healthy subjects. Carbon E153 powder was applied, and the skin was washed under standardized conditions. Images were taken using a dermoscope to determine the area of particle adherence. Each participant served as their own control, with the contralateral forearm being untreated with the FC but otherwise following the same protocol. In a 5-day ex vivo study, skin explants were treated with the FC daily and exposed to vaporized pollutants on day 2 and day 4 via a closed system. Explants were sampled at baseline and day 5 and culture media on day 5. The parameters evaluated were cellular viability on microscopy, Nrf2 immunostaining, malondialdehyde (MDA) levels in culture, melanin levels, and gene expression profile ([i]TYR, IL6,[/i] and [i]CYP1A1[/i]). In the in vivo adhesion study, after standardized washing, carbon particle deposition on skin treated with the FC was significantly lower than that on untreated skin. In the ex vivo study, samples treated with the FC had reduced Nrf2 staining and MDA levels vs polluted controls. Melanin did not change significantly. The FC modulated pollution-induced increases in [i]CYP1A1[/i], [i]IL-6[/i], and [i]TYR[/i]. This FC reduces particle adhesion to skin after a single application and protects against pollution-induced oxidative and inflammatory pathways in the skin.
Keywords
- Nrf2
- TYR
- barrier
- exopolysaccharide
- genomic
- pollution
- shield
- skin aging
The aim of this study was to examine whether cytokines and chemokines expressed in the uterine mucosa play a role in the process of eggshell formation in the chicken uterus. Changes in the expression levels of pro- and anti-inflammatory cytokines and chemokines in the uterine mucosa during an ovulatory cycle (experiment 1) and effects of aging on their expression (experiment 2) were examined. In experiment 1, the expression of the pro-inflammatory cytokines IL1β, IL6, TNFSF15, and IFNγ, and a chemokine CX3CL1 was found to increase during eggshell biomineralization (16 h following oviposition), while anti-inflammatory TGFβ2 expression was found to increase at 4 h following oviposition. In experiment 2, a higher expression of the anti-inflammatory cytokines TGFβ2 and TGFβ3, and chemokines CXCLi2 and CX3CL1, was observed in aged hens than in young hens. A significantly higher number of macrophages and CD8 T cells were observed in the uterine tissue of aged hens than in young hens. Furthermore, the expression of adhesion molecules associated with leukocytic infiltration was found to be higher in aged hens than in young hens. We conclude that the eggshell formation process may be affected by the pro- and anti-inflammatory cytokines and chemokines. The balanced expressions of these molecules might be disrupted in aged hens.
MeSH Terms
- Aging
- Animals
- Chemokines
- Chickens
- Cytokines
- Female
- Inflammation
- Mucous Membrane
- Oviducts
- Oviposition
- Ovulation
- Uterus
Keywords
- Aging
- Chemokines
- Cytokines
- Eggshell
- Laying hens
- Mucosal homeostasis
An age-related dysregulation of immune response, known as immunosenescence, contributes to increased susceptibility to infections, frailty and high risk of mortality in the elderly. Torquetenovirus (TTV), a circular, single-stranded DNA virus, is highly prevalent in the general population and it may persist in the organism, also in association with other viruses such as cytomegalovirus (CMV), causing chronic viremia. The relationship that TTV establishes with the immune system of infected hosts is not clear. It is known that TTV encodes microRNAs (miRNAs) that might contribute to immune evasion and that the highest viral loads are found in peripheral blood cells. Moreover, it is suspected that TTV infection lead to increased production of inflammatory mediators, thus playing a role in immunosenescence. We investigated the association of TTV load and miRNAs expression with inflammatory and immune markers and the influence of TTV load on mortality within a cohort of 379 elderly subjects who were followed up for 3 years. TTV DNA load in polymorphonuclear leukocytes was slightly positively correlated with age and negatively associated with serum albumin levels and NK cell activity. A marginal positive correlation between TTV DNA load, monocytes and IL-8 plasma levels was found in females and males respectively. TTV DNA copies ≥4.0 log represented a strong predictor of mortality (Hazard ratio = 4.78, 95% CI: 1.70-13.44, after adjusting for age, sex and the main predictors of mortality rate) and this association remained significant even after the CMV IgG antibody titer was included in the model (HR = 9.83; 95% CI: 2.48-38.97; N = 343 subjects). Moreover, multiple linear regression model showed that TTV miRNA-t3b of genogroup 3 was inversely associated with triglycerides, monocytes and C-reactive protein, and directly associated with IL6. Overall these findings suggest a role of TTV in immunesenescence and in the prediction of all-cause mortality risk in Italian elderly subjects. Further studies are needed to fully understand the pathogenic mechanisms of TTV infection during aging.
MeSH Terms
- Aged
- Aged, 80 and over
- Cause of Death
- DNA, Viral
- Female
- Humans
- Immunosenescence
- Italy
- Kaplan-Meier Estimate
- Killer Cells, Natural
- Linear Models
- Male
- MicroRNAs
- Middle Aged
- Mortality
- Torque teno virus
- Viral Load
Keywords
- Aging
- Immunesenescence
- Mortality
- NK cell activity
- TTV
Many factors contribute to exceptional longevity, with genetics playing a significant role. However, to date, genetic studies examining exceptional longevity have been inconclusive. This comprehensive review seeks to determine the genetic variants associated with exceptional longevity by undertaking meta-analyses. Meta-analyses of genetic polymorphisms previously associated with exceptional longevity (85 ) were undertaken. For each variant, meta-analyses were performed if there were data from at least three independent studies available, including two unpublished additional cohorts. Five polymorphisms, ACE rs4340, APOE ε2/3/4, FOXO3A rs2802292, KLOTHO KL-VS and IL6 rs1800795 were significantly associated with exceptional longevity, with the pooled effect sizes (odds ratios) ranging from 0.42 (APOE ε4) to 1.45 (FOXO3A males). In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.
MeSH Terms
- Age Factors
- Aged, 80 and over
- Female
- Genotype
- Healthy Aging
- Heredity
- Humans
- Longevity
- Male
- Pedigree
- Phenotype
- Polymorphism, Genetic
Keywords
- ACE
- APOE
- Centenarians
- FOXO3A
- Longevity
- Meta-analysis
Advanced age has been associated with alterations to the microbiome within the intestinal tract as well as intestinal permeability (i.e., "leaky gut"). Prior studies suggest that intestinal permeability may contribute to increases in systemic inflammation-an aging hallmark-possibly via microorganisms entering the circulation. Yet, no studies exist describing the state of the circulating microbiome among older persons. To compare microbiota profiles in serum between healthy young (20-35 years, n = 24) and older adults (60-75 years, n = 24) as well as associations between differential microbial populations and prominent indices of age-related inflammation. Unweighted Unifrac analysis, a measure of β-diversity, revealed that microbial communities clustered differently between young and older adults. Several measures of α-diversity, including chao1 (p = 0.001), observed species (p = 0.001), and phylogenetic diversity (p = 0.002) differed between young and older adults. After correction for false discovery rate (FDR), age groups differed (all p values ≤ 0.016) in the relative abundance of the phyla Bacteroidetes, SR1, Spirochaetes, Bacteria_Other, TM7, and Tenericutes. Significant positive correlations (p values ≤ 0.017 after FDR correction) were observed between IGF1 and Bacteroidetes (ρ = 0.380), Spirochaetes (ρ = 0.528), SR1 (ρ = 0.410), and TM7 (ρ = 0.399). Significant inverse correlations were observed for IL6 with Bacteroidetes (ρ = - 0.398) and TM7 (ρ = - 0.423), as well as for TNFα with Bacteroidetes (ρ = - 0.344). Similar findings were observed at the class taxon. These data are the first to demonstrate that the richness and composition of the serum microbiome differ between young and older adults and that these factors are linked to indices of age-related inflammation.
MeSH Terms
- Adult
- Age Factors
- Aged
- DNA, Bacterial
- Female
- Humans
- Inflammation
- Insulin-Like Growth Factor I
- Interleukin-6
- Male
- Microbiota
- Middle Aged
- Tumor Necrosis Factor-alpha
- Young Adult
Keywords
- Aging
- Inflammation
- Leaky gut
- Microbiome
- Microbiota
Interleukin 6 (IL6) and p53 are linked by mutual regulatory mechanisms and are both upregulated in aging. The aim of this study was to evaluate the effects of aging and IL6 on expression of p53 in the mouse heart. Male C57BL6/J wild-type and IL6 knockout mice at the age of 4-5 months (young adult) and 24-30 months (old) were used. Myocardial expression of proteins such as p53, p21, Mdm2, and phospho-Akt/Akt was estimated using Western blotting and expression of p53 and p21 mRNA using real-time polymerase chain reaction. Expression of p53 protein was lower in IL6 knockout hearts than in wild-type hearts. Aging caused significant upregulation of p53 protein level; however, it was significantly higher in old wild-type hearts than in old IL6 knockout hearts (p < .05). Similar p53 mRNA levels in all groups implied IL6 influence on age-related proteasomal degradation of p53. Localization of p53 mainly in the extranuclear compartment and lack of p21 upregulation in aged hearts may suggest quenched transcriptional activity of p53 despite increased abundance of p53. We conclude that lack of IL6 attenuates expression of p53 protein in the hearts of young mice and diminishes its accumulation with aging by post-transcriptional mechanisms; however, this is not related to altered phenotype of aging heart.
