Kennedy Brian K, Lamming Dudley W
The Buck Institute for Research on Aging, Novato, CA 94945, USA.
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA.
Cell Metab. 2016 Jun 14;23(6):990-1003. doi: 10.1016/j.cmet.2016.05.009.
Since the discovery that rapamycin, a small molecule inhibitor of the protein kinase mTOR (mechanistic target of rapamycin), can extend the lifespan of model organisms including mice, interest in understanding the physiological role and molecular targets of this pathway has surged. While mTOR was already well known as a regulator of growth and protein translation, it is now clear that mTOR functions as a central coordinator of organismal metabolism in response to both environmental and hormonal signals. This review discusses recent developments in our understanding of how mTOR signaling is regulated by nutrients and the role of the mTOR signaling pathway in key metabolic tissues. Finally, we discuss the molecular basis for the negative metabolic side effects associated with rapamycin treatment, which may serve as barriers to the adoption of rapamycin or similar compounds for the treatment of diseases of aging and metabolism.
自从发现雷帕霉素（一种蛋白激酶mTOR（雷帕霉素作用靶点）的小分子抑制剂）能够延长包括小鼠在内的模式生物的寿命以来，人们对了解该信号通路的生理作用和分子靶点的兴趣激增。虽然mTOR作为生长和蛋白质翻译的调节因子已广为人知，但现在很清楚的是，mTOR作为机体代谢的核心协调因子，可响应环境和激素信号。本综述讨论了我们在理解营养物质如何调节mTOR信号传导以及mTOR信号通路在关键代谢组织中的作用方面的最新进展。最后，我们讨论了与雷帕霉素治疗相关的负面代谢副作用的分子基础，这些副作用可能成为采用雷帕霉素或类似化合物治疗衰老和代谢疾病的障碍。
