scholarly journals TET1-mediated DNA hydroxy-methylation regulates adult remyelination

2019 ◽  
Author(s):  
Sarah Moyon ◽  
Rebecca Frawley ◽  
Katy LH Marshall-Phelps ◽  
Linde Kegel ◽  
Sunniva MK Bøstrand ◽  
...  
Keyword(s):  
Young Adult ◽  
Brain Function ◽  
Molecular Mechanisms ◽  
Epigenetic Mark ◽  
Adult Mice ◽  
Age Related ◽  
Genome Wide ◽  
Solute Carrier ◽  
Tet Enzymes ◽  
Old Mice

AbstractAdult myelination is essential for brain function and response to injury, but the molecular mechanisms remain elusive. Here we identify DNA hydroxy-methylation, an epigenetic mark catalyzed by Ten-Eleven translocation (TET) enzymes, as necessary for adult myelin repair.While DNA hydroxy-methylation and high levels of TET1 are detected in young adult mice during myelin regeneration after demyelination, this process is defective in old mice. Constitutive or inducible lineage-specific ablation of Tet1 (but not of Tet2) recapitulate the age-related decline of DNA hydroxy-methylation and inefficient remyelination. Genome-wide hydroxy-methylation and transcriptomic analysis identify numerous TET1 targets, including several members of the solute carrier (Slc) gene family. Lower transcripts for Slc genes, including Slc12a2, are observed in Tet1 mutants and old mice and are associated with swelling at the neuroglial interface, a phenotype detected also in zebrafish slc12a2b mutants.We conclude that TET1-mediated DNA hydroxy-methylation is necessary for adult remyelination after injury.

scholarly journals Healthy Brain Aging Modifies Microglial Calcium Signaling In Vivo

2019 ◽  
Vol 20 (3) ◽  
pp. 589 ◽  
Author(s):  
Maria Olmedillas del Moral ◽  
Nithi Asavapanumas ◽  
Néstor Uzcátegui ◽  
Olga Garaschuk
Keyword(s):  
Young Adult ◽  
Brain Aging ◽  
Critical Role ◽  
Low Grade ◽  
Middle Aged ◽  
Senescent Phenotype ◽  
Adult Mice ◽  
Age Related ◽  
Old Mice

Brain aging is characterized by a chronic, low-grade inflammatory state, promoting deficits in cognition and the development of age-related neurodegenerative diseases. Malfunction of microglia, the brain-resident immune cells, was suggested to play a critical role in neuroinflammation, but the mechanisms underlying this malfunctional phenotype remain unclear. Specifically, the age-related changes in microglial Ca2+ signaling, known to be linked to its executive functions, are not well understood. Here, using in vivo two-photon imaging, we characterize intracellular Ca2+ signaling and process extension of cortical microglia in young adult (2–4-month-old), middle-aged (9–11-month-old), and old (18–21-month-old) mice. Our data revealed a complex and nonlinear dependency of the properties of intracellular Ca2+ signals on an animal’s age. While the fraction of cells displaying spontaneous Ca2+ transients progressively increased with age, the frequencies and durations of the spontaneous Ca2+ transients followed a bell-shaped relationship, with the most frequent and largest Ca2+ transients seen in middle-aged mice. Moreover, in old mice microglial processes extending toward an ATP source moved faster but in a more disorganized manner, compared to young adult mice. Altogether, these findings identify two distinct phenotypes of aging microglia: a reactive phenotype, abundantly present in middle-aged animals, and a dysfunctional/senescent phenotype ubiquitous in old mice.

scholarly journals Modeling human age-associated increase in Gadd45γ expression leads to spatial recognition memory impairments in young adult mice

2020 ◽  
Author(s):  
David V.C. Brito ◽  
Kubra Gulmez Karaca ◽  
Janina Kupke ◽  
Franziska Mudlaff ◽  
Benjamin Zeuch ◽  
...  
Keyword(s):  
Young Adult ◽  
Hippocampal Neurons ◽  
Molecular Mechanisms ◽  
Memory Impairments ◽  
Adult Mice ◽  
Age Related ◽  
Mouse Hippocampus ◽  
Age Dependent ◽  
And Function ◽  
Dependent Processes