MeSH Terms
- Aging
- Animals
- Blotting, Western
- Echocardiography
- Enzyme-Linked Immunosorbent Assay
- Gene Expression Regulation
- Heart Ventricles
- Interleukin-6
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Microscopy, Fluorescence
- Myocardium
- RNA, Messenger
- Random Allocation
- Real-Time Polymerase Chain Reaction
- Tumor Suppressor Protein p53
- Ventricular Function, Left
Previously, we have shown that the transcription factor nuclear factor interleukin (NF-IL)6 can be used as an activation marker for inflammatory lipopolysaccharide (LPS)-induced and psychological novel environment stress (NES) in the rat brain. Here, we aimed to investigate age dependent changes of hypothalamic and pituitary responses to NES (cage switch) or LPS (100 μg/kg) in 2 and 24 months old rats. Animals were sacrificed at specific time points, blood and brains withdrawn and analyzed using immunohistochemistry, RT-PCR and bioassays. In the old rats, telemetric recording revealed that NES-induced hyperthermia was enhanced and prolonged compared to the young group. Plasma IL-6 levels remained unchanged and hypothalamic IL-6 mRNA expression was increased in the old rats. Interestingly, this response was accompanied by a significant upregulation of corticotropin-releasing hormone mRNA expression only in young rats after NES and overall higher plasma corticosterone levels in all aged animals. Immunohistochemical analysis revealed a significant upregulation of NF-IL6-positive cells in the pituitary after NES or LPS-injection. In another important brain structure implicated in immune-to-brain communication, namely, in the median eminence (ME), NF-IL6-immunoreactivity was increased in aged animals, while the young group showed just minor activation after LPS-stimulation. Interestingly, we found a higher amount of NF-IL6-CD68-positive cells in the posterior pituitary of old rats compared to the young counterparts. Moreover, aging affected the regulation of cytokine interaction in the anterior pituitary lobe. LPS-treatment significantly enhanced the secretion of the cytokines IL-6 and TNFα into supernatants of primary cell cultures of the anterior pituitary. Furthermore, in the young rats, incubation with IL-6 and IL-10 antibodies before LPS-stimulation led to a robust decrease of IL-6 production and an increase of TNFα production by the pituitary cells. In the old rats, this specific cytokine interaction could not be detected. Overall, the present results revealed strong differences in the activation patterns and pathways between old and young rats after both stressors. The prolonged hyperthermic and inflammatory response seen in aged animals seems to be linked to dysregulated pituitary cytokine interactions and brain cell activation (NF-IL6) in the hypothalamus-pituitary-adrenal axis.
Keywords
- NF-IL6
- aging
- cage switch
- fever
- hyperthermia
- immune-to-brain communication
- lipopolysaccharide
- novel environment stress
Aging of the arterial endothelial cells results in the appearance of their inflammatory phenotype, which may predispose patients to the acceleration of arteriosclerosis. We studied the effect of serum from patients with peripheral artery disease (PAD) on the senescence of human aortic endothelial cells (HAEC) and how that process is modulated by sulodexide. HAEC replicative aging in vitro was studied in the presence of 10% PAD-serum (PAD Group) or10%PAD serum and Sulodexide 0.5 LRU/mL (PAD-SUL group). In control group cells were cultured in medium supplemented with 10% fetal bovine serum. All studied parameters were evaluated at the beginning and at the end of the study, in all experimental groups. Population doubling time (PDT) was studied from the cells growth rate after repeated passages, and senescence-associated beta- galactosidase activity (SA-β gal activity) was measured with the fluorescence flow cytometry. Expression of IL6, vWF, p21 and p53 genes was measured with the real-time polymerase chain reaction (Real-Time PCR). Concentrations of IL6 and vWF were measured with the standard ELISA kits. PAD serum accelerated the senescence of HAEC as reflected by increased, compared to control, expression of the IL6 gene ( 43%, p<0.05) vWF gene ( 443%, p<0.01), p21 gene ( 124%, p<0.01) and p53 gene ( 85%, p<0.01). Secretion of IL6 and vWF was higher in that group: 101%, p<0.01 and 78%, p<0.01, respectively, as compared to control. Also, SA-β gal activity was higher in the PAD group ( 33%, p<0.05) than in the control group. In the PAD group PDT was longer ( 108%, p<0.01) as compared to control. Simultaneous use of Sulodexide with PAD serum significantly reduced all the above described senescent changes in HAEC. PAD serum accelerates the aging of HAEC which may result in the faster progression of arteriosclerosis. Sulodexide reduces PAD induced senescence of HAEC, which results in lower inflammatory and thrombogenic activity of these cells.
MeSH Terms
- Anticoagulants
- Cell Line
- Cell Proliferation
- Cellular Senescence
- Endothelial Cells
- Glycosaminoglycans
- Humans
- Peripheral Arterial Disease
Keywords
- Atherosclerosis
- Human arterial endothelial cells
- Senescence
- Sulodexide
To evaluate the effects of dexamethasone on the aging of mesenchymal stem cells from human gingiva using next-generation sequencing. Four mRNAs were upregulated and 12 were downregulated when the results of dexamethasone at 24 h were compared with the control at 24 h. Expressions of SIRT1 and IL6 were decreased in dexamethasone at 24 h but expression of EDN1 was increased. Application of dexamethasone reduced the expression of SIRT1 and IL6 but enhanced the expression of EDN1 of stem cells.
MeSH Terms
- Cells, Cultured
- Cellular Senescence
- Dexamethasone
- Endothelin-1
- Gene Expression Profiling
- Gene Expression Regulation
- Gingiva
- Humans
- Interleukin-6
- Mesenchymal Stem Cells
- RNA, Messenger
- Signal Transduction
- Sirtuin 1
Keywords
- Aging
- Dexamethasone
- Gingiva
- Messenger RNA
- Stem cells
Cellular senescence is a damage response aimed to orchestrate tissue repair. We have recently reported that cellular senescence, through the paracrine release of interleukin-6 (IL6) and other soluble factors, strongly favors cellular reprogramming by Oct4, Sox2, Klf4, and c-Myc (OSKM) in nonsenescent cells. Indeed, activation of OSKM in mouse tissues triggers senescence in some cells and reprogramming in other cells, both processes occurring concomitantly and in close proximity. In this system, Ink4a/Arf-null tissues cannot undergo senescence, fail to produce IL6, and cannot reprogram efficiently; whereas p53-null tissues undergo extensive damage and senescence, produce high levels of IL6, and reprogram efficiently. Here, we have further explored the genetic determinants of in vivo reprogramming. We report that Ink4a, but not Arf, is necessary for OSKM-induced senescence and, thereby, for the paracrine stimulation of reprogramming. However, in the absence of p53, IL6 production and reprogramming become independent of Ink4a, as revealed by the analysis of Ink4a/Arf/p53 deficient mice. In the case of the cell cycle inhibitor p21, its protein levels are highly elevated upon OSKM activation in a p53-independent manner, and we show that p21-null tissues present increased levels of senescence, IL6, and reprogramming. We also report that Il6-mutant tissues are impaired in undergoing reprogramming, thus reinforcing the critical role of IL6 in reprogramming. Finally, young female mice present lower efficiency of in vivo reprogramming compared to male mice, and this gender difference disappears with aging, both observations being consistent with the known anti-inflammatory effect of estrogens. The current findings regarding the interplay between senescence and reprogramming may conceivably apply to other contexts of tissue damage.
MeSH Terms
- Animals
- Cellular Reprogramming
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Female
- Humans
- Interleukin-6
- Mice
Keywords
- SASP
- interleukin-6
- p16Ink4a
- plasticity
- pluripotency
- reprogramming
- senescence
Inflammation, particularly elevated IL-6 serum levels, has been associated with increased mortality risk, mostly in Caucasians. The influence of genetic ethno-racial background on this association is unknown. We examined associations between baseline serum levels of Interleukin-6 (IL-6) and other cytokines (IL1-2, TNF, IL-10, and IL1β) and chemokines (CCL2, CCL5, CXCL8, CXCL9 and CXCL10) with 15-year mortality in 1,191 admixed Brazilians aged 60years and over. Elevated IL6 level (but not other biomarkers) was associated with increased risk of deaths with fully adjusted hazard ratios of 1.51 (95% CI=1.15, 1.97), 1.54 (95% CI=1.20, 1.96) and 1.79 (95% CI=1.40, 2.29) for the 2nd, 3rd and the highest quartiles, respectively. Genomic African and Native American proportions did not modify the association (p>0.05). The discriminatory ability to predict death of a model based on IL-6 alone was similar as that of a comprehensive morbidity score (C statistics=0.59 and 0.60, respectively). The abilities of IL-6 and the morbidity score models to predict death remained stable for very long term after the baseline measurement. Our results indicate that genome-based African and Native American ancestries have no impact on the prognostic value of IL-6 for mortality.
