Department of Molecular, Cellular, and Developmental Biology (G.D.), University of Michigan College of Literature, Science and the Arts, Ann Arbor, Michigan 48109; Edison Biotechnology Institute (D.E.B., E.O.L., J.J.K.), Ohio University, Athens, Ohio 45701; Department of Pathology (X.L., R.A.M., G.G.G.), University of Michigan School of Medicine Ann Arbor, Michigan 48109; and University of Michigan Geriatrics Center (R.A.M.), Ann Arbor, Michigan 48109.
Endocrinology. 2015 Feb;156(2):565-75. doi: 10.1210/en.2014-1690. Epub 2014 Dec 2.
The involvement of mammalian target of rapamycin (mTOR) in lifespan control in invertebrates, calorie-restricted rodents, and extension of mouse lifespan by rapamycin have prompted speculation that diminished mTOR function may contribute to mammalian longevity in several settings. We show here that mTOR complex-1 (mTORC1) activity is indeed lower in liver, muscle, heart, and kidney tissue of Snell dwarf and global GH receptor (GHR) gene-disrupted mice (GHR-/-), consistent with previous studies. Surprisingly, activity of mTORC2 is higher in fasted Snell and GHR-/- than in littermate controls in all 4 tissues tested. Resupply of food enhanced mTORC1 activity in both controls and long-lived mutant mice but diminished mTORC2 activity only in the long-lived mice. Mice in which GHR has been disrupted only in the liver do not show extended lifespan and also fail to show the decline in mTORC1 and increase in mTORC2 seen in mice with global loss of GHR. The data suggest that the antiaging effects in the Snell dwarf and GHR-/- mice are accompanied by both a decline in mTORC1 in multiple organs and an increase in fasting levels of mTORC2. Neither the lifespan nor mTOR effects appear to be mediated by direct GH effects on liver or by the decline in plasma IGF-I, a shared trait in both global and liver-specific GHR-/- mice. Our data suggest that a more complex pattern of hormonal effects and intertissue interactions may be responsible for regulating both lifespan and mTORC2 function in these mouse models of delayed aging.
哺乳动物雷帕霉素靶蛋白（mTOR）参与无脊椎动物、限食啮齿动物的寿命控制以及雷帕霉素延长小鼠寿命，这促使人们推测，mTOR 功能的降低可能有助于几种情况下哺乳动物的长寿。我们在这里表明，Snell 侏儒和全球生长激素受体（GHR）基因敲除（GHR-/-）小鼠的肝脏、肌肉、心脏和肾脏组织中的 mTOR 复合物-1（mTORC1）活性确实较低，这与之前的研究一致。令人惊讶的是，在所有 4 种测试组织中，禁食的 Snell 和 GHR-/-中的 mTORC2 活性都高于其同窝对照。食物的重新供应增强了对照组和长寿突变小鼠中 mTORC1 的活性，但仅在长寿小鼠中降低了 mTORC2 的活性。仅在肝脏中破坏 GHR 的小鼠不会延长寿命，也不会显示出 mTORC1 的下降和 mTORC2 的增加，而这种下降和增加在全身失去 GHR 的小鼠中可见。这些数据表明，Snell 侏儒和 GHR-/-小鼠的抗衰老作用伴随着多个器官中 mTORC1 的下降和禁食状态下 mTORC2 水平的升高。无论是寿命还是 mTOR 效应似乎都不是由肝脏中 GH 对直接作用或两种 GHR-/-小鼠中共同存在的血浆 IGF-I 下降所介导的。我们的数据表明，更复杂的激素作用和组织间相互作用模式可能负责调节这些延缓衰老的小鼠模型中的寿命和 mTORC2 功能。
