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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-08, Vol.107 (33), p.14863-14868
• Main Authors: Valdez, Gregorio, Tapia, Juan C., Kang, Hyuno, Clemenson, Gregory D., Gage, F. H., Lichtman, Jeff W., Sanes, Joshua R., Fischbach, Gerald D.
• Format: Article
• Language: English
• Subjects: Age; Aging; Aging - physiology; Animals; Axon sprouting; Axons; Biological Sciences; Caloric Restriction; Comparative analysis; Dietary restrictions; Exercise; Immunohistochemistry; Innervation; Intervention; Life span; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Confocal; Motor neurons; Motor Neurons - metabolism; Motor Neurons - physiology; Muscle fibers; Muscle, Skeletal - abnormalities; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiopathology; Muscles; Nerves; Neuromuscular Junction - abnormalities; Neuromuscular Junction - metabolism; Neuromuscular Junction - physiopathology; Neuromuscular junctions; Neurons; Physical Conditioning, Animal - physiology; Physical training; Receptors, Cholinergic - metabolism; Rodents; Specialization; Synapses; Synapses - metabolism; Wheel running; Young adults
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1002220107

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.