MeSH Terms
- African Continental Ancestry Group
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- Brazil
- Cause of Death
- Chemokine CCL5
- Chemokine CXCL9
- Chemokines
- Female
- Follow-Up Studies
- Humans
- Indians, North American
- Interleukin-6
- Interleukin-8
- Kaplan-Meier Estimate
- Male
- Middle Aged
- Predictive Value of Tests
- Prognosis
- Proportional Hazards Models
- Risk Assessment
- Risk Factors
- Time Factors
Keywords
- Admixed population
- Chemokines
- Cytokines
- Genomic ancestry
- Inflammatory markers
- Interleukin-6
- Mortality
Despite many animal studies and clinical trials, mortality in sepsis remains high. This may be due to the fact that most experimental studies of sepsis employ young animals, whereas the majority of septic patients are elderly (60 - 70 years). The objective of the present study was to examine the sepsis-induced inflammatory and pro-coagulant responses in aged mice. Since running exercise protects against a variety of diseases, we also examined the effect of voluntary running on septic responses in aged mice. Male C57BL/6 mice were housed in our institute from 2-3 to 22 months (an age mimicking that of the elderly). Mice were prevented from becoming obese by food restriction (given 70-90% of ad libitum consumption amount). Between 20 and 22 months, a subgroup of mice ran voluntarily on wheels, alternating 1-3 days of running with 1-2 days of rest. At 22 months, mice were intraperitoneally injected with sterile saline (control) or 3.75 g/kg fecal slurry (septic). At 7 h post injection, we examined (1) neutrophil influx in the lung and liver by measuring myeloperoxidase and/or neutrophil elastase in the tissue homogenates by spectrophotometry, (2) interleukin 6 (IL6) and KC in the lung lavage by ELISA, (3) pulmonary surfactant function by measuring percentage of large aggregates, (4) capillary plugging (pro-coagulant response) in skeletal muscle by intravital microscopy, (5) endothelial nitric oxide synthase (eNOS) protein in skeletal muscle (eNOS-derived NO is putative inhibitor of capillary plugging) by immunoblotting, and (6) systemic blood platelet counts by hemocytometry. Sepsis caused high levels of pulmonary myeloperoxidase, elastase, IL6, KC, liver myeloperoxidase, and capillary plugging. Sepsis also caused low levels of surfactant function and platelet counts. Running exercise increased eNOS protein and attenuated the septic responses. Voluntary running protects against exacerbated sepsis-induced inflammatory and pro-coagulant responses in aged mice. Protection against pro-coagulant responses may involve eNOS upregulation. The present discovery in aged mice calls for clinical investigation into potential beneficial effects of exercise on septic outcomes in the elderly.
MeSH Terms
- Aging
- Analysis of Variance
- Animals
- Enzyme-Linked Immunosorbent Assay
- Interleukin-6
- Leukocyte Elastase
- Male
- Mice
- Mice, Inbred C57BL
- Peroxidase
- Running
- Sepsis
Keywords
- Aging
- Capillary plugging
- Pulmonary inflammation
- Voluntary running
- sepsis
Cellular senescence has been implicated in normal aging, tissue homeostasis, and tumor suppression. Although p53 has been shown to be a central mediator of cellular senescence, the signaling pathway by which it induces senescence remains incompletely understood. In this study, we have shown that both Akt and p21 are required to induce cellular senescence in response to p53 expression. In a p53-induced senescence model, we found that Akt activation was essential for inducing a cellular senescence phenotype. Surprisingly, Akt inhibition did not abolish p53-induced cell cycle arrest, but it suppressed the increase in intracellular reactive oxygen species (ROS) levels. The results of the cell cycle and morphological analysis suggest that p53 induced quiescence, not senescence, following Akt inhibition. Conversely, the inhibition of p21 induction abolished cell cycle arrest but did not affect the p53-induced increase in ROS levels. Additionally, p21 and Akt separately controlled cell cycle arrest and ROS levels, respectively, during H-Ras-induced senescence in human normal fibroblasts. The mechanistic analysis revealed that Akt increased ROS levels through NOX4 induction, and increased Akt-dependent NF-κB binding to the NOX4 promoter is responsible for NOX4 induction upon p53 expression. We further showed that Akt activation upon p53 expression is mediated by mammalian target of rapamycin complex 2. In addition, p53-mediated IL6 and IL8 induction was abrogated by Akt inhibition, suggesting that Akt activation is also required for the senescence-associated secretory phenotype. Collectively, these results suggest that p53 simultaneously controls multiple pathways to induce cellular senescence through p21 and Akt.
MeSH Terms
- Cell Cycle Checkpoints
- Cell Line, Tumor
- Cellular Senescence
- Chromones
- Cyclin-Dependent Kinase Inhibitor p21
- Epithelial Cells
- Fibroblasts
- Gene Expression Regulation
- Humans
- Interleukin-6
- Interleukin-8
- Lymphocytes
- Mechanistic Target of Rapamycin Complex 2
- Morpholines
- NADPH Oxidase 4
- NF-kappa B
- Promoter Regions, Genetic
- Protein Binding
- Proto-Oncogene Proteins c-akt
- Proto-Oncogene Proteins p21(ras)
- RNA, Small Interfering
- Reactive Oxygen Species
- Signal Transduction
- Tumor Suppressor Protein p53
Keywords
- Akt
- NOX4
- p53
- reactive oxygen species
- senescence
Deoxyribonucleic acid (DNA) methylation is an epigenetic modification involved in gene expression regulation, usually via gene silencing, which contributes to the risks of many multifactorial diseases. The aim of the present study was to analyze the influence of resting oxygen consumption on global and gene DNA methylation as well as protein secretion of inflammatory markers in blood cells from obese subjects with sleep apnea-hypopnea syndrome (SAHS). A total of 44 obese participants with SAHS were categorized in 2 groups according to their resting oxygen consumption. DNA methylation levels were evaluated using a methylation-sensitive high resolution melting approach. The analyzed interleukin 6 (IL6) gene cytosine phosphate guanine (CpG) islands showed a hypomethylation, while serum IL-6 was higher in the low compared to the high oxygen consumption group (p < 0.05). Moreover, an age-related loss of DNA methylation of tumor necrosis factor (B = -0.82, 95% CI -1.33 to -0.30) and long interspersed nucleotide element 1 (B = -0.46; 95% CI -0.87 to -0.04) gene CpGs were found. Finally, studied CpG methylation levels of serpin peptidase inhibitor, clade E member 1 (r = 0.43; p = 0.01), and IL6 (r = 0.41; p = 0.02) were positively associated with fat-free mass. These findings suggest a potential role of oxygen in the regulation of inflammatory genes. Oxygen consumption measurement at rest could be proposed as a clinical biomarker of metabolic health.
MeSH Terms
- Adiponectin
- Adult
- Biomarkers
- Body Mass Index
- C-Reactive Protein
- CpG Islands
- DNA Methylation
- Epigenesis, Genetic
- Gene Expression Regulation
- Hemodynamics
- Humans
- Interleukin-6
- Leptin
- Long Interspersed Nucleotide Elements
- Male
- Middle Aged
- Obesity
- Oxygen Consumption
- Plasminogen Activator Inhibitor 1
- Promoter Regions, Genetic
- Serpins
- Sleep Apnea Syndromes
- Tumor Necrosis Factor-alpha
Keywords
- Aging
- High resolution melting assay
- Inflammation
- Metabolic syndrome
- Obesity
There is compelling evidence associating senescent cells with the malignant progression of tumours. Of all senescence-related mechanisms, the so-called senescence-associated secretory phenotype (SASP) has attracted much attention. Since the pro-inflammatory cytokines IL-6 and IL-8 are consistently present in the SASP, and secreted by highly aggressive breast cancer cell lines, we aimed at elucidating their role on the less aggressive breast cancer cell line MCF-7, which does not secret these cytokines. The MCF-7 cell line was treated with either senescence-conditioned medium (SCM), IL-6 or IL-8 and then evaluated for phenotypic (CD44 and CD24 by FACS) and functional changes associated with an EMT program (migration/invasion) and for the acquisition of stem cell properties: mammosphere-forming capacity, expression of reprogramming factors (by qRT-PCR) and multilineage differentiation potential. We also evaluated the role of IL6 and IL8 in the cytokine-secreting, highly tumorigenic cell line MDA-MB-231. Our results show that treatment of MCF-7 cells with IL6 and IL8, alone or together, induced the appearance of cells with fibroblastoid morphology, increased CD44 expression and migration, self-renewal and multilineage differentiation capacity, all characteristics compatible with an EMT program and stemness. These changes closely resembled those induced by a SCM. Interestingly, SCM treatments further increased IL6 and IL8 secretion by MCF-7 cells, thus suggesting the participation of an autocrine loop. Indeed, neutralizing antibodies against IL6 and IL8 reversed the effects of SCM on MCF-7, pinpointing these cytokines as major mediators of EMT and stemness-related effects associated with the senescent microenvironment. Additionally, prolonged exposure of MCF cells to IL6 or IL8 induced the appearance of senescent cells, suggesting a mechanism by which senescence and inflammation are reinforced favouring the acquisition of EMT and stem-like features at the population level, thus increasing tumour aggressiveness. Strikingly, our results also show that both IL6 and IL8 are important to maintain aggressive traits in MDA-MB-231 cells, a highly tumorigenic cell line, which appears to be devoid of stemness-related features. This study demonstrates that, similar to what is observed with a senescent microenvironment, purified IL6 and IL8 induce a self- and cross-reinforced senescence/inflammatory milieu responsible for the emergence of epithelial plasticity and stemness features, thus conferring more aggressive phenotypes to a luminal breast cancer cell line. On the other hand, the basal-like MDA-MB-231 cells, whose aggressiveness-related features depend on IL6 and IL8 secretion, almost completely lack mammosphere formation and differentiation capacities, suggesting that tumour aggressiveness is not always related to stemness.
