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 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 Targeting Age-Related Pathways in Heart Failure

2020 ◽  
Vol 126 (4) ◽  
pp. 533-551 ◽  
Author(s):  
Haobo Li ◽  
Margaret H. Hastings ◽  
James Rhee ◽  
Lena E. Trager ◽  
Jason D. Roh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Elderly Population ◽  
Molecular Mechanisms ◽  
The Elderly ◽  
Structure And Function ◽  
Experimental Platform ◽  
Age Related ◽  
Cardiac Structure And Function ◽  
And Function ◽  
Increased Susceptibility

During aging, deterioration in cardiac structure and function leads to increased susceptibility to heart failure. The need for interventions to combat this age-related cardiac decline is becoming increasingly urgent as the elderly population continues to grow. Our understanding of cardiac aging, and aging in general, is limited. However, recent studies of age-related decline and its prevention through interventions like exercise have revealed novel pathological and cardioprotective pathways. In this review, we summarize recent findings concerning the molecular mechanisms of age-related heart failure and highlight exercise as a valuable experimental platform for the discovery of much-needed novel therapeutic targets in this chronic disease.

scholarly journals Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1

2017 ◽  
Vol 215 (1) ◽  
pp. 51-62 ◽  
Author(s):  
Mark Y. Jeng ◽  
Philip A. Hull ◽  
Mingjian Fei ◽  
Hye-Sook Kwon ◽  
Chia-Lin Tsou ◽  
...  
Keyword(s):  
T Cells ◽  
Molecular Mechanisms ◽  
Memory T Cells ◽  
Cell Metabolism ◽  
Global Gene Expression ◽  
Metabolic Reprogramming ◽  
Transcriptional Reprogramming ◽  
Age Related ◽  
Global Gene Expression Profiling ◽  
And Function

The expansion of CD8+CD28– T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28– T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28– T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28– T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28– T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28– T cells. These data identify the evolutionarily conserved SIRT1–FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans.

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

2020 ◽  
Vol 94 ◽  
pp. 281-286
Author(s):  
David V.C. Brito ◽  
Kubra Gulmez Karaca ◽  
Janina Kupke ◽  
Franziska Mudlaff ◽  
Benjamin Zeuch ◽  
...  
Keyword(s):  
Young Adult ◽  
Recognition Memory ◽  
Memory Impairments ◽  
Adult Mice ◽  
Spatial Recognition

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.

scholarly journals Thrombospondin-1 in maladaptive aging responses: a concept whose time has come

2020 ◽  
Vol 319 (1) ◽  
pp. C45-C63
Author(s):  
Jeffrey S. Isenberg ◽  
David D. Roberts
Keyword(s):  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Genotoxic Stress ◽  
Cell Types ◽  
Cellular Tissue ◽  
Therapeutic Agents ◽  
Age Related ◽  
Organ Systems ◽  
Age Dependent ◽  
Thrombospondin 1

Numerous age-dependent alterations at the molecular, cellular, tissue and organ systems levels underlie the pathophysiology of aging. Herein, the focus is upon the secreted protein thrombospondin-1 (TSP1) as a promoter of aging and age-related diseases. TSP1 has several physiological functions in youth, including promoting neural synapse formation, mediating responses to ischemic and genotoxic stress, minimizing hemorrhage, limiting angiogenesis, and supporting wound healing. These acute functions of TSP1 generally require only transient expression of the protein. However, accumulating basic and clinical data reinforce the view that chronic diseases of aging are associated with accumulation of TSP1 in the extracellular matrix, which is a significant maladaptive contributor to the aging process. Identification of the relevant cell types that chronically produce and respond to TSP1 and the molecular mechanisms that mediate the resulting maladaptive responses could direct the development of therapeutic agents to delay or revert age-associated maladies.

scholarly journals Mimicking Age-Associated Gadd45γ Dysregulation Results in Memory Impairments in Young Adult Mice

2019 ◽  
Vol 40 (6) ◽  
pp. 1197-1210 ◽  
Author(s):  
David V.C. Brito ◽  
Janina Kupke ◽  
Kubra Gulmez Karaca ◽  
Benjamin Zeuch ◽  
Ana M.M. Oliveira
Keyword(s):  
Young Adult ◽  
Memory Impairments ◽  
Adult Mice

scholarly journals Cholinergic Degeneration and Alterations in the TrkA and p75NTR Balance as a Result of Pro-NGF Injection into Aged Rats

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Ashley M. Fortress ◽  
Mona Buhusi ◽  
Kris L. Helke ◽  
Ann-Charlotte E. Granholm
Keyword(s):  
Basal Forebrain ◽  
Cholinergic Neurons ◽  
Memory Impairments ◽  
Age Related ◽  
High Affinity Receptor ◽  
Affinity Receptor ◽  
Cholinergic Degeneration ◽  
And Function ◽  
Do So

Learning and memory impairments occurring with Alzheimer's disease (AD) are associated with degeneration of the basal forebrain cholinergic neurons (BFCNs). BFCNs extend their axons to the hippocampus where they bind nerve growth factor (NGF) which is retrogradely transported to the cell body. While NGF is necessary for BFCN survival and function via binding to the high-affinity receptor TrkA, its uncleaved precursor, pro-NGF has been proposed to induce neurodegeneration via binding to the p75NTR and its coreceptor sortilin. Basal forebrain TrkA and NGF are downregulated with aging while pro-NGF is increased. Given these data, the focus of this paper was to determine a mechanism for how pro-NGF accumulation may induce BFCN degeneration. Twenty-four hours after a single injection of pro-NGF into hippocampus, we found increased hippocampal p75NTR levels, decreased hippocampal TrkA levels, and cholinergic degeneration. The data suggest that the increase in p75NTR with AD may be mediated by elevated pro-NGF levels as a result of decreased cleavage, and that pro-NGF may be partially responsible for age-related degenerative changes observed in the basal forebrain. This paper is the firstin vivoevidence that pro-NGF can affect BFCNs and may do so by regulating expression of p75NTR neurotrophin receptors.

scholarly journals Age-dependent changes in protein incorporation into collagen-rich tissues of mice by in vivo pulsed SILAC labelling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yoanna Ariosa-Morejon ◽  
Alberto Santos ◽  
Roman Fischer ◽  
Simon Davis ◽  
Philip Charles ◽  
...  
Keyword(s):  
Skeletal Maturity ◽  
Tissue Level ◽  
Skeletal Maturation ◽  
Healthy Life ◽  
Adult Mice ◽  
Age Related ◽  
Age Dependent ◽  
Protein Incorporation ◽  
New Protein

Collagen-rich tissues have poor reparative capacity that predisposes to common age-related disorders such as osteoporosis and osteoarthritis. We used in vivo pulsed SILAC labelling to quantify new protein incorporation into cartilage, bone, and skin of mice across the healthy life course. We report dynamic turnover of the matrisome, the proteins of the extracellular matrix, in bone and cartilage during skeletal maturation, which was markedly reduced after skeletal maturity. Comparing young adult with older adult mice, new protein incorporation was reduced in all tissues. STRING clustering revealed changes in epigenetic modulators across all tissues, a decline in chondroprotective growth factors such as FGF2 and TGFβ in cartilage, and clusters indicating mitochondrial dysregulation and reduced collagen synthesis in bone. Several pathways were implicated in age-related disease. Fewer changes were observed for skin. This methodology provides dynamic protein data at a tissue level, uncovering age-related molecular changes that may predispose to disease.

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.

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