scholarly journals Aspirin treatment does not increase microhemorrhage size in young or aged mice

2018 ◽  
Author(s):  
Sandy Chan ◽  
Morgan Brophy ◽  
Nozomi Nishimura ◽  
Chris B. Schaffer
Keyword(s):  
Femtosecond Laser Ablation ◽  
Surrounding Tissue ◽  
Aging Brain ◽  
Older Individuals ◽  
Aged Mice ◽  
Intravenous Heparin ◽  
The Impact ◽  
Old Mice ◽  
The Brain ◽  
Vessel Rupture

AbstractMicrohemorrhages are common in the aging brain and are thought to contribute to cognitive decline and the development of neurodegenerative diseases, such as Alzheimer’s disease. Chronic aspirin therapy is widespread in older individuals and decreases the risk of coronary artery occlusions and stroke. There remains a concern that such aspirin usage may prolong bleeding after a vessel rupture in the brain, leading to larger bleeds that cause more damage to the surrounding tissue. Here, we aimed to understand the influence of aspirin usage on the size of cortical microhemorrhages and explored the impact of age. We used femtosecond laser ablation to rupture arterioles in the cortex of both young (2-5 months old) and aged (18-29 months old) mice dosed on aspirin in their drinking water and measured the extent of penetration of both red blood cells and blood plasma into the surrounding tissue. We found no difference in microhemorrhage size for both young and aged mice dosed on aspirin, as compared to controls (hematoma diameter = 104 +/- 39 (97 +/- 38) μm in controls and 109 +/- 25 (101 +/- 28) μm in aspirin-treated young (aged) mice; mean +/- SD). In contrast, young mice treated with intravenous heparin had an increased hematoma diameter of 136 +/- 44 μm. These data suggest that aspirin does not increase the size of microhemorrhages, supporting the safety of aspirin usage.

scholarly journals Oxidative stress and genetic markers of suboptimal antioxidant defense in the aging brain: a theoretical review

2014 ◽  
Vol 25 (6) ◽  
Author(s):  
Lauren E. Salminen ◽  
Robert H. Paul
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Defense ◽  
Future Research ◽  
Aging Brain ◽  
Older Individuals ◽  
Glutathione S Transferase ◽  
Antioxidant Defense Enzymes ◽  
Repair Mechanisms ◽  
The Impact ◽  
The Brain

AbstractNormal aging involves a gradual breakdown of physiological processes that leads to a decline in cognitive functions and brain integrity, yet the onset and progression of decline are variable among older individuals. While many biological changes may contribute to this degree of variability, oxidative stress is a key mechanism of the aging process that can cause direct damage to cellular architecture within the brain. Oligodendrocytes are at a high risk for oxidative damage due to their role in myelin maintenance and production and limited repair mechanisms, suggesting that white matter may be particularly vulnerable to oxidative activity. Antioxidant defense enzymes within the brain, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione-S-transferase (GST), are crucial for breaking down the harmful end products of oxidative phosphorylation. Previous studies have revealed that allele variations of polymorphisms that encode these antioxidants are associated with abnormalities in SOD, CAT, GPx, and GST activity in the central nervous system. This review will focus on the role of oxidative stress in the aging brain and the impact of decreased antioxidant defense on brain integrity and cognitive function. Directions for future research investigations of antioxidant defense genes will also be discussed.

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 Epigenetic mechanism of carbohydrate sulfotransferase 3 (CHST3) downregulation in the aging brain

2019 ◽  
Author(s):  
David Baidoe-Ansah ◽  
M Sadman Sakib ◽  
Shaobo Jia ◽  
Andre Fischer ◽  
Rahul Kaushik ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Brain Plasticity ◽  
Epigenetic Mechanism ◽  
Aging Brain ◽  
Chondroitin Sulfates ◽  
Expression Of Genes ◽  
Bona Fide ◽  
Old Mice ◽  
The Brain