MeSH Terms
- Breast Neoplasms
- Carcinogenesis
- Cellular Senescence
- Culture Media, Conditioned
- Humans
- Inflammation
- Interleukin-6
- Interleukin-8
- MCF-7 Cells
- Phenotype
Keywords
- Breast cancer
- IL6
- IL8
- Inflammation
- Senescence
- Stemness
Muscle mass in humans is inversely associated with circulating levels of inflammatory cytokines, but the interaction between ageing and training on muscle composition and the intra-muscular signalling behind inflammation and contractile protein synthesis and degradation is unknown. We studied 15 healthy life-long endurance runners, 12 age-matched untrained controls, 10 young trained and 12 young untrained individuals. Thigh muscle composition was investigated by magnetic resonance imaging (MRI), where non-contractile intramuscular tissue (NCIT) area (fat and connective tissue) was found to be greater in older but lower in trained individuals. Subcutaneous adipose tissue was also lower in trained individuals but was not affected by age. In vastus lateralis biopsies, no influence of age or training was found on levels of endomysial collagen, determined by Sirius Red and Collagen III staining, whereas perimysial organisation tended to be more complex in older individuals. No clear difference with training was seen on intramuscular inflammatory signalling, whereas lower protein levels of NFkB subunits p105, p50 and p65 were observed with ageing. Gene expression of IL6 and TNFα was not different between groups, while IL1-receptor and TNFα-receptor1 levels were lower with age. Myostatin mRNA was lower in older and trained groups, while expression of MuRF1 was lower in trained individuals and FoxO3 expression was greater in aged groups. The association of increased muscle NCIT with age-associated muscle loss in humans is not accompanied by any major alterations in intramuscular signalling for inflammation, but rather by direct regulatory factors for protein synthesis and proteolysis in skeletal muscle.
MeSH Terms
- Adult
- Aged
- Aging
- Biopsy
- Gene Expression Regulation
- Glycolysis
- Humans
- Inflammation Mediators
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Muscle Contraction
- Muscle Fibers, Skeletal
- Muscle Proteins
- Muscle, Skeletal
- Myositis
- Physical Endurance
- Running
- Sedentary Behavior
- Signal Transduction
- Subcutaneous Fat
- Young Adult
Keywords
- Ectopic adipose tissue
- Inflammation
- Intramuscular connective tissue
- Master athletes
- Perimysium
- Sarcopenia
Diverse stress signals including irradiation may trigger cellular senescence. We asked whether irradiation induced senescence in mouse hippocampus, and whether p53 or p21 played a role in this response. Following whole-brain irradiation, polymerase chain reaction (PCR) arrays for senescence-associated genes showed increased expression of CDKN1A (p21) and [[CDKN2A]] (p19ARF) in mouse hippocampus at 9 weeks. Upregulation of p21 and p19ARF was confirmed using real-time PCR, which also demonstrated increased [[CDKN2A]]/p16INKa expression after irradiation. No altered regulation of another 17 senescence-associated genes was observed after irradiation. Immunohistochemistry revealed increased nuclear expression of p16INK4A, p19ARF, p53, p21, phosphorylated p38 (pp38), 4-hydroxy-2-nonenal, and interleukin-6 (IL6) in granule cells of dentate gyrus after irradiation. Increased p16 nuclear immunoreactivity was further observed in type -1 cells, the putative neural stem cells. γ-phosphorylated-histone-2A nuclear foci were also seen in dentate gyrus 9 weeks postirradiation. In nonirradiated mice knockout of the TRP53 or p21 gene, there was increased p16INK4A, p19ARF, and IL6, but not pp38 in dentate gyrus. We conclude that irradiation induces transcript and protein expression profile alterations in mouse dentate gyrus consistent with the senescence phenotype. Absence of p53 or p21 results in increase in baseline expression of senescence markers with no further increase in expression after irradiation.
MeSH Terms
- Animals
- Biomarkers
- Cell Nucleus
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Cyclin-Dependent Kinase Inhibitor p21
- Dentate Gyrus
- Hippocampus
- Interleukin-6
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Neural Stem Cells
- Up-Regulation
Keywords
- Cellular senescence
- Hippocampus
- Irradiation
- Neural stem cells
- PCR array
- p21
- p53
Cellular senescence is related to organismal aging and is observed after DNA damaging cancer therapies, that induce tumor-suppressive modifications, but it is characterized by a strong increase in secreted factors, termed the "senescence-associated secretory phenotype" (SASP). Particularly, SASP from stroma senescent fibroblasts creates a cancer-favoring microenvironment, providing targets for anti-cancer interventions. In the present article, chronic treatment (5 weeks) with 5 µM resveratrol has been used to modulate senescence-related protumoral features of MRC5 fibroblasts, reducing SASP-related interleukins IL1α, IL1β, IL6, and IL8; transforming-growth-factor-β (TGFβ); matrix metallo-proteinases MMP3 and MMP2; urokinase plasminogen activator (uPA); receptor proteins uPAR, [[IL6R]], insulin growth factor receptor-1 (IGF-1R), TGFβ-R2, and CXCR4. The cellular nuclear-factor-kB (NF-kB) protein level was also reduced, confirming its role in the induction of SASP. Resveratrol pretreated MRC5 fibroblasts were resistant to activation by TGFβ. Resveratrol treatment of senescent MRC5 induced the production of conditioned media (CM) which counteracted the protumoral effect of senescent CM on A375 and A375-M6 melanoma cell proliferation and invasiveness, and reduced the expression of epithelial-to-mesenchymal transition markers related to malignant features. This experimental approach proposes a treatment that targets the senescent stromal cell phenotype to induce an anti-tumor hosting microenvironment, which is suitable for both preventive and therapeutic purposes.
MeSH Terms
- Animals
- Biomarkers, Tumor
- Blotting, Western
- Cell Line, Tumor
- Cell Proliferation
- Cellular Senescence
- Culture Media, Conditioned
- Fibroblasts
- Humans
- Interleukins
- Melanoma
- Mice
- Phenotype
- Real-Time Polymerase Chain Reaction
- Resveratrol
- Stilbenes
- Tumor Cells, Cultured
- Tumor Microenvironment
Keywords
- cancer
- cellular senescence
- resveratrol
Many kidney-tonifying Chinese herbal medicines exert effects on anti-aging by comprehensive interactions of multiple targets. However, the interactions of multi-targets targeted by effective ingredients of kidney-tonifying Chinese herbal medicines are unknown. In this study, to explore the systems pharmacology mechanisms of kidney-tonifying Chinese medicines on anti-aging, we establish the molecular networks with the interactions of multi-targets, analyze bio-functions and pathways with IPA, and calculated the mutual interaction pairs of targets (target pairs) with data mining, respectively. Kidney-tonifying Chinese medicines with anti-aging effects were screened from the Chinese Pharmacopoeia and the literatures. Target proteins of these herbal medicines were obtained from bioinformatics databases. Comparisons of molecular networks, bio-functions and pathways given by Ingenuity Pathway Analysis system showed the similarities and the differences between kidney Yin-tonifying herbal medicines and kidney Yang-tonifying herbal medicines. Target pairs with high correlation related to anti-aging were also discovered by data mining algorithm. And regulatory networks of targets were built based on the target pairs. Twenty-eight kidney-tonifying herbal medicines with anti-aging effects and 717 related target proteins were collected. The main bio-functions that all targets enriched in were "Cell Death and Survival", "Free Radical Scavenging" and "Cellular Movement", etc. The results of comparison analysis showed that kidney Yin-tonifying herbal medicines focused more on "Cancer related signaling", "Apoptosis related signaling" and "Cardiovascular related signaling". And kidney Yang-tonifying herbal medicines focused more on "Cellular stress and injury related signaling" and "Cellular growth, proliferation and development related signaling". Moreover, the results of regulatory network showed that the anti-aging related target pairs with high correlated degrees of Kidney Yin-tonifying herbal medicines included TNF-PTGS2, TNF-CASP3, PTGS2-CASP3, CASP3-NOS2 and TNF-NOS2, and that of kidney Yang-tonifying herbal medicines included REAL-TNF, REAL-NFKBIA, REAL-JUN, PTGS2-SOD1 and TNF-IL6. In this study, we achieved some important targets, target pairs and regulatory networks with bioinformatics and data mining, to discuss the systems pharmacology mechanisms of kidney-tonifying herbal medicines acting on anti-aging. Mutual target pairs related to anti-aging found in this study included TNF-PTGS2, TNF-CASP3, PTGS2-CASP3, CASP3-NOS2, TNF-NOS2, REAL-TNF, REAL-NFKBIA, REAL-JUN, PTGS2-SOD1 and TNF-IL6. Target pairs and regulatory networks of targets could reflect more potential interactions between targets and comprehensive effects on anti-aging. Compared with the existing researches, it was found that the kidney-tonifying herbal medicines may exert anti-aging effects in multiple pathways in this study.
MeSH Terms
- Aging
- Computational Biology
- Data Mining
- Drugs, Chinese Herbal
- Gene Expression
- Gene Regulatory Networks
- Humans
- Plants, Medicinal
- Proteins
- Signal Transduction
Keywords
- Anti-aging
- Bioinformatics
- Data mining
- Kidney-tonifying
- Molecular Network
A better understanding of the complex relationship between aging and cancer will provide important tools for the prevention and treatment of neoplasia. In these studies, the hypothesis was tested that aging may fuel carcinogenesis via alterations imposed in the tissue microenvironment. Preneoplastic hepatocytes isolated from liver nodules were orthotopically injected into either young or old syngeneic rats and their fate was followed over time using the dipeptidyl-peptidase type IV (DPPIV) system to track donor-derived-cells. At 3 months post-Tx, the mean size of donor-derived clusters was 11±3 cells in young vs. 42±8 in old recipients. At 8 months post-Tx, no visible lesion were detected in any of 21 young recipients, while 17/18 animals transplanted at old age displayed hepatic nodules, including 7 large tumors. All tumors expressed the DPPIV marker enzyme, indicating that they originated from transplanted cells. Expression of senescence-associated β-galactosidase was common in liver of 18-month old animals, while it was a rare finding in young controls. Finally, both mRNA and IL6 protein were found to be increased in the liver of aged rats compared to young controls. These results are interpreted to indicate that the microenvironment of the aged liver promotes the growth of pre-neoplastic hepatocytes.
