scholarly journals Exercise Reduces H3K9me3 and Regulates Brain Derived Neurotrophic Factor and GABRA2 in an Age Dependent Manner

2021 ◽  
Vol 13 ◽  
Author(s):  
Andra Ionescu-Tucker ◽  
Christopher W. Butler ◽  
Nicole C. Berchtold ◽  
Dina P. Matheos ◽  
Marcelo A. Wood ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neuronal Plasticity ◽  
Gaba Receptor ◽  
Receptor Expression ◽  
Aging Brain ◽  
Dependent Manner ◽  
Promoter Regions ◽  
Aged Mice ◽  
Age Dependent ◽  
Young Mice

Exercise improves cognition in the aging brain and is a key regulator of neuronal plasticity genes such as BDNF. However, the mechanism by which exercise modifies gene expression continues to be explored. The repressive histone modification H3K9me3 has been shown to impair cognition, reduce synaptic density and decrease BDNF in aged but not young mice. Treatment with ETP69, a selective inhibitor of H3K9me3’s catalyzing enzyme (SUV39H1), restores synapses, BDNF and cognitive performance. GABA receptor expression, which modulates BDNF secretion, is also modulated by exercise and H3K9me3. In this study, we examined if exercise and ETP69 regulated neuronal plasticity genes by reducing H3K9me3 at their promoter regions. We further determined the effect of age on H3K9me3 promoter binding and neuronal plasticity gene expression. Exercise and ETP69 decreased H3K9me3 at BDNF promoter VI in aged mice, corresponding with an increase in BDNF VI expression with ETP69. Exercise increased GABRA2 in aged mice while increasing BDNF 1 in young mice, and both exercise and ETP69 reduced GABRA2 in young mice. Overall, H3K9me3 repression at BDNF and GABA receptor promoters decreased with age. Our findings suggest that exercise and SUV39H1 inhibition differentially modulate BDNF and GABRA2 expression in an age dependent manner.

Loss of miR-83 extends lifespan and affects target gene expression in an age-dependent manner in Caenorhabditis elegans

2018 ◽  
Vol 45 (12) ◽  
pp. 651-662 ◽  
Author(s):  
Emmanuel Enoch Dzakah ◽  
Ahmed Waqas ◽  
Shuai Wei ◽  
Bin Yu ◽  
Xiaolin Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Caenorhabditis Elegans ◽  
Target Gene ◽  
Dependent Manner ◽  
Target Gene Expression ◽  
Age Dependent

scholarly journals Age-dependent differences in microglial responses to systemic inflammation are evident as early as middle age

2016 ◽  
Vol 48 (5) ◽  
pp. 336-344 ◽  
Author(s):  
Maria Nikodemova ◽  
Alissa L. Small ◽  
Rebecca S. Kimyon ◽  
Jyoti J. Watters
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Systemic Inflammation ◽  
Middle Age ◽  
Middle Aged ◽  
Aged Mice ◽  
Lps Challenge ◽  
Age Dependent ◽  
Proinflammatory Responses

Whereas age increases microglial inflammatory activities and impairs their ability to effectively regulate their immune response, it is unclear at what age these exaggerated responses begin. We tested the hypotheses that augmented microglial responses to inflammatory challenge are present as early as middle age and that repeated stimulation of primed microglia in vivo would reveal microglial senescence. Microglial gene expression was investigated in a mouse model of repeated systemic inflammation induced by intraperitoneal injection of bacterial lipopolysaccharide (LPS). Following LPS, microglia from middle-aged mice (9–10 mo) displayed larger increases in Tnfα, Il-6, and Il-1β gene expression compared with young adults (2 mo). Similar results were observed in the spleens of middle-aged mice, indicating that exaggeration of both central and peripheral immune responses are already evident at early middle age. Interestingly, despite greater proinflammatory responses to the first LPS challenge in the aged mice, there were no age-dependent differences in either microglia or spleen following a subsequent LPS dose, suggesting that animals at this age retain the ability to effectively control their immune response following repeated challenge. The exacerbated microglial immune response to systemic inflammation at early middle age suggests that the CNS may be vulnerable to age-dependent alterations earlier than previously appreciated.

scholarly journals Integrated analysis of the aging brain transcriptome and proteome in tauopathy

2020 ◽  
Author(s):  
Carl Grant Mangleburg ◽  
Timothy Wu ◽  
Hari K. Yalamanchili ◽  
Caiwei Guo ◽  
Yi-Chen Hsieh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Human Brain ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Differentially Expressed ◽  
Integrated Analysis ◽  
Aging Brain ◽  
Brain Gene Expression ◽  
Brain Transcriptome ◽  
Age Dependent

