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

TLDR

Age‑related behavioral decline may stem from synaptic alterations, and caloric restriction and exercise—known anti‑aging interventions—could act through synapses. The authors sought to determine whether caloric restriction and exercise modify neuromuscular junction structure in aging mice. They examined skeletal neuromuscular junctions in young adult and aged mice, using histological analysis and in vivo time‑lapse imaging to quantify structural changes. Age‑related synaptic alterations emerged by 18 months and worsened by 24 months, but lifelong calorie restriction reduced pre‑ and postsynaptic abnormalities, motor neuron loss, and muscle fiber turnover, while one month of wheel running lessened synaptic changes and partially reversed existing alterations, demonstrating that interventions extending health span can partially reverse age‑related synaptic degeneration.

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.