MeSH Terms
- Aging
- Animals
- Hepatocytes
- Liver
- Liver Neoplasms, Experimental
- Precancerous Conditions
- Rats
- Rats, Inbred F344
Keywords
- aging
- liver carcinogenesis
- microenvironment
- pre-neoplastic hepatocytes
- selection
There is increasing evidence documenting gene-by-environment (G × E) interactions for CVD related traits. However, the underlying mechanisms are still unclear. DNA methylation may represent one of such potential mechanisms. The objective of this review paper is to summarise the current evidence supporting the interplay among DNA methylation, genetic variants, and environmental factors, specifically (1) the association between SNP and DNA methylation; (2) the role that DNA methylation plays in G × E interactions. The current evidence supports the notion that genotype-dependent methylation may account, in part, for the mechanisms underlying observed G × E interactions in loci such as APOE, IL6 and ATP-binding cassette A1. However, these findings should be validated using intervention studies with high level of scientific evidence. The ultimate goal is to apply the knowledge and the technology generated by this research towards genetically based strategies for the development of personalised nutrition and medicine.
MeSH Terms
- Biomedical Research
- Cardiovascular Diseases
- Congresses as Topic
- DNA Methylation
- Dietetics
- Epigenesis, Genetic
- Epigenomics
- Gene-Environment Interaction
- Genetic Predisposition to Disease
- Genetic Techniques
- Global Health
- Humans
- Nutrigenomics
- Nutritional Sciences
- Risk Factors
- Societies, Scientific
Keywords
ABCA1
ATP-binding cassette A1
- CHARGE Cohorts for Heart and Aging Research in Genomic Epidemiology
- ENCODE Encyclopedia of DNA elements
- FA fatty acids
- GOLDN Genetics of Lipid-lowering Drugs and Diet Network
- HHcy hyperhomocysteinaemia
- LXR liver X receptors
- SREBP sterol regulatory element-binding proteins
- CVD
- Epigenetics
- Genetics
- Nutrigenetics
Disturbance in the carotid arteries strongly predicts cerebrovascular events and correlates with a systemic inflammatory milieu. We investigated the relationship of a profile of 10 circulating inflammatory mediators with measures of carotid intima-media thickness (cIMT) in elderly subjects, taking traditional risk factors into account. Clinical inspection for present and past chronic conditions and events, as well as biochemical and anthropometric measurements, was performed for patients in ambulatory setting. Scores of cIMT were obtained bilaterally in the distal common carotid artery wall. Serum concentrations of cytokines were assessed by bead-based, multiplexed flow cytometry immunoassays. Correlation analysis between log-transformed cytokines levels implicated the mediators interleukin-1β (IL1β), IL6, IL8, IL10, and tumor necrosis factor-α (TNFα) (P ≤ .005) with scores of the left cIMT. Stepwise multivariate regression showed that TNFα, IL1β, and IL6 levels accounted for most of the variance in the cIMT scores. Comparison of cytokine levels across increasing tertiles of the left cIMT reproduced the positive association with TNFα and IL1β levels. Five out of ten immune mediators independently correlated with cIMT of older subjects in a territory-sensitive manner. This possible contribution of immune mediators to an atherosclerotic process probably relates to the inflammaging process.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Biomarkers
- Brazil
- Carotid Artery Diseases
- Carotid Artery, Common
- Carotid Intima-Media Thickness
- Cross-Sectional Studies
- Cytokines
- Female
- High-Throughput Screening Assays
- Humans
- Inflammation Mediators
- Linear Models
- Male
- Multivariate Analysis
- Predictive Value of Tests
- Prognosis
- Risk Factors
- Severity of Illness Index
Keywords
- Atherosclerosis
- aging
- carotid artery
- inflammation
- interleukin
- intima-media thickness
Cellular senescence is known as an anti-tumor barrier and is characterized by a number of determinants including cell cycle arrest, senescence associated β-galactosidase activity and secretion of pro-inflammatory mediators. Senescent cells are also subjected to enlargement, cytoskeleton-mediated shape changes and organelle alterations. However, the underlying molecular mechanisms responsible for these last changes remain still uncharacterized. Herein, we have identified the Unfolded Protein Response (UPR) as a player controlling some morphological aspects of the senescent phenotype. We show that senescent fibroblasts exhibit ER expansion and mild UPR activation, but conserve an ER stress adaptive capacity similar to that of exponentially growing cells. By genetically invalidating the three UPR sensors in senescent fibroblasts, we demonstrated that ATF6α signaling dictates senescence-associated cell shape modifications. We also show that ER expansion and increased secretion of the pro-inflammatory mediator IL6 were partly reversed by silencing ATF6α in senescent cells. Moreover, ATF6α drives the increase of senescence associated-β-galactosidase activity. Collectively, these findings unveil a novel and central role for ATF6α in the establishment of morphological features of senescence in normal human primary fibroblasts.
MeSH Terms
- Activating Transcription Factor 6
- Adult
- Cells, Cultured
- Cellular Senescence
- Child
- Dermis
- Endoplasmic Reticulum
- Endoplasmic Reticulum Stress
- Female
- Fibroblasts
- Gene Expression Profiling
- Humans
- Infant
- Male
- Microscopy, Electron, Transmission
- RNA Interference
- Signal Transduction
- Unfolded Protein Response
Keywords
- ATF6α
- Gerotarget
- endoplasmic reticulum
- normal human dermal fibroblast
- senescence
- unfolded protein response
Endocrine resistance is a major problem in prostate cancer. Recent studies suggest that cellular plasticity plays a key role in therapy resistance. Yet little is known about the cellular changes of human prostate cancer after androgen deprivation therapy (ADT). In this study, we investigated cellular senescence, senescence-associated secretory phenotypes (SASPs), and anti-oxidant responses. Hormone ablation upregulated senescence-associated (SA)-β-Gal activity in prostate glands, as well as the expressions of p27 and p53, in a mouse castration model. In line with this, the expressions of p21 and p27 were significantly more upregulated in human non-pathological prostatic glands after ADT than in untreated specimens. In a study of SASP markers, the expressions of IL6 and IL8 were also more upregulated in human non-pathological prostatic glands after ADT than in untreated specimens. IL6, IL8, and MMP2 were expressed more strongly in human prostate cancer specimens resected after ADT than in untreated tumors. Of note, treatment with the anti-oxidant reagent NAC significantly suppressed SA-β-Gal activity in androgen-sensitive human prostate cancer LNCaP cells. In immunohistochemical analyses on anti-oxidant response genes, NRF2 and NQO1 were more upregulated after hormone ablation in human prostate gland and carcinoma specimens after ADT than in untreated specimens or in murine prostate glands after castration. Taken together, these findings suggest that ADT induces cellular senescence processes accompanied by secretory phenotypes and anti-oxidant responses in prostate. These cellular changes may be attractive targets for preventing endocrine resistance in prostate cancer.
MeSH Terms
- Androgen Antagonists
- Androgens
- Animals
- Antioxidants
- Cell Line, Tumor
- Cellular Senescence
- Disease Progression
- Endocrine System
- Female
- Humans
- Immunohistochemistry
- Interleukin-6
- Interleukin-8
- Male
- Matrix Metalloproteinase 2
- Matrix Metalloproteinase 9
- Mice
- Mice, Inbred ICR
- Orchiectomy
- Ovariectomy
- Phenotype
- Prostate
- Prostatic Neoplasms
Keywords
- Androgen deprivation therapy
- Anti-oxidant response
- Cellular senescence
- Prostate cancer
- Senescence-associated secretory phenotype
Prolonged unaccustomed exercise involving muscle lengthening (eccentric) actions can result in ultrastructural muscle disruption, impaired excitation-contraction coupling, inflammation and muscle protein degradation. This process is associated with delayed onset muscle soreness and is referred to as exercise-induced muscle damage. Although a certain amount of muscle damage may be necessary for adaptation to occur, excessive damage or inadequate recovery from exercise-induced muscle damage can increase injury risk, particularly in older individuals, who experience more damage and require longer to recover from muscle damaging exercise than younger adults. Furthermore, it is apparent that inter-individual variation exists in the response to exercise-induced muscle damage, and there is evidence that genetic variability may play a key role. Although this area of research is in its infancy, certain gene variations, or polymorphisms have been associated with exercise-induced muscle damage (i.e. individuals with certain genotypes experience greater muscle damage, and require longer recovery, following strenuous exercise). These polymorphisms include ACTN3 (R577X, rs1815739), TNF (-308 G>A, rs1800629), IL6 (-174 G>C, rs1800795), and IGF2 (ApaI, 17200 G>A, rs680). Knowing how someone is likely to respond to a particular type of exercise could help coaches/practitioners individualise the exercise training of their athletes/patients, thus maximising recovery and adaptation, while reducing overload-associated injury risk. The purpose of this review is to provide a critical analysis of the literature concerning gene polymorphisms associated with exercise-induced muscle damage, both in young and older individuals, and to highlight the potential mechanisms underpinning these associations, thus providing a better understanding of exercise-induced muscle damage.