AbstractBackgroundTau neurofibrillary tangle pathology characterizes Alzheimer’s disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes.MethodsPaired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (TauWT) or a mutation causing frontotemporal dementia (TauR406W). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy.ResultsTauWT induced 1,514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5,494 transcripts and 697 proteins. There was a ~70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation, despite the absence of microglia in flies. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes.ConclusionsOur results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.

scholarly journals A novel murine model of multi-day moderate ethanol exposure reveals increased intestinal dysfunction and liver inflammation with age

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Rachel H McMahan ◽  
Kevin M Najarro ◽  
Juliet E Mullen ◽  
Madison T Paul ◽  
David J Orlicky ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alcohol Use ◽  
Murine Model ◽  
Ethanol Exposure ◽  
Alcoholic Beverages ◽  
Liver Inflammation ◽  
Aged Mice ◽  
Increased Risk ◽  
Junction Protein ◽  
Young Mice

Abstract Background There are currently > 600 million people over the age of 65 globally and this number is expected to double by the year 2050. Alcohol use among this population is on the rise, which is concerning as aging is associated with increased risk for a number of chronic illnesses. As most studies investigating the effects of alcohol have focused on young/middle-aged populations, there is a dearth of information regarding the consequences of alcohol use in older consumers. In addition, most murine ethanol models have concentrated on exposure to very high levels of ethanol, while the vast majority of elderly drinkers do not consume alcohol in excess; instead, they drink on average 2 alcoholic beverages a day, 3–4 days a week. Methods We designed a murine model of aging and moderate ethanol consumption to determine if the deleterious effects of alcohol on the gut-liver axis are exacerbated in aged, relative to younger, animals. Aged and young mice were exposed to a multi-day moderate exposure ethanol regimen for 4 weeks and changes in gut permeability along with intestinal tight junction protein and antimicrobial peptide gene expression were measured. In addition, hepatic inflammation was assessed by histological analysis, inflammatory gene expression and flow cytometric analysis of inflammatory infiltrate. Results Our results reveal that in aged, but not young mice, moderate ethanol exposure yielded significantly worsened intestinal permeability, including increased bacterial translocation from the gut, elevated serum iFABP and leakage of FITC-dextran from the gut. Interestingly, moderate ethanol exposure in young animals led to gut protective transcriptional changes in the ileum while this protective response was blunted in aged mice. Finally, moderate ethanol exposure in aged mice also resulted in marked inflammatory changes in the liver. Conclusions These results demonstrate that aged mice are more susceptible to ethanol-induced gut barrier dysfunction and liver inflammation, even at moderate doses of ethanol. This increased vulnerability to ethanol’s gastrointestinal effects has important implications for alcohol use in the aging population. Future studies will explore whether improving intestinal barrier function can reverse these age-related changes.

scholarly journals Increased coagulation and suppressed generation of activated protein C in aged mice during intra-abdominal sepsis

2015 ◽  
Vol 308 (2) ◽  
pp. H83-H91 ◽  
Author(s):  
Marlene E. Starr ◽  
Hitoshi Takahashi ◽  
Daiki Okamura ◽  
Brittany A. Zwischenberger ◽  
Amy A. Mrazek ◽  
...  
Keyword(s):  
Protein C ◽  
Cecal Ligation ◽  
Activated Protein C ◽  
Abdominal Sepsis ◽  
Activation Mechanism ◽  
Experimental Sepsis ◽  
Enhanced Coagulation ◽  
Aged Mice ◽  
Age Dependent ◽  
Young Mice

Sepsis is a life-threatening clinical condition that is particularly serious among the elderly who experience considerably higher mortality rates compared with younger patients. Using a sterile endotoxemia model, we previously reported age-dependent mortality in conjunction with enhanced coagulation and insufficient levels of anti-coagulant factor activated protein C (aPC). The purpose of the present study was to further investigate the mechanisms for age-dependent coagulation and aPC insufficiency during experimental sepsis. Intra-abdominal sepsis was induced by cecal ligation and puncture (CLP) using 21 or 16 gauge (G) needles (double-puncture) on young (4 to 6 mo old) and aged (20 to 25 mo old) male C57BL/6 mice. When compared with young mice, aged mice showed significantly increased mortality (92% vs. 28%), systemic inflammation, and coagulation in the lung and kidney after 21G CLP. Young mice with more severe CLP (16G) showed a mortality rate and inflammation equivalent to aged mice with 21G CLP; however, enhanced coagulation and kidney dysfunction were significant only in the aged. In young mice, increased levels of aPC after CLP were coupled with reduced levels of protein C (PC), suggesting the conversion of PC to aPC; however, PC and aPC levels remained unchanged in aged mice, indicating a lack of PC to aPC conversion. Activation of fibrinolysis, determined by plasma d-dimer levels, was similar regardless of age or CLP severity, and plasminogen activator inhibitor-1, an inhibitor of fibrinolysis, showed severity-dependent induction independent of age. These results suggest that enhanced coagulation in aged mice during sepsis is due to dysfunction of the PC activation mechanism.

