Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise
Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise
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DOI：
10.1073/pnas.1002220107
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发表时间：
2010-08-17
影响因子：
11.1
通讯作者：
Sanes, Joshua R.
中科院分区：
文献类型：
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作者：
Valdez, Gregorio;Tapia, Juan C.;Sanes, Joshua R.
与年龄相关的行为衰退的细胞基础仍然不清楚，但突触的改变可能是候选者。因此，热量限制和运动对神经功能的有益作用，这是已知的最有效的抗衰老治疗方法之一，也可能是由突触介导的。作为测试这些想法的起点，我们研究了骨骼神经肌肉接头（NMJ），一个大的，可接近的外周突触。比较年轻成年和老年小鼠的NMJs发现了各种与年龄相关的结构改变，包括轴突肿胀、出芽、突触脱离、部分或完全从某些突触后位点撤回轴突以及突触后特化的片段化。18个月时变化显著，24个月时变化严重。终身限制热量饮食显著降低了24月龄小鼠突触前和突触后异常的发生率，并减弱了与年龄相关的运动神经元损失和肌纤维周转。在22个月大的小鼠中进行一个月的运动（跑轮子）也减少了与年龄相关的突触变化，但对运动神经元数量或肌纤维周转率没有影响。体内延时成像显示，运动部分逆转了已经发生的突触改变。这些结果证明了衰老对突触结构的关键影响，并提供了证据表明，能够延长健康寿命和寿命的干预措施可以部分逆转这些与年龄相关的突触变化。
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.