MeSH Terms
- Aging
- Athletic Performance
- Cumulative Trauma Disorders
- Genetic Predisposition to Disease
- Genetic Variation
- Humans
- Models, Genetic
- Muscle, Skeletal
- Muscular Diseases
- Polymorphism, Single Nucleotide
Keywords
- Creatine kinase
- Delayed onset muscle soreness
- Elderly
- Exercise-induced muscle damage
- Single nucleotide polymorphism
Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal rare autosomal recessive neurodegenerative disorder characterized by the accumulation of insoluble ubiquitinated polyglucosan inclusions in the cytoplasm of neurons, which is most commonly associated with mutations in two genes: [[EPM2A]], encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. The present study analyzes possible inflammatory responses in the mouse lines Epm2a (laforin knock-out) and Epm2b (malin knock-out) with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the Iba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occur in both mouse lines although with marked genotype differences. C3ar1 and CxCl10 messenger RNAs (mRNAs) are significantly increased in Epm2a mice aged 12 months when compared with age-matched controls, whereas C3ar1, C4b, Ccl4, CxCl10, Il1b, Il6, Tnfα, and Il10ra mRNAs are significantly upregulated in Epm2b at the same age. This is accompanied by increased protein levels of IL1-β, IL6, TNFα, and Cox2 particularly in Epm2b mice. The severity of inflammatory changes correlates with more severe clinical symptoms previously described in Epm2b mice. These findings show for the first time increased innate inflammatory responses in a neurodegenerative disease with polyglucosan intraneuronal deposits which increase with disease progression, in a way similar to what is seen in neurodegenerative diseases with abnormal protein aggregates. These findings also point to the possibility of using anti-inflammatory agents to mitigate the degenerative process in LD.
MeSH Terms
- Aging
- Animals
- Astrocytes
- Biomarkers
- Calcium-Binding Proteins
- Cyclooxygenase 2
- Cytokines
- Disease Models, Animal
- Disease Progression
- Dual-Specificity Phosphatases
- Gene Expression Regulation
- Glial Fibrillary Acidic Protein
- Hippocampus
- Inclusion Bodies
- Inflammation
- Inflammation Mediators
- Lafora Disease
- Mice, Inbred C57BL
- Mice, Knockout
- Microfilament Proteins
- Microglia
- Protein Tyrosine Phosphatases, Non-Receptor
- RNA, Messenger
- Telencephalon
- Ubiquitin-Protein Ligases
Keywords
- Chemokines
- Cytokines
- Inflammation
- Lafora disease
- Microglia
- Polyglucosan
In this study we explored the association between aging-related phenotypes previously reported to predict survival in old age and variation in 77 genes from the DNA repair pathway, 32 genes from the growth hormone 1/ insulin-like growth factor 1/insulin (GH/IGF-1/INS) signalling pathway and 16 additional genes repeatedly considered as candidates for human longevity: APOE, APOA4, APOC3, ACE, CETP, HFE, IL6, [[IL6R]], MTHFR, TGFB1, SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. Altogether, 1,049 single nucleotide polymorphisms (SNPs) were genotyped in 1,088 oldest-old (age 92-93 years) Danes and analysed with phenotype data on physical functioning (hand grip strength), cognitive functioning (mini mental state examination and a cognitive composite score), activity of daily living and self-rated health. Five SNPs showed association to one of the phenotypes; however, none of these SNPs were associated with a change in the relevant phenotype over time (7 years of follow-up) and none of the SNPs could be confirmed in a replication sample of 1,281 oldest-old Danes (age 94-100). Hence, our study does not support association between common variation in the investigated longevity candidate genes and aging-related phenotypes consistently shown to predict survival. It is possible that larger sample sizes are needed to robustly reveal associations with small effect sizes.
MeSH Terms
- Activities of Daily Living
- Aged, 80 and over
- Aging
- Cognition
- Denmark
- Female
- Genotype
- Hand Strength
- Humans
- Linear Models
- Longevity
- Male
- Phenotype
- Polymorphism, Single Nucleotide
- Signal Transduction
- Surveys and Questionnaires
Keywords
- Association study
- Human aging
- Oldest-old
- Single nucleotide polymorphisms
Cellular and molecular immunoinflammatory changes in gingival tissues drive alveolar bone loss in periodontitis. Since ageing is a risk factor for periodontitis, we sought to identify age-related gingival transcriptome changes associated with bone metabolism in both healthy and in naturally occurring periodontitis. Adult (12-16 years) and aged (18-23 years) non-human primates (M. mulatta) (n = 24) were grouped into healthy and periodontitis. Gingival tissue samples were obtained and subjected to microarray analysis using the Gene Chip Macaque Genome Array. Gene expression profiles involved in osteoclast/osteoblast proliferation, adhesion and function were evaluated and compared across and between the age groups. QPCR was also performed on selected genes to validate microarray data. Healthy aged tissues showed a gene profile expression that suggest enhancement of osteoclastic adhesion, proliferation/survival and function (SPP1, TLR4, MMP8 and TFEC) and impaired osteoblastic activity (SMEK3P and SMAD5). The gingival transcriptome in both adult and aged animals with naturally occurring periodontitis (FOS, IL6, TLR4, MMP9, MMP10 and SPP1 genes) was consistent with a local inflammatory response driving towards bone/connective tissue destruction. A pro-osteoclastogenic gingival transcriptome is associated with periodontitis irrespective of age; however; a greater bone-destructive molecular environment is associated with ageing in healthy tissues.
MeSH Terms
- Adolescent
- Aging
- Alveolar Bone Loss
- Animals
- Gingiva
- Humans
- Macaca mulatta
- Periodontitis
- Transcriptome
- Young Adult
Keywords
- ageing
- gene expression
- non-human primates
- osteoclast
- periodontitis
The major histocompatibility complex I (MHCI) pathway, which canonically functions in innate immune viral antigen presentation and detection, is functionally pleiotropic in the central nervous system (CNS). Alternative roles include developmental synapse pruning, regulation of synaptic plasticity, and inhibition of neuronal insulin signaling; all processes altered during brain aging. Upregulation of MHCI components with aging has been reported; however, no systematic examination of MHCI cellular localization, expression, and regulation across CNS regions, life span, and sexes has been reported. In the mouse, MHCI is expressed by neurons and microglia, and MHCI components and receptors (H2-K1, H2-D1, β2M, Lilrb3, Klra2, CD247) display markedly different expression profiles across the hippocampus, cortex, cerebellum, brainstem, and retina. MHCI components, receptors, associated inflammatory transcripts (IL1α, IL1β, IL6, TNFα), and TAP (transporter associated with antigen processing) components are induced with aging and to a greater degree in female than male mice across CNS regions. H2-K1 and H2-D1 expression is associated with differential CG and non-CG promoter methylation across CNS regions, ages, and between sexes, and concomitant increased expression of proinflammatory genes. Meta-analysis of human brain aging data also demonstrates age-related increases in MHCI. Induction of MHCI signaling could contribute to altered synapse regulation and impaired synaptic plasticity with aging.
MeSH Terms
- Aging
- Animals
- Brain
- Female
- Major Histocompatibility Complex
- Male
- Mice
- Mice, Inbred C57BL
- Neuronal Plasticity
- Sex Factors
- Signal Transduction
Keywords
- Aging
- DNA methylation
- Gene expression
- MHCI
- Sex differences
- brain
Monocyte phenotype and output changes with age, but why this occurs and how it impacts anti-bacterial immunity are not clear. We found that, in both humans and mice, circulating monocyte phenotype and function was altered with age due to increasing levels of TNF in the circulation that occur as part of the aging process. Ly6C monocytes from old (18-22 mo) mice and CD14 CD16 intermediate/inflammatory monocytes from older adults also contributed to this "age-associated inflammation" as they produced more of the inflammatory cytokines IL6 and TNF in the steady state and when stimulated with bacterial products. Using an aged mouse model of pneumococcal colonization we found that chronic exposure to TNF with age altered the maturity of circulating monocytes, as measured by F4/80 expression, and this decrease in monocyte maturation was directly linked to susceptibility to infection. Ly6C monocytes from old mice had higher levels of CCR2 expression, which promoted premature egress from the bone marrow when challenged with Streptococcus pneumoniae. Although Ly6C monocyte recruitment and TNF levels in the blood and nasopharnyx were higher in old mice during S. pneumoniae colonization, bacterial clearance was impaired. Counterintuitively, elevated TNF and excessive monocyte recruitment in old mice contributed to impaired anti-pneumococcal immunity since bacterial clearance was improved upon pharmacological reduction of TNF or Ly6C monocytes, which were the major producers of TNF. Thus, with age TNF impairs inflammatory monocyte development, function and promotes premature egress, which contribute to systemic inflammation and is ultimately detrimental to anti-pneumococcal immunity.
MeSH Terms
- Aging
- Animals
- Female
- Flow Cytometry
- Humans
- Mice
- Mice, Inbred C57BL
- Monocytes
- Pneumococcal Infections
- Streptococcus pneumoniae
- Tumor Necrosis Factor-alpha
Prior studies of aging and neuropathic injury have focused on senescent animals compared to young adults, while changes in middle age, particularly in the dorsal root ganglia (DRG), have remained largely unexplored. 14 neuroimmune mRNA markers, previously associated with peripheral nerve injury, were measured in multiplex assays of lumbar spinal cord (LSC), and DRG from young and middle-aged (3, 17 month) naïve rats, or from rats subjected to chronic constriction injury (CCI) of the sciatic nerve (after 7 days), or from aged-matched sham controls. Results showed that CD2, CD3e, CD68, CD45, TNF-α, IL6, CCL2, ATF3 and TGFβ1 mRNA levels were substantially elevated in LSC from naïve middle-aged animals compared to young adults. Similarly, LSC samples from older sham animals showed increased levels of T-cell and microglial/macrophage markers. CCI induced further increases in CCL2, and IL6, and elevated ATF3 mRNA levels in LSC of young and middle-aged adults. Immunofluorescence images of dorsal horn microglia from middle-aged naïve or sham rats were typically hypertrophic with mostly thickened, de-ramified processes, similar to microglia following CCI. Unlike the spinal cord, marker expression profiles in naïve DRG were unchanged across age (except increased ATF3); whereas, levels of GFAP protein, localized to satellite glia, were highly elevated in middle age, but independent of nerve injury. Most neuroimmune markers were elevated in DRG following CCI in young adults, yet middle-aged animals showed little response to injury. No age-related changes in nociception (heat, cold, mechanical) were observed in naïve adults, or at days 3 or 7 post-CCI. The patterns of marker expression and microglial morphologies in healthy middle age are consistent with development of a para-inflammatory state involving microglial activation and T-cell marker elevation in the dorsal horn, and neuronal stress and satellite cell activation in the DRG. These changes, however, did not affect the establishment of neuropathic pain.
