IL10
Interleukin-10 precursor (IL-10) (Cytokine synthesis inhibitory factor) (CSIF)
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Old age is associated with a loss of motor functions and a general progressive decline in cognitive functions. Physical exercise is one of the ways in which inflammatory levels in general can be reduced, and therefore physical exercise can be considered a biological aging decelerator. In this article we examine the relationships between physical exercise and inflammatory markers reported for the different physical exercise protocols that have been used in studies with older individuals, as well as the effects of these regimens. The different types of exercises programmed, and methods used to implement them were very heterogeneous in the articles we analysed. Both, the aerobic exercise and resistance training protocols produced a decrease in plasma levels of IL-6, CRP and TNF-α, and an increase of IL10 plasma levels as a chronic effect. However, the acute-response of physical exercise appeared to be an initial increase in IL-6 expression and plasma IL-6 levels. Continuing with these exercise programs usually subsequently achieved a chronic response in which there was a decrease in both the basal levels of IL-6, CRP and TNF-α, and the IL-6 produced as acute responses. Regardless of the type of exercise performed, it seems that the exercise parameters, intensity, duration, subject variables, fitness, and level of inflammation are key factors in achieving the expected balance between pro-inflammatory and antiinflammatory cytokines.
Keywords
- IL-6 expression
- Inflammatory markers
- aerobic exercise
- aging
- plasma IL-6 levels
- resistance training
The accumulation of senescent cells in tissues is causally linked to the development of several age-related diseases; the removal of senescent glial cells in animal models prevents Tau accumulation and cognitive decline. Senescent cells can arise through several distinct mechanisms; one such mechanism is dysregulation of alternative splicing. In this study, we characterised the senescent cell phenotype in primary human astrocytes in terms of SA-β-Gal staining and SASP secretion, and then assessed splicing factor expression and candidate gene splicing patterns. Finally, we assessed associations between expression of dysregulated isoforms and premature cognitive decline in 197 samples from the InCHIANTI study of ageing, where expression was present in both blood and brain. We demonstrate here that senescent astrocytes secrete a modified SASP characterised by increased IL8, MMP3, MMP10, and TIMP2 but decreased IL10 levels. We identified significant changes in splicing factor expression for 10/20 splicing factors tested in senescent astrocytes compared with early passage cells, as well as dysregulation of isoform levels for 8/13 brain or senescence genes tested. Finally, associations were identified between peripheral blood GFAPα, TAU3, and [[CDKN2A]] (P14 ) isoform levels and mild or severe cognitive decline over a 3-7-year period. Our data are suggestive that some of the features of cognitive decline may arise from dysregulated splicing of important genes in senescent brain support cells, and that defects in alternative splicing or splicing regulator expression deserve exploration as points of therapeutic intervention in the future.
MeSH Terms
- Aged
- Alternative Splicing
- Astrocytes
- Cells, Cultured
- Cellular Senescence
- Cognitive Dysfunction
- Cytokines
- Gene Expression
- Glial Fibrillary Acidic Protein
- Humans
- Matrix Metalloproteinases
- Transcription, Genetic
- Tumor Suppressor Protein p14ARF
- tau Proteins
Keywords
- Alternative splicing
- Gene expression
- Neurodegenerative disease
- Senescence
Aging is characterized by chronic, low-grade inflammation that correlates with cognitive decline. Dietary supplementation with spray-dried porcine plasma (SDP) reduces immune activation in rodent models of inflammation and aging. We investigated whether the anti-inflammatory properties of SDP could ameliorate age-related cognitive deterioration and preserve brain homeostasis in an aging mouse model of senescence. Male senescence-accelerated prone 8 (SAMP8) mice were used. In Experiment 1, cognitive performance (n = 10-14 mice/group) was analyzed by the novel object recognition test in 2-mo-old mice (2M group) and in mice fed a control diet or a diet supplemented with 8% SDP for 2 (4M-CTL and 4M-SDP groups) and 4 mo (6M-CTL and 6M-SDP groups). In Experiment 2, the permeability of the blood-brain barrier and junctional proteins in brain tissue was assessed, as well as synaptic density, oxidative stress markers, and inflammatory genes and proteins in mice from the 2M, 6M-CTL, and 6M-SDP groups ( n = 5-11). Statistical analyses included one-factor ANOVA followed by Fisher's posthoc test. 6M-SDP mice had better cognitive performance than 6M-CTL mice in both short-term (P = 0.024) and long-term (P = 0.017) memory tests. In brain tissue, 6M-SDP mice showed reduced brain capillary permeability (P = 0.034) and increased ZO1 and E-cadherin expression (both P <0.04) compared with 6M-CTL mice. SDP also prevented the NFκB activation observed in 6M-CTL mice (P = 0.002) and reduced Il6 expression and hydrogen peroxide concentration (both P <0.03) observed in 6M-CTL mice. SDP also increased the concentration of IL10 (P = 0.027), an anti-inflammatory cytokine correlated with memory preservation. In senescent SAMP8 mice, dietary supplementation with SDP attenuated cognitive decline and prevented changes in brain markers of neuroinflammation and oxidative stress.
