Aging pathobiology and therapeutics最新文献

Background: Sleep deprivation is a universal issue that affects individuals in different ways. While some individuals experience a deficit in performance, others experience resiliency as they maintain high levels of physical and mental activity. Sleep loss is known to cause cognitive dysfunction in areas such as learning and memory, but little is known about neural mechanisms that contribute to resilience to this adverse effect.

Methods: An existing database of a learning paradigm in sleep deprived and non-sleep deprived 16 to 18-month old C57BL/6 mice was used to identify fast learners and slow learners based on an R2 value representing the learning curve of each individual mouse.

Results: Results showed that sleep deprived mice had more slow learners compared to fast learners whereas non-sleep-deprived mice showed the opposite. Hippocampal immunohistochemistry and digital imaging analysis showed sleep deprived, fast learners expressed lower levels of monocyte chemoattractant protein-1 and histone deacetylase 2 and higher levels of synaptophysin and brain-derived neurotrophic factor compared to sleep-deprived slow learners.

Conclusions: These observations provide evidence to suggest that sleep-deprived mice that performed well in a cognitive assay show less hippocampal mediated learning impairment and provide the rationale for further investigations into neurobiological resilience to sleep deprivation with increasing age.

Eosinophilic crystalline pneumonia (ECP), also known as acidophilic macrophage pneumonia (AMP), is a common intrapulmonary lesion that increases in prevalence with age in mice, especially those on a C57BL/6 and 129Sv background. Gross changes may be evident in severe cases as lobar to diffuse red to brown foci throughout the lungs, which fail to collapse. Definitive diagnosis is by histopathology, which shows the accumulation of brightly eosinophilic crystals within macrophages or free within lumens of alveolar spaces and conducting airways. Granulocytes, multinucleated giant cells, and epithelial hyalinosis may also be present in affected areas of the lung. The disease may represent a cause of morbidity and mortality when other disease processes interfere with clearance, leading to the accumulation of crystals and crystal laden macrophages in airways, resulting in dyspnea. Other anatomic locations may be affected by epithelial hyalinosis and/or crystals as part of the syndrome, including respiratory tract, stomach, gall bladder, bile duct, and pancreatic duct.

A female UM-HET3 mouse from the Study of Longitudinal Aging in Mice (SLAM) was euthanized at 164 weeks of age due to hind limb weakness. Necropsy and histological analysis revealed that the most probable cause of the clinical finding was the compression of the thoracolumbar segment of the spinal cord by herniated intervertebral disks. In addition, a spontaneous chordoma was incidentally found in the coccygeal bones. Given the rarity of this type of tumor, bio-clinical annotations acquired throughout lifespan, detailed histopathological assessment, and comparative clinical-pathological correlations for this mouse are presented and discussed.

Objective: Mitochondrial dysfunction comprises part of the etiology of myriad health issues, particularly those that occur with advancing age. Methionine sulfoxide reductase A (MsrA) is a ubiquitous protein oxidation repair enzyme that specifically and catalytically reduces a specific epimer of oxidized methionine: methionine sulfoxide. In this study, we tested the ways in which mitochondrial bioenergetic functions are affected by increasing MsrA expression in different cellular compartments.

Methods: In this study, we tested the function of isolated mitochondria, including free radical generation, ATP production, and respiration, from the skeletal muscle of two lines of transgenic mice with increased MsrA expression: mitochondria-targeted MsrA overexpression or cytosol-targeted MsrA overexpression.

Results: Surprisingly, in the samples from mice with mitochondrial-targeted MsrA overexpression, we found dramatically increased free radical production though no specific defect in respiration, ATP production, or membrane potential. Among the electron transport chain complexes, we found the activity of complex I was specifically reduced in mitochondrial MsrA transgenic mice. In mice with cytosolic-targeted MsrA overexpression, we found no significant alteration made to any of these parameters of mitochondrial energetics.

Conclusions: There is also a growing amount of evidence that MsrA is a functional requirement for sustaining optimal mitochondrial respiration and free radical generation. MsrA is also known to play a partial role in maintaining normal protein homeostasis by specifically repairing oxidized proteins. Our studies highlight a potential novel role for MsrA in regulating the activity of mitochondrial function through its interaction with the mitochondrial proteome.

Background: Sleep deprivation-induced cognitive impairment is a major health concern and an age-related risk factor for dementia. There is an urgent need to develop ways of preventing the adverse neurological effects of sleep deprivation, but current preclinical animal models of short-term sleep deprivation are not well described.

Methods: C57BL6 mice of varying ages were sleep deprived for 4 hours a day for 4 days, and then tested with a Box maze navigation task.

Results: Sleep deprived mice at young, middle and older ages showed learning impairment that varied by strain and gender. In general, females were more sensitive to sleep deprivation than males. To determine whether sleep deprivation-induced learning impairment would respond to therapeutic intervention, an independent cohort of mice was treated with rapamycin daily during the 4 days of sleep deprivation. Mice that were sleep deprived and treated with rapamycin showed significant improvement in learning time suggesting that the cognitive impairment might be associated in part with molecular and cellular mechanisms targeted by rapamycin.

Conclusions: The observations from this study suggest that aging mice would be productive models to study pathobiology and therapeutic intervention of cognitive impairment triggered by age-related sleeping disorders in people.