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Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.

ABSTRACT: The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice revealed a variety of age-related structural alterations, including axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites, and fragmentation of the postsynaptic specialization. Alterations were significant by 18 mo of age and severe by 24 mo. A life-long calorie-restricted diet significantly decreased the incidence of pre- and postsynaptic abnormalities in 24-mo-old mice and attenuated age-related loss of motor neurons and turnover of muscle fibers. One month of exercise (wheel running) in 22-mo-old mice also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover. Time-lapse imaging in vivo revealed that exercise partially reversed synaptic alterations that had already occurred. These results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes.

SUBMITTER: Valdez G

PROVIDER: S-EPMC2930485 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.

Valdez Gregorio G Tapia Juan C JC Kang Hyuno H Clemenson Gregory D GD Gage F H FH Lichtman Jeff W JW Sanes Joshua R JR

Proceedings of the National Academy of Sciences of the United States of America 20100802 33

The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice re ...[more]

PMID: 20679195

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Project description:Immunosenescence refers to age-related declines in the capacity to respond to infections such as influenza (flu). Caloric restriction represents a known strategy to slow many aging processes, including those involving the immune system. More recently, some changes in the microbiome have been described with aging, while the gut microbiome appears to influence responses to flu vaccination and infection. With these considerations in mind, we used a well-established mouse model of flu infection to explore the impact of flu infection, aging, and caloric restriction on the gut microbiome. Young, middle-aged, and aged caloric restricted (CR) and ad lib fed (AL) mice were examined after a sublethal flu infection. All mice lost 10-20% body weight and, as expected for these early time points, losses were similar at different ages and between diet groups. Cytokine and chemokine levels were also similar with the notable exception of IL-1?, which rose more than fivefold in aged AL mouse serum, while it remained unchanged in aged CR serum. Fecal microbiome phyla abundance profiles were similar in young, middle-aged, and aged AL mice at baseline and at 4?days post flu infection, while increases in Proteobacteria were evident at 7?days post flu infection in all three age groups. CR mice, compared to AL mice in each age group, had increased abundance of Proteobacteria and Verrucomicrobia at all time points. Interestingly, principal coordinate analysis determined that diet exerts a greater effect on the microbiome than age or flu infection. Percentage body weight loss correlated with the relative abundance of Proteobacteria regardless of age, suggesting flu pathogenicity is related to Proteobacteria abundance. Further, several microbial Operational Taxonomic Units from the Bacteroidetes phyla correlated with serum chemokine/cytokines regardless of both diet and age suggesting an interplay between flu-induced systemic inflammation and gut microbiota. These exploratory studies highlight the impact of caloric restriction on fecal microbiome in both young and aged animals, as well as the many complex relationships between flu responses and gut microbiota. Thus, these preliminary studies provide the necessary groundwork to examine how gut microbiota alterations may be leveraged to influence declining immune responses with aging.

Project description:BackgroundThe root mean square surface electromyographic activity of lumbar extensor muscles during dynamic trunk flexion and extension from a standing position and task specific spine ranges of motion objectively assess muscle function in healthy young and middle age individuals. However, literature on neuromuscular activation and associated spine and hip kinematics in older individuals is sparse. This cross sectional study sought to examine the sex and age (<40 versus >60 years) related differences in the neuromuscular activation profiles of the lumbar extensors and the related spine and hip kinematics from healthy individuals during a standardized trunk flexion-extension task.MethodsTwenty five older (13 females, 60-90 years) and 24 younger (12 females, 18-40 years) healthy individuals performed trunk flexion-extension testing by holding static positions at half-flexion way and full range of motion between standing and maximum trunk flexion. The associated lumbar extensor muscle activity was derived from measurements at standing, half, and maximum flexion positions. The range of motion at the hip and lumbar spine was recorded using 3d accelerometers attached to the skin overlying the multifidus and semispinalis thoracis muscles lateral to the L5 and T4 spinous processes, respectively. Statistical calculations were performed using a permutation ANOVA with bootstrap confidence intervals.ResultsThe muscle activity in the half related to the maximum flexion position (half flexion relaxation ratio) was significantly smaller in older males when compared with younger males. Moreover, measurements revealed smaller activity changes from standing to the half and from half to the maximum flexion position in older compared to younger individuals. Older males displayed smaller gross trunk range of motion from standing to maximum flexion than any other group.ConclusionsGender and normal aging significantly affect both the activation patterns of the lumbar extensor muscles and the kinematics of the trunk during a standardized trunk flexion-extension task. Measurement results from healthy young and middle age individuals should not be used for the assessment of individuals older than 60 years of age.

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Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.

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Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.

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