MeSH Terms
- Age Factors
- Aging
- Animals
- Antigens, CD
- Cytokines
- Ganglia, Spinal
- Male
- Microglia
- Neuralgia
- Nociception
- Rats
- Satellite Cells, Perineuronal
- Sciatic Neuropathy
- Spinal Cord
Aging is accompanied by a loss of homeostasis, which leads to increase of susceptibility and vulnerability to cancers, cardiovascular, neurodegenerative and autoimmune diseases. Numerous studies have been suggested that even in the absence of acute infection ageing associated with chronic low-grade inflammation and the underlying cause of this process may be an immunosenescence as well as shifts production of cytokines levels. However, the results on age-related alterations of these cytokine levels are inconsistent. The main aim of our study was to evaluate how the pro- and anti-inflammatory cytokines and lipoproteins fraction varies through aging as well as how these changes related each other in an apparently healthy population. For this purposes, 220 healthy volunteers were selected on the basis of clinical records and laboratory examinations. Individuals with various health problems were excluded. Fasting triglycerids (TG), low and high density lipoproteins (LDL and HDL) and cytokines (IL-6, IL4, 10, 17, IFN, TNF) levels were measured using commercial assay kits. The statistical analysis was performed using SPSS (Chicago, IL, USA). The results revealed that all studied cytokines levels did not fluctuate by gender. LDL means value differ significantly between men and women. Age are not main predictor for HDL, TG, IL4, IL6, IFN circulating levels, however, the production of LDL, IL17 and IL10 showed significant deviations through aging: especially, LDL and IL17 were augmented, while IL-10 were reduced. It is interestingly, that besides the age, LDL levels were correlated with TNF-alfa and IL10, while triglyceride were only associated with IL10 levels. It has to be note that the correlations did not changes after adjustment of age. The result of our study shown that lipoproteins (LDL, TG) and cytokines (TNF, IL10, IL17) levels are linked and can be used as a prognostic markers of cardiovascular diseases development.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Cholesterol
- Dyslipidemias
- Female
- Healthy Volunteers
- Humans
- Inflammation
- Lipids
- Lipoproteins
- Male
- Middle Aged
- Triglycerides
Chronically elevated circulating inflammatory markers are common in older persons but mechanisms are unclear. Many blood transcripts (>800 genes) are associated with interleukin-6 protein levels (IL6) independent of age. We aimed to identify gene transcripts statistically mediating, as drivers or responders, the increasing levels of IL6 protein in blood at older ages. Blood derived in-vivo RNA from the Framingham Heart Study (FHS, n=2422, ages 40-92 yrs) and InCHIANTI study (n=694, ages 30-104 yrs), with Affymetrix and Illumina expression arrays respectively (>17,000 genes tested), were tested for statistical mediation of the age-IL6 association using resampling techniques, adjusted for confounders and multiple testing. In FHS, IL6 expression was not associated with IL6 protein levels in blood. 102 genes (0.6% of 17,324 expressed) statistically mediated the age-IL6 association of which 25 replicated in InCHIANTI (including 5 of the 10 largest effect genes). The largest effect gene (SLC4A10, coding for NCBE, a sodium bicarbonate transporter) mediated 19% (adjusted CI 8.9 to 34.1%) and replicated by PCR in InCHIANTI (n=194, 35.6% mediated, p=0.01). Other replicated mediators included PRF1 (perforin, a cytolytic protein in cytotoxic T lymphocytes and NK cells) and IL1B (Interleukin 1 beta): few other cytokines were significant mediators. This transcriptome-wide study on human blood identified a small distinct set of genes that statistically mediate the age-IL6 association. Findings are robust across two cohorts and different expression technologies. Raised IL6 levels may not derive from circulating white cells in age related inflammation.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- Cohort Studies
- Female
- Gene Expression Profiling
- Genetic Markers
- Humans
- Inflammation
- Inflammation Mediators
- Interleukin-6
- Male
- Middle Aged
Keywords
- Aging
- Blood
- Epidemiology
- Human
- Inflammation
- Transcriptome
Increased age is the most prominent risk factor for the initiation and progression of osteoarthritis (OA). The effects of human growth hormone (hGH) combined or not with hyaluronan amide derivative (HAD) were evaluated on human OA chondrocytes, to define their biological action and potentiality in OA treatment. Cell viability, metabolic activity, gene expression and factors released were tested at different time points on chondrocytes treated with different concentrations of hGH (0.01-10 μg/ml) alone or in combination with HAD (1 mg/ml). We found that OA chondrocytes express GH receptor and that the different doses of hGH tested did not affect cell viability, metabolic activity or the expression of collagen type 2, 1, or 10 nor did it induce the release of IGF-1 or FGF-2. Conversely, hGH treatment increased the expression of hyaluronan receptor CD44. HAD combined with hGH reduced metabolic activity, IL6 release and gene expression, but not the suppressor of cytokine signaling 2 (SOCS2), which was significantly induced and translocated into the nucleus. The parameters analyzed, independently of the treatments used proportionally decreased with increasing age of the patients. hGH only induced CD44 receptor on OA chondrocytes but did not affect other parameters, such as chondrocytic gene markers or IGF-1 or FGF-2 release. HAD reduced all the effects induced by hGH partially through a significant induction of SOCS2. These data show that GH or HAD treatment does not influence the response of the OA chondrocytes, thus the modulation of cellular response is age-independent.
MeSH Terms
- Aged
- Aging
- Cells, Cultured
- Chondrocytes
- Female
- Human Growth Hormone
- Humans
- Hyaluronic Acid
- Male
- Middle Aged
- Osteoarthritis, Hip
Keywords
- Age
- chondrocytes
- growth hormone
- hyaluronan
- osteoarthritis
Although pituitary adenomas represent 25% of intracranial tumors, they are usually benign, with the mechanisms by which these tumors usually avoid an invasive profile and metastatic growth development still remaining unclear. In this context, cellular senescence might constitute a plausible explanation for the benign nature of pituitary adenomas. In this study, we investigated the emergence of cellular senescence as a growth control mechanism during the progression of estrogen-induced pituitary tumors. The quantification of Ki67-immunopositive cells in the pituitaries of estrogenized male rats after 10, 20, 40, and 60 days revealed that the mitogenic potential rate was not sustained for the whole period analyzed and successively decreased after 10 days of estrogen exposure. In addition, the expression of cellular senescence features, such as the progressive rise in the enzymatic senescence-associated b-galactosidase (SA-b-gal) activity, IL6, IL1b, and TGFb expression, was observed throughout pituitary tumor development. Furthermore, tumoral pituitary cells also displayed nuclear pATM expression, indicating activated DNA damage signaling, with a significant increase in p21 expression also being detected. The associations among DNA damage signaling activation, SA-b-gal expression, and p21 may provide a reliable combination of senescence-associated markers for in vivo pituitary senescence detection. These results suggest a role for this cellular process in the regulation of pituitary cell growth. Thus, cellular senescence should be conceived as a contributing component to the benign nature of pituitary adenomas, thereby influencing the capability of the pituitary gland to avoid unregulated cell proliferation.
MeSH Terms
- Animals
- Cellular Senescence
- Disease Progression
- Estrogens
- Male
- Pituitary Neoplasms
- Rats
- Rats, Wistar
- Signal Transduction
Keywords
- cellular senescence
- estrogen
- immunohistochemistry
- pituitary
- tumor
Senescence is a highly stable cell cycle arrest which limits the replication of cells with damaged genomes. The senescence program is activated during aging or in response to insults like DNA damage or oncogenic signaling. Upon induction of senescence, cells undergo profound changes on their transcription program, chromatin organization, and they secrete a complex mixture of mainly pro-inflammatory components termed the senescence-associated secretory phenotype (SASP). The SASP mediates multiple effects, including reinforcing senescence and activating immune surveillance responses. Given the important role that senescence has in aging, cancer and other pathologies, identifying mechanisms regulating senescence has therapeutic potential. Here we describe a role for TRIM28 (also known as KRAB-associated protein 1, KAP1) on mediating oncogene-induced senescence (OIS). TRIM28 accumulates during OIS becoming phosphorylated on serine 824. To investigate the role of TRIM28, we knocked down its expression and observed that the depletion of TRIM28 partially prevented cell arrest during OIS. While induction of p53 and p21 during OIS, was not affected by TRIM28 depletion, p16(INK4a) induction was partially prevented. Finally, we observed that the induction of IL8, IL6 and other SASP components were strongly suppressed upon TRIM28 depletion. In conclusion, the above-described results show that TRIM28 regulates senescence and affects the induction of the senescence-associated secretory phenotype.
MeSH Terms
- Cell Line
- Cellular Senescence
- Cyclin-Dependent Kinase Inhibitor p16
- Humans
- Inflammation Mediators
- Oncogenes
- Phosphorylation
- Repressor Proteins
- Tripartite Motif-Containing Protein 28
Keywords
- SASP
- Senescence
- TRIM28
- p16
Foot and mouth disease (FMD) is an economically important disease and a whole-virus inactivated trivalent virus vaccine is the mainstay for controlling the disease in India. The protective humoral immune response to FMD vaccination is a complex, but, tightly regulated process mediated by the interplay of interleukins (IL). Based on the specific role of IL6 and 21 in adaptive immune response, we hypothesized that inactivated trivalent FMD vaccine would stimulate IL6 and 21 expression in the circulating lymphocytes. The expressions of IL6 and 21 were assayed on 0, 28, 60, 90, and 120 d post-vaccination (DPV) by quantitative PCR (qPCR) with simultaneous assessment of FMDV antibody titer by liquid phase blocking ELISA. The results revealed that the peak expression of IL6 and 21 was on DPV 28 which correlated well with the FMDV antibody titer and plummeted to the prevaccination titer level by 60 DPV. As IL21 is the final effector of antibody production as compared to IL6, we investigated the expression of IL21 in calves that had protective titer (>1.8) with the unprotected group (<1.8). Expression of IL21 on 28 DPV was numerically higher in the protected than that of the unprotected group of calves.