MeSH Terms
- Animals
- Cognition Disorders
- Encephalitis
- Male
- Mice
- Oxidative Stress
- Plasma
- Swine
Keywords
- aging
- cognitive decline
- dietary supplementation
- neuroinflammation
- spray-dried animal plasma
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
Sarcopenia is a common impairment in the elderly population responsible for poor outcomes later in life; it can be caused by age-related alternations. Only a few strategies have been reported to reduce sarcopenia. [i]Lactobacillus paracasei[/i] PS23 (LPPS23) has been reported to delay some age-related disorders. Therefore, here we investigated whether LPPS23 decelerates age-related muscle loss and its underlying mechanism. Female senescence-accelerated mouse prone-8 (SAMP8) mice were divided into three groups (n=6 each): non-aging (16-week-old), control (28-week-old), and PS23 (28-week-old) groups. The control and PS23 groups were given saline and LPPS23, respectively. We evaluated the effects of LPPS23 by analyzing body weight and composition, muscle strength, protein uptake, mitochondrial function, reactive oxygen species (ROS), antioxidant enzymes, and inflammation-related cytokines. LPPS23 significantly attenuated age-related decreases of muscle mass and strength. Compared to the control group, the non-aging and PS23 groups exhibited higher mitochondrial function, IL10, antioxidant enzymes, and protein uptake. Moreover, inflammatory cytokines and ROS were lower in the non-aging and PS23 groups than the control group. Taken together, LPPS23 extenuated sarcopenia progression during aging; this effect might have been enacted by preserving the mitochondrial function via reducing age-related inflammation and ROS and by retaining protein uptake in the SAMP8 mice.
MeSH Terms
- Aging
- Animals
- Body Composition
- Body Weight
- Cytokines
- Dietary Proteins
- Digestion
- Feces
- Gene Expression Regulation
- Inflammation
- Lactobacillus paracasei
- Mice
- Mice, Inbred Strains
- Mitochondria
- Oxidative Stress
- Probiotics
- Sarcopenia
Keywords
- PS23 Lactobacillus paracasei
- age-related inflammation
- mitochondrial function
- protein uptake
- sarcopenia
Aging is characterized with immunosenescence associated with a hyper-inflammatory state, characterized by elevated circulating levels of pro-inflammatory mediators. Physical exercise is a potential strategy for improving the immune system dysfunction and chronic inflammation that accompanies aging. However, there is a need to differentiate between aerobic and resistance exercise training regarding human immune system and systemic inflammation among the elderly Saudi population. The aim of this study was to compare the impact of 6 months of aerobic versus resisted exercise training on inflammatory cytokines and immune system response among elderly. Sixty previously sedentary elderly subjects participated in this study, their age ranged from 61-66 years. All Subjects were randomly assigned to supervised aerobic exercise intervention group (group A, n=40) or resistance exercise group (group B, n=40). Number of CD3 ,CD4 ,CD8 T cells count and CD4/CD8 ratio were quantified, IL-6, TNF-α and IL10 were measured before and after 6 months, at the end of the study. The mean values of CD3 , CD4 and CD8 T cells count and IL-10 were significantly increased, whereas the mean values of CD4/CD8 ratio, IL-6 and TNF-α were significantly decreased in group (A) and group (B). Also; there were significant differences between mean levels of the investigated parameters in group (A) and group (B) after treatment. The current study provides evidence that aerobic exercise is more appropriate in modulating the immune system and inflammatory markers among the elderly population.
