Age-Related Neurodegeneration Prevention Through mTOR Inhibition: Potential Mechanisms and Remaining Questions.
Age-Related Neurodegeneration Prevention Through mTOR Inhibition: Potential Mechanisms and Remaining Questions.
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DOI：
10.2174/1568026615666150610125856
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发表时间：
2015
影响因子：
3.4
通讯作者：
Laberge RM
中科院分区：
文献类型：
--
作者：
Jahrling JB;Laberge RM
随着全球人口老龄化，阿尔茨海默病、帕金森病和轻度认知功能障碍的患病率不断上升。雷帕霉素作为延长包括小鼠在内的各种生物体寿命的药物的成功，带来了长期mTOR抑制也可以抑制年龄相关的神经退行性变的希望。在这里，我们回顾的证据表明，mTOR抑制-主要与雷帕霉素-是一种有效的干预措施，以延缓年龄相关的神经退行性变。我们讨论了雷帕霉素可能促进神经变性预防或认知功能恢复的潜在机制。我们还讨论了已知的雷帕霉素的副作用，并提供证据，以减轻夸大的关注，其更广泛的临床应用。我们探索了雷帕霉素的小分子替代品，并提出了未来的发展方向，主要是通过探索靶向mTOR下游效应子的可能性：S6 K1，特别是S6 K2。最后，我们讨论了用于确定神经退行性疾病干预效果的模型的优点和缺点。我们解决的困难，解释数据使用调查干预措施的有效性，以延迟/预防神经退行性变的常见方式，通过观察动物的行为，而这些动物正在接受治疗。我们提出了一种实验设计，该设计应在实验设计中隔离衰老变量并解决最近文献中存在的模糊性。
With the global aging population, Alzheimer's disease, Parkinson's disease and mild cognition impairment are increasing in prevalence. The success of rapamycin as an agent to extend lifespan in various organisms, including mice, brings hope that chronic mTOR inhibition could also refrain age-related neurodegeneration. Here we review the evidence suggesting that mTOR inhibition - mainly with rapamycin - is a valid intervention to delay age-related neurodegeneration. We discuss the potential mechanisms by which rapamycin may facilitate neurodegeneration prevention or restoration of cognitive function. We also discuss the known side effects of rapamycin and provide evidence to alleviate exaggerated concerns regarding its wider clinical use. We explore the small molecule alternatives to rapamycin and propose future directions for their development, mainly by exploring the possibility of targeting the downstream effectors of mTOR: S6K1 and especially S6K2. Finally, we discuss the strengths and weaknesses of the models used to determine intervention efficacy for neurodegeneration. We address the difficulties of interpreting data using the common way of investigating the efficacy of interventions to delay/prevent neurodegeneration by observing animal behavior while these animals are under treatment. We propose an experimental design that should isolate the variable of aging in the experimental design and resolve the ambiguity present in recent literature.