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.aging | neuromuscular junction | muscle | motor neuron | sarcopenia A ging is accompanied by numerous functional alterations of both the central and peripheral nervous systems (1). Until recently, it was thought that many of these age-associated changes were secondary to neuronal degeneration. Recent studies show, however, that little neuronal death occurs in most areas of the aging nervous system (2). Although many possible explanations exist (3-6), a particularly attractive hypothesis is that some agerelated alterations in mental function result from synaptic alterations. Supporting this idea, alterations in synapse number, spine densities, and synaptic plasticity have been documented in the brains of aging humans and experimental animals (1,7,8).If synaptic changes underlie age-related defects in neural function, one might look to synapses as targets for treatments that minimize the decline. Two lifestyle regimens that have been consistently demonstrated to extend lifespan and mitigate agerelated changes in neural function are caloric restriction and exercise (9). In that the cellular bases of age-related changes in mental activity are obscure, it is not surprising that the means by which exercise and caloric restriction attenuate these changes are also unknown. For both regimens, however, synaptic alterations have figured prominently among proposed mechanisms (9, 10).An obstacle to progress in this area is the complexity and diversity of synaptic neuropil in the brain, which impedes detailed analysis of aging central syna...