AbstractAging is associated with the progressive decay of cognitive function. Hippocampus-dependent processes, such as the formation of spatial memory, are particularly vulnerable to aging. Currently, the molecular mechanisms responsible for age-dependent cognitive decline are largely unknown. Here, we investigated the expression and function of the growth arrest DNA damage gamma (Gadd45γ) during aging and cognition. We report that Gadd45γ expression is increased in the hippocampus of aged humans and that Gadd45γ overexpression in the young adult mouse hippocampus compromises cognition. Moreover, Gadd45γ overexpression in hippocampal neurons disrupted CREB signaling and the expression of well-established activity-regulated genes. This work shows that Gadd45γ expression is tightly controlled in the hippocampus and its disruption may be a mechanism contributing to age-related cognitive impairments observed in humans.

scholarly journals Old Mice Have Less Transcriptional Activation But Similar Periosteal Cell Proliferation Compared to Young‐Adult Mice in Response to in vivo Mechanical Loading

2020 ◽  
Vol 35 (9) ◽  
pp. 1751-1764 ◽  
Author(s):  
Christopher J Chermside‐Scabbo ◽  
Taylor L Harris ◽  
Michael D Brodt ◽  
Ingrid Braenne ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Young Adult ◽  
Mechanical Loading ◽  
Transcriptional Activation ◽  
Adult Mice ◽  
Periosteal Cell ◽  
Old Mice

scholarly journals Influence of Aging on the Retina and Visual Motion Processing for Optokinetic Responses in Mice

2020 ◽  
Vol 14 ◽  
Author(s):  
Yuko Sugita ◽  
Haruka Yamamoto ◽  
Yamato Maeda ◽  
Takahisa Furukawa
Keyword(s):  
Young Adult ◽  
Visual Function ◽  
Visual Motion ◽  
Late Phase ◽  
Normal Aging ◽  
Motion Processing ◽  
Adult Mice ◽  
Visual Motion Processing ◽  
Age Related ◽  
Optokinetic Responses

The decline in visual function due to normal aging impacts various aspects of our daily lives. Previous reports suggest that the aging retina exhibits mislocalization of photoreceptor terminals and reduced amplitudes of scotopic and photopic electroretinogram (ERG) responses in mice. These abnormalities are thought to contribute to age-related visual impairment; however, the extent to which visual function is impaired by aging at the organismal level is unclear. In the present study, we focus on the age-related changes of the optokinetic responses (OKRs) in visual processing. Moreover, we investigated the initial and late phases of the OKRs in young adult (2–3 months old) and aging mice (21–24 months old). The initial phase was evaluated by measuring the open-loop eye velocity of OKRs using sinusoidal grating patterns of various spatial frequencies (SFs) and moving at various temporal frequencies (TFs) for 0.5 s. The aging mice exhibited initial OKRs with a spatiotemporal frequency tuning that was slightly different from those in young adult mice. The late-phase OKRs were investigated by measuring the slow-phase velocity of the optokinetic nystagmus evoked by sinusoidal gratings of various spatiotemporal frequencies moving for 30 s. We found that optimal SF and TF in the normal aging mice are both reduced compared with those in young adult mice. In addition, we measured the OKRs of 4.1G-null (4.1G–/–) mice, in which mislocalization of photoreceptor terminals is observed even at the young adult stage. We found that the late phase OKR was significantly impaired in 4.1G–/– mice, which exhibit significantly reduced SF and TF compared with control mice. These OKR abnormalities observed in 4.1G–/– mice resemble the abnormalities found in normal aging mice. This finding suggests that these mice can be useful mouse models for studying the aging of the retinal tissue and declining visual function. Taken together, the current study demonstrates that normal aging deteriorates to visual motion processing for both the initial and late phases of OKRs. Moreover, it implies that the abnormalities of the visual function in the normal aging mice are at least partly due to mislocalization of photoreceptor synapses.