MeSH Terms
- Adult
- Aged
- Aging
- Biomarkers
- Cytokines
- Exercise
- Female
- Humans
- Immune System
- Inflammation
- Inflammation Mediators
- Interleukin-10
- Male
- Middle Aged
- Resistance Training
- Saudi Arabia
- Treatment Outcome
- Tumor Necrosis Factor-alpha
Keywords
- Immune function
- aerobic exercise
- aging
- inflammatory cytokines
- resistance exercise
Neonatal inflammation, mediated in part through Toll-like receptor (TLR) and inflammasome signaling, contributes to adverse outcomes including organ injury. Pentoxifylline (PTX), a phosphodiesterase inhibitor which potently suppresses cytokine production in newborn cord blood, is a candidate neonatal anti-inflammatory agent. We hypothesized that combinations of PTX with other anti-inflammatory agents, the steroid dexamethasone (DEX) or the macrolide azithromycin (AZI), may exert broader, more profound and/or synergistic anti-inflammatory activity towards neonatal TLR- and inflammasome-mediated cytokine production. Whole newborn and adult blood was treated with PTX (50-200 μM), DEX (10-10-10-7 M), or AZI (2.5-20 μM), alone or combined, and cultured with lipopolysaccharide (LPS) (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/adenosine triphosphate (ATP) (inflammasome induction). Supernatant and intracellular cytokines, signaling molecules and mRNA were measured by multiplex assay, flow cytometry and real-time PCR. Drug interactions were assessed based on Loewe's additivity. PTX, DEX and AZI inhibited TLR- and/or inflammasome-mediated cytokine production in newborn and adult blood, whether added before, simultaneously or after TLR stimulation. PTX preferentially inhibited pro-inflammatory cytokines especially TNF. DEX inhibited IL-10 in newborn, and TNF, IL-1β, IL-6 and interferon-α in newborn and adult blood. AZI inhibited R848-induced TNF, IL-1β, IL-6 and IL-10, and LPS-induced IL-1β and IL-10. (PTX DEX) synergistically decreased LPS- and LPS/ATP-induced TNF, IL-1β, and IL-6, and R848-induced IL-1β and interferon-α, while (PTX AZI) synergistically decreased induction of TNF, IL-1β, and IL-6. Synergistic inhibition of TNF production by (PTX DEX) was especially pronounced in newborn vs. adult blood and was accompanied by reduction of TNF mRNA and enhancement of IL10 mRNA. Age, agent, and specific drug-drug combinations exert distinct anti-inflammatory effects towards TLR- and/or inflammasome-mediated cytokine production in human newborn blood in vitro. Synergistic combinations of PTX, DEX and AZI may offer benefit for prevention and/or treatment of neonatal inflammatory conditions while potentially limiting drug exposure and toxicity.