AbstractNeural extracellular matrix (ECM) is a complex molecular meshwork surrounding neurons and glial cells in the extracellular space. Structural and functional state of ECM in the brain is tightly regulated by various components of neural ECM such as hyaluronic acid, chondroitin sulfate proteoglycans, link proteins, tenascins, various matrix-modifying enzymes such as chondroitin sulfate synthases and carbohydrate sulfotransferase together with matrix-degrading enzymes. Age-dependent accumulation of ECM molecules is implicated in the age-associated decline in synaptic and cognitive functions. Understanding age-associated changes in the expression of genes involved in regulating various components of ECM can provide an insight into the role of ECM in the aging brain. Hence, in this study, we compared the expression levels of ECM regulating genes in three groups of mice: 2-3 months old mice (2-3M), 22- to 26-month-old mice (22-26M) and more than 30-month-old mice (>30M). Using qPCR, we discovered that in the hippocampus of >30M old mice, the majority of ECM related genes are downregulated, while genes related to neuroinflammation are highly upregulated. This pattern was accompanied by a decrease in cognitive performance of the >30M old mice and was most correlated among ECM-related genes with the downregulation of carbohydrate sulfotransferase 3 (CHST3) gene expression. Interestingly, in 24-26M mice, no general decrease in the expression of ECM related genes was observed, although we still found the upregulation in neuroinflammatory genes and downregulation of CHST3. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of CHST3 gene in non-neuronal (NeuN-negative) but not in neuronal (NeuN-positive) cells. We conclude that in 22-26 M old brains there are minor changes in expression of the studied bona fide neural ECM genes but there is a prominent epigenetic dysregulation of the CHST3 gene responsible for 6-sulfation of chondroitin sulfates, which may lead to impaired brain plasticity and cognitive decline.

scholarly journals Cognitively Impaired Old Mice Display Correlated Reduction in Cortical NMDA Receptor and Complex IV

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 118-118
Author(s):  
Ramkumar Thiyagarajan ◽  
Yonas Redae ◽  
Kenneth Seldeen ◽  
Bruce Troen
Keyword(s):  
Nmda Receptor ◽  
Neuronal Cell ◽  
Learning Ability ◽  
Escape Time ◽  
Mitochondrial Complex ◽  
Bdnf Expression ◽  
Complex Iv ◽  
Aged Mice ◽  
The Impact ◽  
Old Mice

Abstract Cognitive decline in older adults represents a major challenge since cognitive impairment is found in 10% of those ≥ 65 and 50% ≥ 85. Thus it is increasingly important to understand the impact of aging on cognitive health. We performed a battery of tests to assess cognition in 6 month-old (n=12) and 24 month-old (n=8) C57BL/6J mice, equivalent to 30 and 70 year old humans, respectively, and also assessed protein markers in cortex for mitochondrial health and cognition. We found that aged mice displayed fewer spontaneous alternations in the T maze test (p=0.034) and lower recognition of novel objects (p=0.022). In addition, aged mice showed prolonged escape time in the Barnes maze (p=0.035), all of which taken together suggest reduced capacity for learning and recall. Aged mice also exhibited diminished nest building (p<0.001), revealing an impaired functional capacity analogous to the instrumental activities of daily living (IADL) geriatric assessment. We found reduced mitochondrial complex IV expression in the cortices of aged mice concomitant with less expression of N-Methyl D-Aspartate (NMDA) receptor subunits 1, 2A and 2B. The cortices from old mice also exhibited greater expression of immature brain derived neurotrophic factor (pro-BDNF). The alterations in NMDA receptors and pro BDNF are consistent with memory impairment and greater neuronal cell death. Therefore, aged mice exhibit significantly reduced recall and learning ability alongside marked alterations in mitochondrial complex, NMDA receptor, and pro-BDNF expression. Studies are underway to assess whether these molecular changes are responsible for the cognitive declines with aging.

scholarly journals 3D Neuronal Mitochondrial Morphology in Axons, Dendrites, and Somata of the Aging Mouse Hippocampus