Free radical injury to skeletal muscles of young, adult, and old mice

1990 ◽  
Vol 258 (3) ◽  
pp. C429-C435 ◽  
Author(s):  
E. Zerba ◽  
T. E. Komorowski ◽  
J. A. Faulkner
Keyword(s):  
Free Radical ◽  
Young Adult ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Free Radical Damage ◽  
Control Value ◽  
Delayed Onset ◽  
Adult Mice ◽  
Old Mice

We tested the hypotheses that 1) muscles of old mice are more susceptible to injury than muscles of young and adult mice, and 2) secondary or delayed onset injury results from free radical damage. Extensor digitorum longus muscles were injured in situ by lengthening contractions. Injury was assessed by measurement of maximum isometric tetanic force (Po) expressed as a percentage of the control value and by morphological damage. Mice were treated with a free radical scavenger, polyethylene glycol-superoxide dismutase (PEG-SOD). Three days postinjury, the Po of 44% for muscles of nontreated old mice was significantly lower than the Po of 58 and 61% for those of young and adult mice. In each group, the secondary injury at 3 days was alleviated by treatment with PEG-SOD. For treated muscles of young, adult, and old mice, values for Po were 88, 80, and 70%, respectively. We conclude that muscles of old mice are more susceptible to injury than muscles of young or adult mice and that free radicals contribute to the secondary or delayed onset injury.

scholarly journals Neuroinflammation Induced by Surgery Does Not Impair the Reference Memory of Young Adult Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Yanhua Zhao ◽  
Lili Huang ◽  
Huan Xu ◽  
Guangxi Wu ◽  
Mengyi Zhu ◽  
...  
Keyword(s):  
Risk Factor ◽  
Young Adult ◽  
Postoperative Cognitive Dysfunction ◽  
Underlying Mechanism ◽  
Reference Memory ◽  
Behavior Changes ◽  
Spatial Reference ◽  
Adult Mice ◽  
Spatial Reference Memory ◽  
Old Mice

Postoperative cognitive dysfunction (POCD) increases morbidity and mortality after surgery. But the underlying mechanism is not clear yet. While age is now accepted as the top one risk factor for POCD, results from studies investigating postoperative cognitive functions in adults have been controversial, and data about the very young adult individuals are lacking. The present study investigated the spatial reference memory, IL-1β, IL-6, and microglia activation changes in the hippocampus in 2-month-old mice after anesthesia and surgery. We found that hippocampal IL-1βand IL-6 increased at 6 hours after surgery. Microglia were profoundly activated in the hippocampus 6 to 24 hours after surgery. However, no significant behavior changes were found in these mice. These results indicate that although anesthesia and surgery led to neuroinflammation, the latter was insufficient to impair the spatial reference memory of young adult mice.

scholarly journals FTIR Spectroscopy as a Tool to Study Age-Related Changes in Cardiac and Skeletal Muscle of Female C57BL/6J Mice

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6410
Author(s):  
Sandra Magalhães ◽  
Idália Almeida ◽  
Filipa Martins ◽  
Fátima Camões ◽  
Ana R. Soares ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Ftir Spectroscopy ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Protein Secondary Structure ◽  
Multivariate Statistical ◽  
Age Related ◽  
Muscle Tissues ◽  
Aging Studies ◽  
Old Mice

Studying aging is important to further understand the molecular mechanisms underlying this physiological process and, ideally, to identify a panel of aging biomarkers. Animals, in particular mice, are often used in aging studies, since they mimic important features of human aging, age quickly, and are easy to manipulate. The present work describes the use of Fourier Transform Infrared (FTIR) spectroscopy to identify an age-related spectroscopic profile of the cardiac and skeletal muscle tissues of C57BL/6J female mice. We acquired ATR-FTIR spectra of cardiac and skeletal muscle at four different ages: 6; 12; 17 and 24 months (10 samples at each age) and analyzed the data using multivariate statistical tools (PCA and PLS) and peak intensity analyses. The results suggest deep changes in protein secondary structure in 24-month-old mice compared to both tissues in 6-month-old mice. Oligomeric structures decreased with age in both tissues, while intermolecular β-sheet structures increased with aging in cardiac muscle but not in skeletal muscle. Despite FTIR spectroscopy being unable to identify the proteins responsible for these conformational changes, this study gives insights into the potential of FTIR to monitor the aging process and identify an age-specific spectroscopic signature.

