scholarly journals Stroke Induces a BDNF-Dependent Improvement in Cognitive Flexibility in Aged Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Josh Houlton ◽  
Lisa Y. Y. Zhou ◽  
Deanna Barwick ◽  
Emma K. Gowing ◽  
Andrew N. Clarkson
Keyword(s):  
Animal Model ◽  
Cognitive Flexibility ◽  
Cognitive Deficits ◽  
Cox Regression ◽  
Reversal Task ◽  
Critical Window ◽  
Aged Mice ◽  
Sham Surgery ◽  
Age Related ◽  
Old Mice

Stroke remains a leading cause of disability worldwide. Recently, we have established an animal model of stroke that results in delayed impairment in spatial memory, allowing us to better investigate cognitive deficits. Young and aged brains show different recovery profiles after stroke; therefore, we assessed aged-related differences in poststroke cognition. As neurotrophic support diminishes with age, we also investigated the involvement of brain-derived neurotrophic factor (BDNF) in these differences. Young (3-6 months old) and aged (16-21 months old) mice were trained in operant touchscreen chambers to complete a visual pairwise discrimination (VD) task. Stroke or sham surgery was induced using the photothrombotic model to induce a bilateral prefrontal cortex stroke. Five days poststroke, an additional cohort of aged stroke animals were treated with intracerebral hydrogels loaded with the BDNF decoy, TrkB-Fc. Following treatment, animals underwent the reversal and rereversal task to identify stroke-induced cognitive deficits at days 17 and 37 poststroke, respectively. Assessment of sham animals using Cox regression and log-rank analyses showed aged mice exhibit an increased impairment on VD reversal and rereversal learning compared to young controls. Stroke to young mice revealed no impairment on either task. In contrast, stroke to aged mice facilitated a significant improvement in reversal learning, which was dampened in the presence of the BDNF decoy, TrkB-Fc. In addition, aged stroke control animals required significantly less consecutive days and correction trials to master the reversal task, relative to aged shams, an effect dampened by TrkB-Fc. Our findings support age-related differences in recovery of cognitive function after stroke. Interestingly, aged stroke animals outperformed their sham counterparts, suggesting reopening of a critical window for recovery that is being mediated by BDNF.

Link between aging and atheroprotection in Mif-deficient atherosclerotic mice

2021 ◽  
Author(s):  
Christine Maria Krammer ◽  
Bishan Yang ◽  
Sabrina Reichl ◽  
Verena Bolini ◽  
Corinna Schulte ◽  
...  
Keyword(s):  
Atherogenic Diet ◽  
Cell Recruitment ◽  
Aged Mice ◽  
Cell Responses ◽  
Gene Deficiency ◽  
Cytokines And Chemokines ◽  
Age Related ◽  
Chronic Inflammatory Condition ◽  
Antibody Levels ◽  
Old Mice

Atherosclerosis is a lipid-triggered chronic inflammatory condition of our arteries and the main underlying pathology of myocardial infarction and stroke. Pathogenesis is age-dependent, but the mechanistic links between disease progression, age, and atherogenic cytokines and chemokines are incompletely understood. Here, we studied the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) in atherogenic Apoe-/- mice across different stages of aging and cholesterol-rich high-fat diet (HFD). MIF promotes atherosclerosis by mediating atherogenic monocyte and T-cell recruitment, amplifying lesional inflammation, and suppressing atheroprotective B-cell responses. However, age-related links between atherogenesis and MIF and its role in advanced atherosclerosis in aged mice have not been systematically explored. We compared effects of global Mif-gene deficiency in 30-, 42-, and 48-week-old Apoe-/- mice on HFD for 24, 36, or 42 weeks, respectively, and in 52-week-old mice on a 6-week HFD. While a regio-specific atheroprotective phenotype of Mif-deficiency was observed in the 30/24-week-old group, atheroprotection was not detected in the 48/42- and 52/6-week-old groups, suggesting that atheroprotection afforded by global Mif-gene deletion differs across aging stages and atherogenic diet duration. We identify a combination of mechanisms that could explain this phenotype: i) Mif-deficiency promotes lesional Trem2+ macrophage numbers in younger but not aged mice; ii) Mif-deficiency favors formation of lymphocyte-rich stage-I/II ATLOs in younger mice but ATLO numbers equalize with those in Apoe-/- controls in the older mice; and iii) plasma anti-oxLDL-IgM antibody levels are decreased in aged Mif-deficient mice. Of note, these three markers (Trem2+ macrophages, ATLOs, anti-oxLDL-IgM antibodies) have been previously linked to atheroprotection. Together, our study thus suggests that regio-specific atheroprotection due to global Mif-gene deficiency in atherogenic Apoe-/- mice is lost upon advanced aging and identifies mechanisms that could explain this phenotype shift. These observations may have implications for translational MIF-directed strategies.

