Science：美国科学家破解雷帕霉素双重性质之谜

雷帕霉素分子式

宾夕法尼亚大学的科学家们研究破解了雷帕霉素双重性质之谜。 相关研究结果发表于2012年3月30日出版的《Science》期刊上。

早在2009年，人们发现雷帕霉素可延长雌性小鼠的寿命约15%及雄性小鼠的寿命10%。 但是，该药也在啮齿类动物中引起了许多代谢问题，如葡萄糖耐受不良及胰岛素抵抗。 现在，研究人员终于厘清了该药的有益的作用——即会延长某些生物的寿命——和该药负面的代谢效应。

Dudley Lamming及其同事们用转基因小鼠做实验发现，雷帕霉素不但抑制了一种叫做mTORC1的蛋白激酶以产生其延长生命的效应，而且它还破坏了一个叫做mTORC2的相关的复合物。

研究人员提示，这一对MTORC2的抑制产生了在先前研究中所观察到的糖尿病样的症状，而MTORC1则独立地与寿命的增加有关。 一篇由Katherine Hughes和Brian Kennedy撰写的《观点栏目》文章更为详细地解释了这些发现并提出，只需适量的mTORC1抑制——或者也许是mTORC1 与 mTORC2活性之间的一种微妙的平衡——来开启雷帕霉素延长寿命的效应。（生物谷 bioon.com）

doi:10.1126/science.1215135
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Rapamycin-Induced Insulin Resistance Is Mediated by mTORC2 Loss and Uncoupled from Longevity

Dudley W. Lamming, Lan Ye, Pekka Katajisto, Marcus D. Goncalves, Maki Saitoh, Deanna M. Stevens, James G. Davis, Adam B. Salmon, Arlan Richardson, Rexford S. Ahima, David A. Guertin, David M. Sabatini, Joseph A. Baur

Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.