Abstract 123: Age-Related Diminishment of the Subventricular Zone Cytogenic Response and Its Contributions to Motor Recovery After Cortical Infarcts

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Michael R Williamson ◽  
Stephanie Le ◽  
Ronald L Franzen ◽  
Michael R Drew ◽  
Theresa A Jones
Keyword(s):  
Young Adult ◽  
Subventricular Zone ◽  
Motor Recovery ◽  
Lineage Tracing ◽  
Stem Cell Markers ◽  
Middle Aged ◽  
Reaching Task ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related

Stroke increases proliferation within the subventricular zone (SVZ) cytogenic niche and causes subsequent migration of newborn cells towards the site of injury. We investigated the functional consequences of age-related blunting of the SVZ cytogenic response to ischemia. We found that there was a marked reduction in proliferation and neural stem cell markers within the SVZ of middle aged (aged 12-16 months) versus young adult (aged 3-5 months) mice in the intact brain and after photothrombotic infarcts in motor cortex. Using an inducible, heritable lineage tracing system (Nestin-CreER T2 :: Ai14 mice) to quantify SVZ-derived neural precursor cells (NPCs) that migrated towards the infarct, we found that there was a considerable age-related reduction in the number of NPCs in peri-infarct cortex. These findings indicate a marked diminishment of SVZ NPC proliferation and migration after focal ischemia by middle age. Next, we assessed the contributions of the SVZ cytogenic response to recovery of skilled motor function. We used glial fibrillary acidic protein-thymidine kinase mice to conditionally ablate NPCs with ganciclovir administration. In young adult mice, NPC ablation significantly impaired recovery of motor performance on the single seed reaching task after motor cortical infarcts. By contrast, NPC ablation did not affect motor recovery in middle aged mice. Importantly, the magnitude of recovery was less in middle aged mice—regardless of NPC ablation—than in control young adult mice. Middle aged mice recovered similarly to young adult mice lacking NPCs. These results indicate that SVZ cytogenesis contributes to functional improvements after cortical infarcts and that the diminishment of the cytogenic response with age may be implicated in age-related worsening of outcome after stroke. Restoration of SVZ cytogenesis in aged animals might improve behavioral recovery.

scholarly journals Testosterone Supplementation Reverses Sarcopenia in Aging through Regulation of Myostatin, c-Jun NH2-Terminal Kinase, Notch, and Akt Signaling Pathways

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 628-638 ◽  
Author(s):  
Ekaterina L. Kovacheva ◽  
Amiya P. Sinha Hikim ◽  
Ruoqing Shen ◽  
Indranil Sinha ◽  
Indrani Sinha-Hikim
Keyword(s):  
Muscle Mass ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Muscle Growth ◽  
Fiber Types ◽  
Cross Sectional ◽  
Testosterone Treatment ◽  
Age Related ◽  
Muscle Cell Apoptosis ◽  
Old Mice

Aging in rodents and humans is characterized by loss of muscle mass (sarcopenia). Testosterone supplementation increases muscle mass in healthy older men. Here, using a mouse model, we investigated the molecular mechanisms by which testosterone prevents sarcopenia and promotes muscle growth in aging. Aged mice of 22 months of age received a single sc injection of GnRH antagonist every 2 wk to suppress endogenous testosterone production and were implanted subdermally under anesthesia with 0.5 or 1.0 cm testosterone-filled implants for 2 months (n = 15/group). Young and old mice (n = 15/group), of 2 and 22 months of age, respectively, received empty implants and were used as controls. Compared with young animals, a significant (P < 0.05) increase in muscle cell apoptosis coupled with a decrease in gastrocnemius muscles weight (by 16.7%) and muscle fiber cross-sectional area, of both fast and slow fiber types, was noted in old mice. Importantly, such age-related changes were fully reversed by higher dose (1 cm) of testosterone treatment. Testosterone treatment effectively suppressed age-specific increases in oxidative stress, processed myostatin levels, activation of c-Jun NH2-terminal kinase, and cyclin-dependent kinase inhibitor p21 in aged muscles. Furthermore, it restored age-related decreases in glucose-6-phosphate dehydrogenase levels, phospho-Akt, and Notch signaling. These alterations were associated with satellite cell proliferation and differentiation. Collectively these results suggest involvement of multiple signal transduction pathways in sarcopenia. Testosterone reverses sarcopenia through stimulation of cellular metabolism and survival pathway together with inhibition of death pathway.

scholarly journals Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders

2021 ◽  
Vol 22 (8) ◽  
pp. 4052
Author(s):  
Kévin Nay ◽  
William J. Smiles ◽  
Jacqueline Kaiser ◽  
Luke M. McAloon ◽  
Kim Loh ◽  
...  
Keyword(s):  
Brain Function ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Well Being ◽  
Developed Countries ◽  
Beneficial Effects ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Underlying Mechanisms ◽  
The Impact

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle–brain, liver–brain and gut–brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise–brain communication and their benefits for physiology and brain function.

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