2021 ◽  
Author(s):  
Julie Faitg ◽  
Clay Lacefield ◽  
Tracey Davey ◽  
Kathryn White ◽  
Ross Laws ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Cell Types ◽  
Aging Brain ◽  
Mitochondrial Morphology ◽  
Mitochondrial Network ◽  
Age Related ◽  
Mouse Hippocampus ◽  
Old Mice ◽  
The Brain

The brain′s ability to process complex informations relies on the constant supply of energy through aerobic respiration by mitochondria. Neurons contain three anatomically distinct compartments – the soma, dendrites, and projecting axons – which have different energetic and biochemical requirements, as well as different mitochondrial morphologies in cultured systems. Here we apply a quantitative three-dimensional electron microscopy approach to map mitochondrial network morphology and complexity in the mouse brain. We examine three neuronal sub–compartments – the soma, dendrites, myelinated axons – in the dentate gyrus and CA1 of the mouse hippocampus, two subregions with distinct principal cell types and functions. We also establish compartment-specific differences in mitochondrial morphology across these cell types between young and old mice, highlighting differences in age-related morphological recalibrations. Overall, these data define the nature of the neuronal mitochondrial network in the mouse hippocampus, providing a foundation to examine the role of mitochondrial morpho–function in the aging brain.

scholarly journals Brain aging-dependent glioma traits reversible by NAD+/BDNF-mediated neuronal reactivation

2020 ◽  
Author(s):  
Daisuke Yamashita ◽  
Victoria L Flanary ◽  
Rachel B Munk ◽  
Kazuhiro Sonomura ◽  
Saya Ozaki ◽  
...  
Keyword(s):  
Brain Aging ◽  
Tumor Burden ◽  
Synaptic Activity ◽  
Aging Brain ◽  
Neuronal Signaling ◽  
Nicotinamide Mononucleotide ◽  
Brain Responses ◽  
Phenotypic Reversal ◽  
The Impact ◽  
Old Mice

SummaryThe rise in aging population worldwide is increasing death from cancer, including glioblastoma. Here, we explore the impact of brain aging on glioma tumorigenesis. We find that glioblastoma in older patients and older mice displayed reduced neuronal signaling, including a decline of NTRK-like family member 6 (SLITRK6), a receptor for neurotrophic factor BDNF. This reduction was linked to the systemic decline of nicotinamide adenine dinucleotide (NAD+) with aging, as old mice exposed to young blood via parabiosis or supplemented with the NAD+ precursor NMN (nicotinamide mononucleotide) reverted phenotypically to young-brain responses to glioma, with reactivated neuronal signaling and reduced death from tumor burden. Interestingly, the phenotypic reversal by NMN was largely absent in old mice undergoing parabiosis with BDNF+/- young mice and in BDNF+/- mice undergoing tumor challenge, supporting the notion that the lower NAD+-BDNF signaling in the aging brain aggravated glioma tumorigenesis. We propose that the aging-associated decline in brain NAD+ worsens glioma outcomes at least in part by decreasing neuronal/synaptic activity and increasing neuroinflammation.

scholarly journals Engineering Organoids for in vitro Modeling of Phenylketonuria

2022 ◽  
Vol 14 ◽  
Author(s):  
Alice C. Borges ◽  
Kerensa Broersen ◽  
Paula Leandro ◽  
Tiago G. Fernandes
Keyword(s):  
Acid Metabolism ◽  
Phenylalanine Hydroxylase ◽  
Genetic Disorder ◽  
Aging Brain ◽  
Chronic Effect ◽  
Induced Pluripotent ◽  
Open Question ◽  
The Impact ◽  
The Brain