Vas deferens epithelial cells in subculture: a model to study androgen regulation of gene expression

1995 ◽  
Vol 15 (2) ◽  
pp. 129-141 ◽  
Author(s):  
A Dassouli ◽  
Ch Darne ◽  
S Fabre ◽  
M Manin ◽  
G Veyssière ◽  
...  
Keyword(s):  
Gene Expression ◽  
Androgen Receptor ◽  
Epithelial Cells ◽  
Vas Deferens ◽  
Regulatory Elements ◽  
Receptor Expression ◽  
Time Dependent ◽  
Dependent Manner ◽  
Regulated Gene Expression ◽  
Cat Gene

ABSTRACT The understanding of androgen-regulated gene expression requires a cell culture system that mimics the functions of cells in vivo. In the present paper we have examined a vas deferens epithelial cell subculture system. Cultured vas deferens epithelial cells have been shown to exhibit polarized properties characteristic of functioning epithelia and to display a high level of androgen receptors. Incubation of cells with androgen caused a decrease in cellular androgen receptor mRNA that was time-dependent. Total suppression was observed after 24 h of exposure to androgen. By contrast, incubation of vas deferens epithelial cells with androgen resulted in a threefold increase in the cellular content of androgen receptor protein, as assayed by ligand binding. In response to androgens, vas deferens epithelial cells expressed mouse vas deferens protein mRNA (MVDP mRNA). Maximum expression of the MVDP gene, at both mRNA and protein levels, was observed after 24 h of androgen induction. DEAE-dextran transfection conditions were defined using the MMTV-CAT vector. Dihydrotestosterone stimulated the transcription activation of MMTV-CAT gene in vas deferens epithelial cells in a dose- and time-dependent manner. No induction was seen when fragments of the MVDP promoter region were cloned directly in front of the CAT gene and transiently transfected into vas deferens epithelial cells. It was found that cotransfection of cells with MVDP-CAT constructs and with an androgen receptor expression vector resulted in a small but consistent androgen-dependent increase in reporter gene activity. Transiently transfected vas deferens epithelial cells are a suitable model with which to study the effect of androgen on gene regulatory elements.

Age-dependent hypothalamic expression of neuropeptides in wild-type and melanocortin-4 receptor-deficient mice

2003 ◽  
Vol 16 (1) ◽  
pp. 38-46 ◽  
Author(s):  
Janine Arens ◽  
Kim M. Moar ◽  
Sandra Eiden ◽  
Karin Weide ◽  
Ingrid Schmidt ◽  
...  
Keyword(s):  
Body Fat ◽  
Fat Content ◽  
Wild Type ◽  
Middle Aged ◽  
Aged Mice ◽  
Melanocortin 4 Receptor ◽  
Body Fat Content ◽  
Age Dependent ◽  
Deficient Mice ◽  
Young Mice

In young (35- to 56-day-old) and middle-aged (9-mo-old) wild-type (+/+) and melanocortin-4 receptor (MC4R)-deficient (+/−, −/−) mice, expressions of neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin (POMC), and cocaine-and-amphetamine-regulated transcript (CART) were analyzed in the arcuate nucleus (ARC) and adjacent regions comprising the dorsomedial (DMN) and ventromedial (VMN) nucleus. In the ARC of young mice, NPY and AGRP expression increased and POMC and CART expression decreased with body fat content. Adjusting for the influence of body fat content by ANCOVA showed that the levels of NPY, POMC, and CART were highest and of AGRP lowest in young −/− mice. In the middle-aged mice, feedback from body fat content was weakened. For −/− mice ANCOVA revealed higher NPY and AGRP, lower POMC, and unchanged CART expression levels relative to young −/− mice. In the DMN and VMN, POMC and AGRP signals were absent at each age. CART was expressed in the DMN independent of age, fat content, and genotype. For NPY expression, an age-dependent induction was found in the DMN and VMN; it was absent in the young but present in the middle-aged mice, showing close positive correlations between body fat content and the numbers of NPY-labeled cells which were further enhanced in −/− mice. Thus MC4R deficiency augments age-induced NPY expression in the DMN and VMN with no feedback from body fat content. Negative feedback control by body fat content on ARC neuropeptide expression is present in young animals but vanishes with age and is modulated by MC4R deficiency.