scholarly journals Neuroinflammation in Aged Brain: Impact of the Oral Administration of Ellagic Acid Microdispersion

2020 ◽  
Vol 21 (10) ◽  
pp. 3631 ◽  
Author(s):  
Raffaella Boggia ◽  
Federica Turrini ◽  
Alessandra Roggeri ◽  
Guendalina Olivero ◽  
Francesca Cisani ◽  
...  
Keyword(s):  
Oral Administration ◽  
Ellagic Acid ◽  
Ex Vivo ◽  
Behavioral Skills ◽  
Aged Mice ◽  
Age Related ◽  
The Central Nervous System ◽  
The Impact ◽  
Old Mice

The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in “ex-vivo, in vitro” parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, GFAP staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates; it diminished GFAP immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.

scholarly journals Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging

2020 ◽  
Vol 117 (52) ◽  
pp. 33561-33569
Author(s):  
Megumi Inomata ◽  
Shuying Xu ◽  
Pallavi Chandra ◽  
Simin N. Meydani ◽  
Genzou Takemura ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Inflammatory Responses ◽  
The Elderly ◽  
Invasive Disease ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Murine Bone Marrow ◽  
Aged Mice ◽  
Age Related ◽  
Old Mice

Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.

scholarly journals Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL/6 Male Mouse Model

2020 ◽  
Vol 21 (11) ◽  
pp. 4169 ◽  
Author(s):  
Chang Ho Yoon ◽  
Jin Suk Ryu ◽  
Ho Sik Hwang ◽  
Mee Kum Kim
Keyword(s):  
Oxidative Stress ◽  
Mouse Model ◽  
Dependent Manner ◽  
Ki 67 ◽  
Aged Mice ◽  
Age Related ◽  
Ifn Γ ◽  
One Year ◽  
Corneal Staining ◽  
Old Mice

It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45+, 8-OHdG+, Ki-67+, and BrdU+ cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4+ interferon (IFN)-γ+ cells in LGs were found in both aged mice. An increase in 8-OHdG+ cells in both glands was evident in 2Y-old mice. Reduced Ki-67+ cells, but no change in CD45+ cells, was observed in the MGs of 1Y-old mice. Increased BrdU+ cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands.

scholarly journals HDAC6 inactivates Runx2 promoter to block osteogenesis of bone marrow stromal cells in age-related bone loss of mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chao Ma ◽  
Juan Gao ◽  
Jun Liang ◽  
Weixiang Dai ◽  
Zhenfei Wang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Osteogenic Differentiation ◽  
Differentiation Potential ◽  
Runx2 Expression ◽  
Aged Mice ◽  
Age Related ◽  
Old Mice

Abstract Background Senile osteoporosis can cause bone fragility and increased risk for fractures and has been one of the most prevalent and severe diseases affecting the elderly population worldwidely. The underlying mechanisms are currently intensive areas of investigation. In age-related bone loss, decreased bone formation overweighs increased bone resorption. The molecular mechanisms underlying defective bone formation in age-related bone loss are not completely understood. In particular, the specific role of histone acetylation in age-related bone loss has not been examined thoroughly. Methods We employed 6- and 18-month-old mice to investigate the mechanisms of defective bone formation in age-related bone loss. Bone marrow stromal cells (BMSCs) were induced to undergo in vitro osteogenic differentiation. Chromatin immunoprecipitation (ChIP) was used to investigate the binding of histone deacetylases (HDACs) on Runx2 promoter in BMSCs. Luciferase reporter and transient transfection assay were employed to study Runx2 gene expression modulation by HDAC and androgen receptor (AR). siRNA and HDAC6 inhibitor, Tubastatin A, were used to inhibit HDAC6 in vitro. And systemic administration of Tubastatin A was used to block HDAC6 in vivo. Results Age-related trabecular bone loss was observed in 18-month-old mice compared with 6-month-old mice. In vitro osteogenic differentiation potential of BMSCs from 18-month-old mice was weaker than 6-month-old mice, in which there was Runx2 expression inactivation in BMSCs of 18-month-old mice compared with 6-month-old mice, which was attributable to HDAC6-mediated histone hypoacetylation in Runx2 promoter. There was competitive binding of HDAC6 and AR on Runx2 promoter to modulate Runx2 expression in BMSCs. More importantly, through siRNA- or specific inhibitor-mediated HDAC6 inhibition, we could activate Runx2 expression, rescue in vitro osteogenesis potential of BMSCs, and alleviate in vivo age-related bone loss of mice. Conclusion HDAC6 accumulation and histone hypoacetylation on Runx2 promoter contributed to the attenuation of in vitro osteogenic differentiation potential of BMSCs from aged mice. Through HDAC6 inhibition, we could activate Runx2 expression and osteogenic differentiation potential of BMSCs from aged mice and alleviate the age-related bone loss of aged mice. Our study will benefit not only for understanding the age-related bone loss, but also for finding new therapies to treat senile osteoporosis.

