A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration.
A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration.
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DOI：
10.1523/jneurosci.5657-12.2013
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发表时间：
2013-05-22
期刊：
影响因子：
--
通讯作者：
Tsai LH
中科院分区：
文献类型：
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作者：
Gräff J;Kahn M;Samiei A;Gao J;Ota KT;Rei D;Tsai LH
热量限制（CR）是一种饮食疗法，已知可以通过减缓年龄相关疾病的发生来延长寿命。大脑神经退行性变的最大危险因素是年龄，因此 CR 还可能减轻通常与认知能力受损相关的神经元进行性丧失。在这项研究中，我们使用了转基因小鼠模型，该模型允许在时间和空间上控制神经变性的发生，以测试 CR 的潜在有益作用。我们发现，在这个模型中，CR 显着延迟了神经退行性变、突触丧失和功能障碍的发生，从而保留了认知能力。从机制上讲，CR 诱导了已知的寿命调节蛋白 SIRT1 的表达，促使我们测试 SIRT1 的药理学激活是否可能重现 CR。我们发现口服 SIRT1 激活化合物基本上复制了 CR 的有益效果。因此，SIRT1 激活化合物可能为针对神经退行性变及其相关疾病的 CR 治疗方案提供一种药理学替代方案。
Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration, synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments.