scholarly journals 2010 Use it but still lose it: Exploring age-related changes in skeletal stem cell location and activation in response to physical stimulation

2018 ◽  
Vol 2 (S1) ◽  
pp. 35-35
Author(s):  
Pamela C. Zuckerman ◽  
Chao Liu ◽  
Alesha B. Castillo
Keyword(s):  
Mechanical Loading ◽  
Cell Population ◽  
Cell Number ◽  
Medial Region ◽  
Physical Stimulation ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related ◽  
Periosteal Cell ◽  
Periosteal Cells

OBJECTIVES/SPECIFIC AIMS: Our goal is to assess age-related changes in osteogenic stem cell populations of bone tissue. We hypothesize that aging mice have reduced osteogenic capacity in response to physical stimulation due to aging-associated decline in osteoprogenitor cell number and their proliferative capacity. METHODS/STUDY POPULATION: Mechanical loading: The NYU School of Medicine Institutional Animal Care and Use Committee approved all procedures. The response of tibial periosteal cells to physical stimulation or mechanical loading was assessed in 16-week-old adult (n=6) and aged 78-week-old female (n=4) mice subjected to 4 consecutive days of strain-matched axial compressive loading (1400 μm, 120 cycles, 2 Hz). Whole Mount Staining: Baseline periosteal cell numbers and nuclear morphology were assessed by whole bone DAPI staining of the antero-medial region of the tibiae in adult and aged mice (n=6). Immunohistochemistry: Tibiae were fixed in 4% PFA, decalcified in 19% EDTA, OCT-embedded, and thickly sectioned (150 μm) at midshaft. Sca1+, Prrx1+, and Ki67+cell numbers were quantified by simultaneous fluorescent immunohistochemical staining from loaded and nonloaded contralateral tibiae. Nonimmune species specific serum served as negative controls. Imaging: 3D image datasets of the periosteum at the antero-medial region of the tibial midshaft were acquired by multi-photon and confocal microscopy. Quantification of Sca1+, Prrx1+, and Ki67+ cells was carried out using Particle Analysis software (ImageJ) and Imaris 7.4.2 Surface Rendering Statistics functions. Cell number was normalized to periosteal area (~0.04 mm2). A Student t-test determined significance at p<0.05. RESULTS/ANTICIPATED RESULTS: At baseline, aged periosteal cell nuclei (DAPI+) area (14% decrease, p<0.0001), nuclei number, and Prrx1+ cell number (22% decrease) was significantly lower compared with adult mice. In loaded adult mice, Prrx1+but not Sca1+cell number increased significantly (35%, p=0.0115). Proliferating Sca1+(top panel) and Prrx1+(top panel) cells also increased with loading, 62%, p=0.0253 and 115%, p=0.0004, respectively, in adult but not aged mice. The percentage of Prrx1+ cells undergoing proliferation (co-expressing Ki67+) in the total Prrx1+ cell population increased significantly with loading (bottom panel). Aged mice did not exhibit significant differences in loaded versus nonloaded controls for all other outcomes. Our data suggest fundamental changes in periosteal cell morphology, number and response to mechanical loading with aging. The significant increase in total Prrx1+ cell number and the number of Prrx1+ cells undergoing proliferation with loading in adult mice, suggest that the Prrx1+ cell population expands through proliferation. In fact, loading resulted in a 2-fold increase in the percentage of Prrx1+ preosteogenic cells undergoing proliferation. Accordingly, the significant age-related decrease in Prrx1+ cells may explain, in part, the attenuation of load-induced bone formation in aged mice. Loading resulted in greater numbers of proliferating Sca1+ cells (the more primitive cell) in adult mice, though this represented only a small percentage (<10%) of the total Sca1+ population. Mechanical loading expands the Prrx1+ pre-osteogenic cell population, but not the more primitive Sca1+ population. However, this load-induced osteogenic effect in the periosteum is not observed in aged mice, which may explain age-related diminishment of load-induced bone formation. DISCUSSION/SIGNIFICANCE OF IMPACT: Mechanical loading presents an inexpensive treatment for increasing bone mass and bone strength, but may be insufficient to prevent or reverse age-related bone loss due to reduced numbers of osteogenic progenitors in the periosteum. Therapeutic approaches targeting the osteogenic capacity of periosteal cells will be required to address declining mechanoresponsiveness with age.

scholarly journals Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway

2021 ◽  
Vol 15 ◽  
Author(s):  
Eduard Bentea ◽  
Laura De Pauw ◽  
Lise Verbruggen ◽  
Lila C. Winfrey ◽  
Lauren Deneyer ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Proteasome Inhibition ◽  
Cell Loss ◽  
Redox Balance ◽  
Nigrostriatal Pathway ◽  
Knock Out ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related ◽  
Nigrostriatal Degeneration

The astrocytic cystine/glutamate antiporter system xc– (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson’s disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT–/–) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT+/+) littermates. Contrary to adult mice, aged xCT–/– mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT+/+ littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT–/– mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice (Bentea et al., 2015a), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT–/– mice when compared to age-matched xCT+/+ littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT–/– mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system xc– in mechanisms of dopaminergic cell loss and its interaction with aging.

scholarly journals Aging Influences the Metabolic and Inflammatory Phenotype in an Experimental Mouse Model of Acute Lung Injury

2020 ◽  
Author(s):  
Kevin W Gibbs ◽  
Chia-Chi Chuang Key ◽  
Lanazha Belfield ◽  
Jennifer Krall ◽  
Lina Purcell ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Fatty Acid ◽  
Lung Injury ◽  
Whole Body ◽  
Acid Oxidation ◽  
Aged Mice ◽  
Protein Levels ◽  
Adult Mice ◽  
Age Related ◽  
Before And After

Abstract Increased age is a risk factor for poor outcomes from respiratory failure and acute respiratory distress syndrome (ARDS). In this study, we sought to define age-related differences in lung inflammation, muscle injury, and metabolism after intratracheal lipopolysaccharide (IT-LPS) acute lung injury (ALI) in adult (6 months) and aged (18–20 months) male C57BL/6 mice. We also investigated age-related changes in muscle fatty acid oxidation (FAO) and the consequences of systemic FAO inhibition with the drug etomoxir. Aged mice had a distinct lung injury course characterized by prolonged alveolar neutrophilia and lack of response to therapeutic exercise. To assess the metabolic consequences of ALI, aged and adult mice underwent whole body metabolic phenotyping before and after IT-LPS. Aged mice had prolonged anorexia and decreased respiratory exchange ratio, indicating increased reliance on FAO. Etomoxir increased mortality in aged but not adult ALI mice, confirming the importance of FAO on survival from acute severe stress and suggesting that adult mice have increased resilience to FAO inhibition. Skeletal muscles from aged ALI mice had increased transcription of key fatty acid metabolizing enzymes, CPT-1b, LCAD, MCAD, FATP1 and UCP3. Additionally, aged mice had increased protein levels of CPT-1b at baseline and after lung injury. Surprisingly, CPT-1b in isolated skeletal muscle mitochondria had decreased activity in aged mice compared to adults. The distinct phenotype of aged ALI mice has similar characteristics to the adverse age-related outcomes of ARDS. This model may be useful to examine and augment immunologic and metabolic abnormalities unique to the critically ill aged population.

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 Remodeling of Actin Cytoskeleton in Mouse Periosteal Cells under Mechanical Loading Induces Periosteal Cell Proliferation during Bone Formation

PLoS ONE ◽  
2011 ◽  
Vol 6 (9) ◽  
pp. e24847 ◽  
Author(s):  
Daisuke Sakai ◽  
Isao Kii ◽  
Kazuki Nakagawa ◽  
Hiroko N. Matsumoto ◽  
Masateru Takahashi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bone Formation ◽  
Actin Cytoskeleton ◽  
Mechanical Loading ◽  
Periosteal Cell ◽  
Periosteal Cells

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 Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

2018 ◽  
Author(s):  
Andrea KH Stavoe ◽  
Erika LF Holzbaur
Keyword(s):  
Young Adult ◽  
Late Onset ◽  
Transmembrane Protein ◽  
Autophagosome Formation ◽  
Common Risk Factor ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related ◽  
Assembly Kinetics ◽  
Exogenous Expression

SUMMARYAutophagy defects have been implicated in multiple late-onset neurodegenerative diseases. Since aging is the most common risk factor in neurodegeneration, we asked how autophagy is modulated in aging neurons. We compared the dynamics of autophagosome biogenesis in neurons from young adult and aged mice, identifying a significant decrease in biogenesis during aging. Autophagosome assembly kinetics are disrupted, with frequent production of stalled isolation membranes in neurons from aged mice; these precursors failed to resolve into LC3-positive autophagosomes. We did not detect alterations in the initial induction/nucleation steps of autophagosome formation. However, we found that the transmembrane protein Atg9 remained aberrantly associated with stalled isolation membranes, suggesting a specific disruption in the WIPI-dependent retrieval of Atg9. Depletion of WIPI2 from young neurons was sufficient to induce a similar deficit. Further, exogenous expression of WIPI2 in neurons from aged mice was sufficient to restore autophagosome biogenesis to the rates seen in neurons from young adult mice, suggesting a novel therapeutic target for age-associated neurodegeneration.

scholarly journals Prx1-Expressing Progenitor Primary Cilia Mediate Bone Formation in response to Mechanical Loading in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Emily R. Moore ◽  
Julia C. Chen ◽  
Christopher R. Jacobs
Keyword(s):  
Bone Formation ◽  
Mechanical Loading ◽  
Cell Population ◽  
Primary Cilia ◽  
Complete Response ◽  
Fracture Repair ◽  
Bone Tissue Regeneration ◽  
Attractive Alternative ◽  
Physical Stimulation

Increases in mechanical loading can enhance the addition of new bone, altering geometry and density such that bones better withstand higher forces. Bone-forming osteoblasts have long been thought to originate from progenitors, but the exact source is yet to be identified. Previous studies indicate osteogenic precursors arise from Prx1-expressing progenitors during embryonic development and adult fracture repair. However, it is unknown whether this cell population is also a source for mechanically induced active osteoblasts. We first identified that Prx1 is expressed in skeletally mature mouse periosteum, a thin tissue covering the surface of the bone that is rich in osteoprogenitors. We then traced Prx1 progenitor lineage using a transgenic mouse model carrying both a Prx1-driven tamoxifen-inducible Cre and a ROSA-driven lacZ reporter gene. Cells that expressed Prx1 when compressive axial loading was applied were detected within the cortical bone days after stimulation, indicating osteocytes are of Prx1-expressing cell origin. In addition, we evaluated how these cells sense and respond to physical stimulation in vivo by disrupting their primary cilia, which are antenna-like sensory organelles known to enhance mechanical and chemical signaling kinetics. Although Prx1-driven primary cilium disruption did not affect osteoblast recruitment to the bone surface, the relative mineral apposition and bone formation rates were decreased by 53% and 34%, respectively. Thus, this cell population contributes to load-induced bone formation, and primary cilia are needed for a complete response. Interestingly, Prx1-expressing progenitors are easily extracted from periosteum and are perhaps an attractive alternative to marrow stem cells for bone tissue regeneration strategies.

Impaired febrile responses of aging mice are mediated by endogenous lipocortin-1 (annexin-1)

1993 ◽  
Vol 265 (2) ◽  
pp. E289-E297 ◽  
Author(s):  
P. J. Strijbos ◽  
M. A. Horan ◽  
F. Carey ◽  
N. J. Rothwell
Keyword(s):  
Body Temperature ◽  
Interleukin 1 ◽  
Age Groups ◽  
Plasma Corticosterone ◽  
Interleukin 1 Beta ◽  
Febrile Response ◽  
Aged Mice ◽  
Annexin 1 ◽  
Adult Mice ◽  
Age Related