Phenylketonuria is a recessive genetic disorder of amino-acid metabolism, where impaired phenylalanine hydroxylase function leads to the accumulation of neurotoxic phenylalanine levels in the brain. Severe cognitive and neuronal impairment are observed in untreated/late-diagnosed patients, and even early treated ones are not safe from life-long sequelae. Despite the wealth of knowledge acquired from available disease models, the chronic effect of Phenylketonuria in the brain is still poorly understood and the consequences to the aging brain remain an open question. Thus, there is the need for better predictive models, able to recapitulate specific mechanisms of this disease. Human induced pluripotent stem cells (hiPSCs), with their ability to differentiate and self-organize in multiple tissues, might provide a new exciting in vitro platform to model specific PKU-derived neuronal impairment. In this review, we gather what is known about the impact of phenylalanine in the brain of patients and highlight where hiPSC-derived organoids could contribute to the understanding of this disease.

scholarly journals The Impact of SARS-CoV-2 (COVID-19) and its Lockdown Measures on the Mental and Functional Health of Older Individuals

2021 ◽  
Author(s):  
Maria Chiara Fastame ◽  
Ilaria Mulas ◽  
Valeria Putzu ◽  
Gesuina Asoni ◽  
Daniela Viale ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Wearable Sensors ◽  
Well Being ◽  
Functional Health ◽  
Cognitive Deterioration ◽  
Older Individuals ◽  
Physical And Mental Health ◽  
Psychological Well Being ◽  
The Impact ◽  
Healthy Participants

AbstractThe effect of the COVID-19 on the physical and mental health of Italian older individuals displaying signs of cognitive deterioration has not been deeply investigated. This longitudinal study examined the impact of COVID-19 lockdown measures on the psychological well-being and motor efficiency of a sample of Italian community-dwellers with and without cognitive decline. Forty-seven participants underwent instrumental gait analysis performed in ecological setting using wearable sensors, and completed a battery of tasks assessing cognitive functioning and psychological well-being, before and after the full lockdown due to the COVID-19 spreading. A series of Multivariate Analyses of Variance (MANOVAs) documented that the superior gait performance of the cognitively healthy participants exhibited before the COVID-19 spread, vanished when they were tested at the end of the lockdown period. Moreover, before the outbreak of the COVID-19, cognitively healthy participants and those with signs of cognitive decline reported similar levels of psychological well-being, whereas, after the lockdown, the former group reported better coping, emotional competencies, and general well-being than the participants displaying signs of cognitive decline. In conclusion, the full COVID-19 outbreak had a significant impact on the mental and motor functioning of older individuals with and without signs of cognitive deterioration living in Italy.

scholarly journals Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 892
Author(s):  
Elisa L. J. Moya ◽  
Elodie Vandenhaute ◽  
Eleonora Rizzi ◽  
Marie-Christine Boucau ◽  
Johan Hachani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Blood Brain Barrier ◽  
Early Stage ◽  
Molecular Transport ◽  
Brain Barrier ◽  
Blood Brain ◽  
Cns Drugs ◽  
The Impact ◽  
The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

scholarly journals The Impact of Bone on the Biology of Aging

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 740-740
Author(s):  
Gerard Karsenty
Keyword(s):  
Muscle Function ◽  
Male Fertility ◽  
Leydig Cells ◽  
Memory Loss ◽  
Age Related ◽  
Systematic Exploration ◽  
Biology Of Aging ◽  
The Impact ◽  
The Brain ◽  
Regulate Energy Metabolism

Abstract We hypothesized that bone may secrete hormones that regulate energy metabolism and reproduction. Testing this hypothesis revealed that the osteoblast-specific secreted protein osteocalcin is a hormone regulating glucose homeostasis and male fertility by signaling through a GPCR, Gprc6a, expressed in pancreatic β bells and Leydig cells of the testes. The systematic exploration of osteocalcin biology, revealed that it regulates an unexpectedly large spectrum of physiological functions in the brain and peripheral organs and that it has most features of an antigeromic molecule. As will be presented at the meeting, this body of work suggests that harnessing osteocalcin for therapeutic purposes may be beneficial in the treatment of age-related diseases such as depression, age-related memory loss and the decline in muscle function seen in sarcopenia.

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