MeSH Terms
- Adolescent
- Adult
- Aging
- Anti-Inflammatory Agents
- Azithromycin
- Caspase 1
- Cytokines
- Dexamethasone
- Drug Synergism
- Dual Specificity Phosphatase 1
- Enzyme Activation
- Female
- Gene Expression Regulation
- Humans
- Infant, Newborn
- Inflammasomes
- Middle Aged
- Mitogen-Activated Protein Kinases
- Monocytes
- NF-kappa B
- Pentoxifylline
- Pregnancy
- RNA, Messenger
- Signal Transduction
- Toll-Like Receptors
- Young Adult
Protein tyrosine phosphatase PTP1B is a critical regulator of signaling pathways controlling metabolic homeostasis, cell proliferation, and immunity. In this study, we report that global or myeloid-specific deficiency of PTP1B in mice decreases lifespan. We demonstrate that myeloid-specific deficiency of PTP1B is sufficient to promote the development of acute myeloid leukemia. LysM-PTP1B mice lacking PTP1B in the innate myeloid cell lineage displayed a dysregulation of bone marrow cells with a rapid decline in population at midlife and a concomitant increase in peripheral blood blast cells. This phenotype manifested further with extramedullary tumors, hepatic macrophage infiltration, and metabolic reprogramming, suggesting increased hepatic lipid metabolism prior to overt tumor development. Mechanistic investigations revealed an increase in anti-inflammatory M2 macrophage responses in liver and spleen, as associated with increased expression of arginase I and the cytokines IL10 and IL4. We also documented STAT3 hypersphosphorylation and signaling along with JAK-dependent upregulation of antiapoptotic proteins Bcl2 and BclXL. Our results establish a tumor suppressor role for PTP1B in the myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. This study defines a tumor suppressor function for the protein tyrosine phosphatase PTP1B in myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. [i]Cancer Res; 78(1); 75-87. ©2017 AACR[/i].
MeSH Terms
- Animals
- Cytokines
- Female
- Leukemia, Myeloid, Acute
- Liver
- Longevity
- Macrophages
- Male
- Mice, Knockout
- Myeloid Cells
- Protein Tyrosine Phosphatase, Non-Receptor Type 1
- Proto-Oncogene Proteins c-bcl-2
- Pyrazoles
- STAT3 Transcription Factor
- STAT5 Transcription Factor
- Spleen
- bcl-X Protein
Women are living longer than men and it seems that one of the reasons could be better immune system of females. In Poland, contrary to many European countries, women retire earlier than men, namely at 60 and 65, respectively. We asked the question how the gender and labour status were interconnected with some immunological parameters included in the so called immune risk profile (IRP), such as CD4 /CD8 ratio, percentage of CD8 CD28-, and NK, and the level of circulating cytokines. A total of 92 men and 100 women past the retirement age, namely 65-74 years old, still working or not, were examined. We have found statistically significant lower percentage of CD8 CD28- cells and non-statistically significant higher CD4 /CD8 ratio in women, whereas the percentage of NK was higher in men. Moreover, the percentage of CD8 CD28- cells was negatively correlated with the CD4 /CD8 ratio and the concentration of IL8 was positively correlated with the concentration of IL10 both in men and women. In men, the level of IL10 was higher than in women. Altogether, we found that gender, but not labour status, influences immunosenescence of the examined population of 65-74 years old Polish people.
MeSH Terms
- Age Factors
- Aged
- Aging
- CD28 Antigens
- CD4-CD8 Ratio
- CD4-Positive T-Lymphocytes
- CD8-Positive T-Lymphocytes
- Employment
- Female
- Humans
- Immunosenescence
- Interleukin-10
- Interleukin-8
- Killer Cells, Natural
- Male
- Retirement
- Sex Factors
Keywords
- CD8 CD28−
- Human ageing
- IL10
- IL8
- Immune risk profile
- T-cells
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