The mechanisms underlying age-related impairments in febrile responses were investigated in female C57Bl/lcrf-a(t) mice. Injection of norepinephrine, to assess total thermogenic capacity, significantly increased oxygen consumption (VO2) in all age groups, although the responses of the aged mice were significantly reduced. Injection of lipopolysaccharide or murine interleukin-1 beta (mIL-1 beta) significantly increased body temperature and VO2 in the young and adult mice but not in the aged mice. The impaired responses to mIL-1 beta in the aged mice were normalized by either injection of the glucocorticoid receptor antagonist RU-38486 or by injection of an antiserum to lipocortin-1 or its purified immunoglobulin G fraction. Injection of prostaglandin E2 significantly increased VO2 and body temperature in all age groups. Resting plasma corticosterone concentrations were significantly elevated in the aged and adult mice, whereas injection of mIL-1 beta significantly raised plasma corticosterone concentrations in all animals. These findings indicate that the impaired febrile response of aged female C57Bl/lcrf-a(t) mice may be caused by increased concentrations and/or sensitivity to endogenous glucocorticoids. The impaired febrile responses of aged mice appear to be mediated by endogenous lipocortin-1.

scholarly journals Effect of chronic intranasal administration of α-synuclein oligomers on motor activity and anxiety in adult and middle-aged mice

2019 ◽  
pp. 34-40
Author(s):  
О.А. Соловьева ◽  
М.А. Грудень ◽  
В.В. Шерстнев
Keyword(s):  
Motor Activity ◽  
Motor Behavior ◽  
Lewy Body Dementia ◽  
Chronic Administration ◽  
Middle Aged ◽  
Aged Mice ◽  
Adult Mice ◽  
Age Related ◽  
Plus Maze ◽  
Age Dependent

К числу наименее экспериментально изученных аспектов патогенеза α-синуклеинопатий (основными представителями которых являются болезнь Паркинсона и деменция с тельцами Леви) относятся возрастные особенности влияния амилоидогенных форм α-синуклеина, образующихся в результате его гиперэкспрессии и мисфолдинга, на поведение и физиологические функции млекопитающих. Цель исследования состояла в изучении влияния олигомеров α-синуклеина на двигательную активность и тревожность взрослых и стареющих мышей. Материалы и методы. Опыты проводили на 6- и 12-месячных самцах мышей C57Bl/6, которым на протяжении 14 дней один раз в сутки вводили раствор олигомеров α-синуклеина (суммарная доза 0,48 мг/кг) или физиологический раствор. Для оценки общей двигательной активности и тревожности использовали тесты «Открытое поле» и «Приподнятый крестообразный лабиринт». Результаты. Обнаружено, что олигомеры α-синуклеина при хроническом введении вызывают у взрослых мышей возрастание тревожности без общих двигательных нарушений, в то время как у стареющих мышей - нарушение двигательной активности (снижение средней скорости и длины пройденного пути) и рост тревожности. Выводы. Полученные данные свидетельствуют о возраст зависимом характере поведенческих эффектов олигомеров α-синуклеина в условиях хронического интраназального введения. Among the least experimentally studied aspects of the pathogenesis of α- synucleinopathies (major representatives, Parkinson`s disease and Lewy body dementia) are age-related effects of amyloidogenic α-synuclein species resulting from overexpression and misfolding on mammalian behavior and physiological functions. The aim of this study was to evaluate effects of α-synuclein oligomers on motor behavior and anxiety in adult and middle-aged mice. Methods. Experiments were performed on 6- and 12-month-old male C57Bl/6 mice. A solution of α-synuclein oligomers or saline was administered once a day for 14 days (total dose, 0.48 mg/kg). To evaluate the overall motor activity and anxiety, the open field and elevated plus maze tests were used. Results. Chronic administration of α-synuclein oligomers to adult mice increased anxiety without overall motor disorders while middle-aged mice demonstrated both changes in their motor activity (decreases in average speed and path length) and increased anxiety. Conclusions. The study showed that the behavioral effects of α-synuclein oligomers administered chronically, intranasally were age-dependent.

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