Abstract 124: Supplementation With Growth Differentiation Factor11 Promotes Tissue Recovery and Angiogenesis After Ischemic Stroke in Aged Mice

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Jacob Hudobenko ◽  
Bhanu Priya Ganesh ◽  
Jianjun Jiang ◽  
Eric Mohan ◽  
Songmi Lee ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Brain Tissue ◽  
Stroke Recovery ◽  
Tissue Loss ◽  
Postmortem Human Brain ◽  
Stroke Treatment ◽  
Aged Mice ◽  
Sensorimotor Deficits ◽  
Age Related ◽  
Old Mice

Introduction: Growth differentiation factor (GDF) 11 levels decline with aging. This age-related loss of GDF11 has been implicated in a variety of age-related diseases. Supplementation with GDF11 reverses cardiac hypertrophy, bone loss, and pulmonary dysfunction in old mice, suggesting a rejuvenation effect of GDF11. Hypothesis: Brain levels of GDF11 would decline in aged animals, and that stroke would accelerate the age-related loss of GDF11. Exogenous administration of GDF11 would improve stroke outcomes in old mice. Methods: GDF11/8 levels were assessed in young and old mice and in postmortem human brain samples. In older mice, five days after MCAO, GDF11, and BrdU were administered for five days. Neurobehavioral assessments were performed during stroke recovery. MRI was used to determine cerebrospinal fluid (CSF), corpus callosum (CC) area, and percentage of brain tissue loss. Ten days post MCAo, brain expression of claudin5, collagen IV, BDNF, VEGF, pSmad2/3, activin type IIb receptor was assessed by western blotting. We performed immunohistochemistry to investigate IBA1, GFAP, NeuN, doublecortin, BDNF, MBP, synaptophysin, and CD31 immunoreactivity 30 days post-MCAo. Results: A decline in brain GDF11/8 was seen with age and after stroke in both mice and humans (p<0.05). Exogenous GDF11 supplementation reduced mortality and improved sensorimotor deficits thirty days after stroke. Treatment resulted in a reduction (p<0.05) in brain atrophy and CSF volume, and increased corpus callosum thickness as assessed by MRI. GDF11 treatment reduced gliosis, increased angiogenesis, and improved white matter integrity in aged mice. Conclusions: Brain GDF11/8 levels are reduced with aging, and after stroke. Exogenous GDF11 supplementation reduced mortality, decreased brain tissue damage, improved sensorimotor deficits, reduced gliosis, and increased angiogenesis in old mice after stroke.

scholarly journals Pro-Cognitive Properties of the Immunomodulatory Polypeptide Complex, Yolkin, from Chicken Egg Yolk and Colostrum-Derived Substances: Analyses Based on Animal Model of Age-Related Cognitive Deficits

2016 ◽  
Vol 64 (5) ◽  
pp. 425-434 ◽  
Author(s):  
Marta Lemieszewska ◽  
Marta Jakubik-Witkowska ◽  
Bartłomiej Stańczykiewicz ◽  
Aleksandra Zambrowicz ◽  
Agnieszka Zabłocka ◽  
...  
Keyword(s):  
Animal Model ◽  
Cognitive Deficits ◽  
Egg Yolk ◽  
Chicken Egg ◽  
Age Related ◽  
Chicken Egg Yolk

scholarly journals NAD+ flux is maintained in aged mice

2020 ◽  
Author(s):  
Melanie McReynolds ◽  
Karthikeyani Chellappa ◽  
Eric Chiles ◽  
Connor Jankowski ◽  
Yishui Shen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Calorie Restriction ◽  
Living Cells ◽  
Isotope Tracing ◽  
Aged Mice ◽  
Age Related ◽  
Old Mice ◽  
Increased Activity