Macrophage dysfunction plays a pivotal role during neovascular proliferation in diseases of ageing including cancers, atherosclerosis and blinding eye disease. In the eye, choroidal neovascularization (CNV) causes blindness in patients with age-related macular degeneration (AMD). Here we report that increased IL10, not IL4 or IL13, in senescent eyes activates STAT3 signalling that induces the alternative activation of macrophages and vascular proliferation. Targeted inhibition of both IL10 receptor-mediated signalling and STAT3 activation in macrophages reverses the ageing phenotype. In addition, adoptive transfer of STAT3-deficient macrophages into eyes of old mice significantly reduces the amount of CNV. Systemic and CD163( ) eye macrophages obtained from AMD patients also demonstrate STAT3 activation. Our studies demonstrate that impaired SOCS3 feedback leads to permissive IL10/STAT3 signalling that promotes alternative macrophage activation and pathological neovascularization. These findings have significant implications for our understanding of the pathobiology of age-associated diseases and may guide targeted immunotherapy.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Animals
- Eye
- Female
- Humans
- Interleukin-10
- Macrophages
- Macular Degeneration
- Male
- Mice
- Mice, Inbred C57BL
- Middle Aged
- Neovascularization, Pathologic
- Porphyrins
- RAW 264.7 Cells
- Receptors, Interleukin-10
- STAT3 Transcription Factor
- Suppressor of Cytokine Signaling 3 Protein
- Suppressor of Cytokine Signaling Proteins
Hip fracture is a common physical trauma in older adults that is also associated with a high incidence of new onset depression. The immune system declines with age and is also compromised by physical and psychological stress. This study examined whether hip fracture and depressive symptoms had additive effects upon the aged immune system that might contribute to poor health outcomes after hip fracture. We assessed the frequency of regulatory T cells, Tregs (CD4( ) CD25( ) Foxp3( )) and IL10 production by CD4 T cells, and the frequency and IL10 production by regulatory B cells, Bregs (CD19( ) CD24(hi) CD38(hi)) in 101 hip fracture patients (81 female) 6 weeks after injury and 43 healthy age-matched controls (28 female). 38 hip fracture patients (37%) developed depressive symptoms. Hip fracture did not have an effect on circulating Tregs frequency but a significant reduction in the frequency of Bregs was observed in patients who developed depression compared with non-depressed patients (p = 0.001) or healthy controls (p < 0.001). Bregs also showed a significant decline in IL10 production in depressed hip fracture patients compared with controls (p = 0.04) and non-depressed patients (p = 0.01). In contrast, there was an increase in IL10 production by CD4 T cells in hip fracture patients with new onset depression compared to hip fracture patients without depression (p = .04) and healthy controls (p = .02). We conclude that the reduced immunity associated with new onset depression post hip fracture could include a contribution by heightened Tregs function.
MeSH Terms
- Adaptive Immunity
- Aged
- Aged, 80 and over
- Aging
- B-Lymphocytes
- Cytokines
- Depression
- Female
- Hip Fractures
- Humans
- Immune Tolerance
- Immunosenescence
- Male
- Middle Aged
- T-Lymphocytes, Regulatory
Keywords
- Depression
- Hip fracture
- Immunesenescence
- Regulatory B cell
- Regulatory T cell
- Stress
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
Astaxanthin (Ax) is a ketocarotenoid of the xanthophyll family with activities such as antioxidation, preservation of the integrity of cell membranes and protection of the redox state and functional integrity of mitochondria. The aim of this study was to investigate potential gender-related differences in the effect of Ax on the aging rat brain. In females, interleukin 1 beta (IL1β) was significantly lower in treated rats in both cerebral areas, and in the cerebellum, treated animals also had significantly higher IL10. In males, no differences were found in the cerebellum, but in the hippocampus, IL1β and IL10 were significantly higher in treated rats. These are the first results to show gender-related differences in the effect of Ax on the aging brain, emphasizing the necessity to carefully analyze female and male peculiarities when the anti-aging potentialities of this ketocarotenoid are evaluated. The observations lead to the hypothesis that Ax exerts different anti-inflammatory effects in female and male brains.