scholarly journals The Influence of Orally Administered N-Docosahexanoylethanolamine (Synaptamide) on Cognitive Function in Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1216-1216
Author(s):  
Sasuke Kimura ◽  
Eri Nakazaki ◽  
Aya Miyamoto ◽  
Yukihiro Hishida ◽  
Tetsuro Ujihara ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cognitive Function ◽  
Oral Administration ◽  
Memory Formation ◽  
Normal Brain ◽  
Dependent Manner ◽  
Aged Mice ◽  
Icr Mice ◽  
Maze Test ◽  
Y Maze

Abstract Objectives Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is essential for normal brain development and cognitive function, and also consumed as a dietary supplement in worldwide. Recently, N-Docosahexanoylethanolamine (synaptamide) has been reported as an endocannabinoid-like metabolite endogenously synthesized from DHA, which produces neuritogenic and synaptogenic effects in vitro studies. These suggest synaptamide plays crucial roles in brain function and can be a novel dietary intervention to prevent cognitive dysfunction. The purpose of this study was to investigate how orally administered synaptamide act on cognitive function in mice. Methods: Exp1. Male ICR mice were oral ingested synaptamide (100 or 500 mg/kg body weight (BW) and measured synaptamide concentration in blood flow. Exp2. Male ICR mice at 4 weeks of age, and male C57BL/6 J mice at 54 weeks of age were orally administered vehicle (corn oil), or synaptamide (100 or 500 mg/kg BW) for 4 weeks. After that, we performed the Y-maze test and Object Recognition test (ORT) to evaluate cognitive function. Only ICR mice were intraperitoneally injected scopolamine just before 30 minutes performing Y-maze test or ORT. Hippocampal gene expression was analyzed by qPCR, and hippocampal phosphoprotein profiles were analyzed using the Phospho Explorer Antibody Array. Results Synaptamide level in plasma was increased by oral administration of synaptamide. Behavioral performance in the Y-maze test were comparable irrespective of administration. On the other hand, in the ORT, synaptamide-administered mice spent significantly more time exploring the novel object compared to familiar object in a dose dependent manner, while control mice did not discriminate between the objects. Furthermore, in hippocampus from aged mice administered synaptamide, expression of PSS2 gene was increased and several phosphoprotein profiles modification involved in inflammatory signal such as Nf-κB were observed. Conclusions We found that oral administration of synaptamide ameliorates cognitive function in scopolamine-administered mice and aged mice, and increases PSS2 gene expression which is involved in memory formation, in hippocampus of aged mice. Our results suggest that supplementation with synaptamide could improve hippocampal-dependent memory formation. Funding Sources Kyowa Hakko Bio Co., Ltd.

scholarly journals Genomic Analysis Reveals Age-Dependent Innate Immune Responses to Severe Acute Respiratory Syndrome Coronavirus

2008 ◽  
Vol 82 (19) ◽  
pp. 9465-9476 ◽  
Author(s):  
Tracey Baas ◽  
Anjeanette Roberts ◽  
Thomas H. Teal ◽  
Leatrice Vogel ◽  
Jun Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Host Response ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genomic Analysis ◽  
Host Responses ◽  
Aged Mice ◽  
Young Mice

ABSTRACT The relationship between immunosenescence and the host response to virus infection is poorly understood at the molecular level. Two different patterns of pulmonary host responses to virus were observed when gene expression profiles from severe acute respiratory syndrome coronavirus (SARS-CoV)-infected young mice that show minimal disease were compared to those from SARS-CoV-infected aged mice that develop pneumonitis. In young mice, genes related to cellular development, cell growth, and cell cycle were downregulated during peak viral replication, and these transcripts returned to basal levels as virus was cleared. In contrast, aged mice had a greater number of upregulated immune response and cell-to-cell signaling genes, and the expression of many genes was sustained even after viral clearance, suggesting an exacerbated host response to virus. Interestingly, in SARS-CoV-infected aged mice, a subset of genes, including Tnfa, Il6, Ccl2, Ccl3, Cxcl10, and Ifng, was induced in a biphasic pattern that correlated with peak viral replication and a subsequent influx of lymphocytes and severe histopathologic changes in the lungs. We provide insight into gene expression profiles and molecular signatures underlying immunosenescence in the context of the host response to viral infection.

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