Abstract NAD+ is an essential coenzyme found in all living cells. NAD+ concentrations decline during aging, but whether this reflects impaired production or accelerated consumption remains unclear. Here we employed isotope tracing and mass spectrometry to probe NAD+ metabolism across tissues in aged mice. In 25-month-old mice, we observe modest tissue NAD+ depletion (median decrease ~ 30%) without significant changes in circulating NAD+ precursors. Isotope tracing showed unimpaired synthesis of circulating nicotinamide from tryptophan, and maintained flux of circulating nicotinamide into tissue NAD+ pools. Although absolute NAD+ biosynthetic flux was maintained in most tissues of aged mice, fractional tissue NAD+ labeling from infused labeled nicotinamide was modestly accelerated, consistent with increased activity of NAD+ consuming enzymes. Long-term calorie restriction partially mitigated age-associated NAD+ decline despite decreasing NAD+ synthesis, suggesting that calorie restriction reduces NAD+ consumption. Thus, age-related decline in NAD+ is relatively subtle and driven by increased NAD+ consumer activity rather than impaired production.

scholarly journals Effects of Zinc Status and Aging on Age-Related Immune Dysfunction and Chronic Inflammation

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1854-1854
Author(s):  
Carmen Wong ◽  
Kendra Braun ◽  
John Bouranis ◽  
Edward Davis ◽  
Thomas Sharpton ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Chronic Inflammation ◽  
Zinc Deficiency ◽  
Serum Zinc ◽  
Immune Dysfunction ◽  
Zinc Status ◽  
Aged Mice ◽  
Age Related ◽  
Marginal Zinc Deficiency ◽  
Old Mice

Abstract Objectives Aging is associated with progressive immune dysfunction, including impaired adaptive response, increased susceptibility to infection, and reduced vaccination efficacy. Aging is also associated with chronic inflammation that correlated with the promotion of many age-related diseases. Zinc is an essential micronutrient critical for immune function. In US, 12% of the population do not consume the estimated average requirement for zinc. The prevalence of inadequate zinc intake is even higher among older populations, and are at increased risk for marginal zinc deficiency. Effects of zinc deficiency share similarities to age-related immune dysfunction, including impaired adaptive immunity and increased in proinflammatory response. The goal of this study is to understand the effects of zinc status and aging on age-related immune dysfunction and chronic inflammation. We hypothesize that age-related decline in zinc status contributes to immune dysregulation and chronic inflammation in the elderly. Methods We studied the effects of dietary zinc supplementation and marginal zinc deficiency on changes in mucosal immunity and inflammatory response in young and old mice. Young (2 mo) and old (24 mo) C57Bl/6 mice were fed a zinc adequate (ZA, 30 ppm Zn), zinc supplemented (ZS, 300 ppm Zn), or marginal zinc deficient (MZD, 6 ppm Zn) diets for 6 wks. Serum zinc status, cytokines, and naïve/memory T-cell phenotypes, were determined at the end of the study. Results Old mice had reduced zinc and increased proinflammatory cytokines MCP1 and IL6 in the serum, increased Th1/Th17/inflammatory cytokines (IFNγ, IL17, TNFα, respectively) and decreased naïve CD4 T-cells in the mesenteric lymph nodes (MLN). ZS significantly increased serum zinc levels, decreased TNFα, IFNγ, IL17 in MLN, and increased naïve T-cell populations in aged mice. MZD further reduced serum zinc and increased serum IL6 levels in aged mice. Conclusions ZS improved the immune function of aged mice and reduced inflammatory response, and MZD further increased age-related inflammation. Our data suggest that zinc status is an important contributing factor in age-related immune dysfunction and chronic inflammation. Funding Sources NIFA, USDA.

scholarly journals Age-related susceptibility to insulin resistance is due to a combination of CPT1B decline and lipid overload

2021 ◽  
Author(s):  
Marcel A. Vieira-Lara ◽  
Marleen B. Dommerholt ◽  
Wenxuan Zhang ◽  
Maaike Blankestijn ◽  
Justina C. Wolters ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Accumulation ◽  
Computational Modelling ◽  
Dietary Lipid ◽  
Aged Mice ◽  
Protein Levels ◽  
Age Related ◽  
Intramuscular Lipid ◽  
Key Driver ◽  
Old Mice

AbstractBACKGROUNDAdvanced age increases the susceptibility to diet-induced insulin resistance (IR). A key driver of this phenomenon is lipid accumulation in the skeletal muscle. It is debated, however, whether this is due to dietary lipid overload or decline of mitochondrial function. To address the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we put young and aged mice on a low- or high-fat diet (HFD).RESULTSAs expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals glycolytic protein levels were reduced and less flexible to the diet.CONCLUSIONWe conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their interaction. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.

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