MeSH Terms
- Aging
- Animals
- Brain
- Brain Chemistry
- Cerebellum
- Female
- Hippocampus
- Inflammation
- Interleukin-10
- Interleukin-1beta
- Male
- Rats
- Rats, Wistar
- Sex Characteristics
- Xanthophylls
Keywords
- aging
- astaxanthin
- brain
- gender
- inflammation
Optimism and resilience promote health and well-being in older adults, and previous reports suggest that these traits are heritable. We examined the association of selected single-nucleotide polymorphisms (SNPs) with optimism and resilience in older adults. Candidate gene association study that was a follow-on at the University of California, San Diego, sites of two NIH-funded multi-site longitudinal investigations: Women's Health Initiative (WHI) and SELenium and vitamin E Cancer prevention Trial (SELECT). 426 women from WHI older than age 50 years, and 509 men older than age 55 years (age 50 years for African American men) from SELECT. 65 candidate gene SNPs that were judged by consensus, based on a literature review, as being related to predisposition to optimism and resilience, and 31 ancestry informative marker SNPs, genotyped from blood-based DNA samples and self-report scales for trait optimism, resilience, and depressive symptoms. Using a Bonferroni threshold for significant association (p = 0.00089), there were no significant associations for individual SNPs with optimism or resilience in single-locus analyses. Exploratory multi-locus polygenic analyses with p <0.05 showed an association of optimism with SNPs in MAOA, IL10, and FGG genes, and an association of resilience with a SNP in MAOA gene. Correcting for Type I errors, there were no significant associations of optimism and resilience with specific gene SNPs in single-locus analyses. Positive psychological traits are likely to be genetically complex, with many loci having small effects contributing to phenotypic variation. Our exploratory multi-locus polygenic analyses suggest that larger sample sizes and complementary approaches involving methods such as sequence-based association studies, copy number variation analyses, and pathway-based analyses could be useful for better understanding the genetic basis of these positive psychological traits.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Depression
- European Continental Ancestry Group
- Female
- Fibrinogens, Abnormal
- Genetic Association Studies
- Genotype
- Humans
- Interleukin-10
- Male
- Middle Aged
- Monoamine Oxidase
- Multifactorial Inheritance
- Personality
- Polymorphism, Single Nucleotide
- Resilience, Psychological
Keywords
- Optimism
- aging
- depression
- genotyping
- resilience
- single-nucleotide polymorphisms
Growing insight into the pathogenesis of type 1 diabetes (T1D) and numerous studies in preclinical models highlight the potential of antigen-specific approaches to restore tolerance efficiently and safely. Oral administration of protein antigens is a preferred method for tolerance induction, but degradation during gastrointestinal passage can impede such protein-based therapies, reducing their efficacy and making them cost-ineffective. To overcome these limitations, we generated a tolerogenic bacterial delivery technology based on live Lactococcus lactis (LL) bacteria for controlled secretion of the T1D autoantigen GAD65370-575 and the anti-inflammatory cytokine interleukin-10 in the gut. In combination with short-course low-dose anti-CD3, this treatment stabilized insulitis, preserved functional β-cell mass, and restored normoglycemia in recent-onset NOD mice, even when hyperglycemia was severe at diagnosis. Combination therapy did not eliminate pathogenic effector T cells, but increased the presence of functional CD4( )Foxp3( )CD25( ) regulatory T cells. These preclinical data indicate a great therapeutic potential of orally administered autoantigen-secreting LL for tolerance induction in T1D.
MeSH Terms
- Administration, Oral
- Aging
- Animals
- Autoantigens
- Diabetes Mellitus
- Forkhead Transcription Factors
- Gene Expression Regulation
- Glutamate Decarboxylase
- Interleukin-10
- Lactococcus lactis
- Mice
- Mice, Inbred NOD
- Peptide Fragments
- T-Lymphocytes, Regulatory
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
Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of IL10. In humans, immature transitional B cells with a CD19( ) CD24(hi) CD38(hi) phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19( ) CD24(hi) CD38(hi) cells were reduced in the PBMC pool with age. IL10 expression and secretion following activation via either CD40, or Toll-like receptors was also impaired in CD19( ) CD24(hi) CD38(hi) B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19( ) CD24(hi) CD38(hi) B-cell function was compromised by age-related effects on both T cells and B cells: specifically, CD40 ligand expression was lower in CD4 T cells from older donors following CD3 stimulation, and signalling through CD40 was impaired in CD19( ) CD24(hi) CD38(hi) B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of STAT3. However, there was no age-associated change in expression of costimulatory molecules CD80 and CD86 on CD19( ) CD24(hi) CD38(hi) cells, suggesting IL10-dependent immune suppression is impaired, but contact-dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19( ) CD24(hi) CD38(hi) B-cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19( ) CD24(hi) CD38(hi) B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Antigens, CD
- Autoimmunity
- B-Lymphocytes
- Cell Differentiation
- Female
- Humans
- Male
- Middle Aged
- Signal Transduction
- Young Adult
Keywords
- B cells
- autoimmunity
- cellular immunology
- inflammation
- rheumatoid factor
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