MeSH Terms
- Aging
- Animals
- Cattle
- Cattle Diseases
- Female
- Foot-and-Mouth Disease
- Gene Expression Regulation
- Hybridization, Genetic
- Interleukin-6
- Interleukins
- Male
- Up-Regulation
- Vaccines, Inactivated
- Viral Vaccines
Hip fracture is a common trauma in older adults with a high incidence of depression, which relates to poorer prognosis including increased risk of infection. Ageing is accompanied by reduced immunity, termed immunesenescence, resulting in increased susceptibility to infection. We examined whether physical trauma (hip fracture) and psychological distress (depressive symptoms) had additive effects upon the aged immune system that might contribute to poor outcomes after injury. Neutrophil function was assessed in 101 hip fracture patients (81 female) 6 weeks and 6 months after injury and 43 healthy age-matched controls (28 female). Thirty eight fracture patients had depressive symptoms at 6 weeks. No difference in neutrophil phagocytosis of Escherichia coli was observed between controls and hip fracture patients, but superoxide production was significantly reduced in hip fracture patients with depressive symptoms compared with patients without symptoms (p=.001) or controls (p=.004) at 6 weeks. Superoxide production improved 6 months following fracture to the level seen in controls. We detected elevated serum cortisol, reduced dehydroepiandrosterone sulphate (DHEAS) and an increased cortisol:DHEAS ratio in fracture patients with depressive symptoms compared with patients without depressive symptoms or controls at 6 weeks and 6 months after injury. Serum IL6, TNFα and IL10 were higher among patients with depressive symptoms at 6 weeks. The cortisol:DHEAS ratio and IL6 levels related to depressive symptom scores but not to neutrophil function. In conclusion, depressive symptoms related to poorer neutrophil function after hip fracture, but this was not driven by changes in stress hormone or cytokine levels.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Case-Control Studies
- Depression
- Down-Regulation
- Escherichia coli
- Female
- Hip Fractures
- Humans
- Male
- Middle Aged
- Neutrophils
- Phagocytosis
- Prospective Studies
Keywords
- Ageing
- Cortisol
- Dehydroepiandrosterone
- Depressive symptoms
- Hip fracture
- Neutrophil function
Cellular senescence, a state of sustained cell cycle arrest, has been identified as an important anti-tumor barrier. Senescent cells secrete various growth factors and cytokines, such as IL6 and IL8, which collectively constitute the senescence-associated secretory phenotype (SASP). The SASP can signal to the tumor environment and elicit the immune-mediated clearance of tumor cells or, depending on the context, could potentially promote tumor progression. Despite the importance of the SASP to tumor biology, its regulation remains relatively unknown. Here, we show that IκBζ, an atypical member of the inhibitor of NFκB proteins and selective coactivator of particular NFκB target genes, is an important regulator of SASP expression. Several models of DNA damage- and oncogene-induced senescence revealed a robust induction of IκBζ expression. RNAi-mediated knockdown of IκBζ impaired IL6 and IL8 expression, whereas transgenic IκBζ expression resulted in enhanced SASP cytokine expression. Importantly, during senescence of IκBζ knockout cells induction of IL6 and IL8, but not of the cell cycle inhibitor p21(WAF/CIP1), was completely abolished. Thus, we propose an important and hitherto unappreciated role of IκBζ in SASP formation in both DNA damage- and oncogene-induced senescence.
MeSH Terms
- Cell Cycle Checkpoints
- Cell Line, Tumor
- Cellular Senescence
- Cytokines
- DNA Damage
- Humans
- I-kappa B Proteins
- MCF-7 Cells
- Oncogenes
- Phenotype
- Signal Transduction
Keywords
- Cytokines
- DNA damage
- IκBζ
- NFκB
- SASP
- Senescence
Aging is often accompanied by cognitive decline, memory impairment and an increased susceptibility to neurodegenerative disorders. Most of these age-related alterations have been associated with deleterious processes such as changes in the expression of inflammatory cytokines. Indeed, higher levels of pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines are found in the aged brain. This perturbation in pro- and anti-inflammatory balance can represent one of the mechanisms that contribute to age-associated neuronal dysfunction and brain vulnerability. We conducted an experimental study to investigate whether an aerobic exercise program could promote changes in inflammatory response in the brains of aged rats. To do so, we evaluated the levels of tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL1β), interleukin 6 (IL6) and interleukin 10 (IL10) in the hippocampal formation of 18 month old rats that underwent treadmill training over 10 consecutive days. Quantitative immunoassay analyses showed that the physical exercise increased anti-inflammatory cytokine levels IL10 in the hippocampal formation of aged rats, when compared to the control group. The hippocampal levels of pro-inflammatory cytokines IL1β, IL6 and TNFα were not statistically different between the groups. However, a significant reduction in IL1β/IL10, IL6/IL10 and TNFα/IL10 ratio was observed in the exercised group in relation to the control group. These findings indicate a favorable effect of physical exercise in the balance between hippocampal pro- and anti-inflammatory during aging, as well as reinforce the potential therapeutic of exercise in reducing the risk of neuroinflammation-linked disorders.
MeSH Terms
- Aging
- Animals
- Fluorescent Antibody Technique
- Hippocampus
- Immunoassay
- Inflammation
- Interleukin-10
- Interleukin-1beta
- Interleukin-6
- Male
- Neuronal Plasticity
- Physical Conditioning, Animal
- Rats
- Rats, Wistar
- Tumor Necrosis Factor-alpha
Women, and those older than 65 years of age, are particularly susceptible to dry eye disorders (DEDs). Inflammation is clearly involved in the pathogenesis of DEDs, and there is mounting evidence on the antioxidant and antiinflammatory properties of essential polyunsaturated fatty acids (EPUFAs). To analyze whether a combined formulation of antioxidants and long-chain EPUFAs may improve the evolution of DEDs. We used a prospective study to address the relationship between risk factors, clinical outcomes, and expression levels of inflammation and immune response (IIR) mediators in human reflex tear samples. Participants included: (1) patients diagnosed with nonsevere DEDs (DED group [DEDG]); and (2) healthy controls (control group [CG]). Participants were randomly assigned to homogeneous subgroups according to daily oral intake ( S) or not (-NS) of antioxidants and long-chain EPUFAs for 3 months. After an interview and a systematized ophthalmic examination, reflex tears were collected simultaneously from both eyes; samples were later subjected to a multiplexed particle-based flow cytometry assay. A specific set of IIR mediators was analyzed. All data were statistically processed through the SPSS 15.0 software program. Significantly higher expressions of interleukin (IL)-1β, IL6, and IL10 and significantly lower vascular endothelial growth factor expressions were found in the DEDG as compared to the CG. In the DEDG, significant negative correlations were detected between the Schirmer test and IL-1β, IL6, IL8, and vascular endothelial growth factor levels, and between the fluorescein breakup time with IL6 and IL8 levels. However, levels of IL-1β, IL6, and IL10 in tears were significantly lower in the DEDG S versus the DEDG-NS and in the CG S versus the CG-NS. Subjective symptoms of dry eye significantly improved in the DEDG S versus the DEDG-NS. IIR mediators showed different expression patterns in DED patients, and these patterns changed in response to a combined formulation of antioxidant and EPUFAs supplementation. Our findings may be considered for future protocols integrating clinical/biochemical data to help manage DED patients.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Antioxidants
- Dietary Supplements
- Dry Eye Syndromes
- Fatty Acids, Omega-3
- Female
- Humans
- Inflammation Mediators
- Interleukin-10
- Interleukin-1beta
- Interleukin-6
- Male
- Middle Aged
- Prospective Studies
- Risk Factors
- Tears
- Vascular Endothelial Growth Factor A
Keywords
- aging
- cytokines
- essential polyunsaturated fatty acids
- nutraceutics
- tears
- women
High levels of inflammatory mediators are associated with reduced physical capabilities and muscle function in the elderly. Single nucleotide polymorphisms (SNPs) may affect the expression and synthesis of these molecules, thus influencing the intensity of the inflammatory response and susceptibility to certain diseases. Physical exercise may attenuate age-related chronic inflammation and improve physical performance. This study evaluated the interaction between the SNP rs1800629 in TNF-α, rs1800795 in IL6, and rs1800896 in IL10 and the effect of physical exercise on physical performance and inflammation in elderly women. There was a significant interaction between rs1800629 and the effect of exercise on physical performance and between the combined 3-SNP genotype and changes in physical performance in response to exercise. These SNPs did not influence the effect of exercise on inflammatory parameters. Elderly women with a combination of genotypes associated with an anti-inflammatory profile (low TNF-α and IL-6 production, high IL-10 production) showed better physical performance independent of exercise modality, evidence of an interactive influence of genetic and environmental factors on improving physical performance in elderly women.
MeSH Terms
- Aged
- Aging
- DNA
- Exercise Tolerance
- Female
- Genotype
- Humans
- Interleukin-10
- Interleukin-6
- Polymorphism, Genetic
- Tumor Necrosis Factor-alpha