Department of Dairy Science, University of Wisconsin-Madison, Madison, United States.
William S. Middleton Memorial Veterans Hospital, Madison, United States.
Elife. 2020 Jul 28;9:e56177. doi: 10.7554/eLife.56177.
Inhibition of mTOR (mechanistic Target Of Rapamycin) signaling by rapamycin promotes healthspan and longevity more strongly in females than males, perhaps because inhibition of hepatic mTORC2 (mTOR Complex 2) specifically reduces the lifespan of males. Here, we demonstrate using gonadectomy that the sex-specific impact of reduced hepatic mTORC2 is not reversed by depletion of sex hormones. Intriguingly, we find that ovariectomy uncouples lifespan from metabolic health, with ovariectomized females having improved survival despite paradoxically having increased adiposity and decreased control of blood glucose levels. Further, ovariectomy unexpectedly promotes midlife survival of female mice lacking hepatic mTORC2, significantly increasing the survival of those mice that do not develop cancer. In addition to identifying a sex hormone-dependent role for hepatic mTORC2 in female longevity, our results demonstrate that metabolic health is not inextricably linked to lifespan in mammals, and highlight the importance of evaluating healthspan in mammalian longevity studies.
雷帕霉素抑制 mTOR（机械靶标雷帕霉素）信号转导能更显著地延长雌性而非雄性的寿命，这可能是因为肝脏 mTORC2（mTOR 复合物 2）的抑制特异性地降低了雄性的寿命。在这里，我们通过性腺切除术证明，减少肝脏 mTORC2 的性别特异性影响并不会被性激素耗竭所逆转。有趣的是，我们发现卵巢切除术将寿命与代谢健康分离，尽管卵巢切除的雌性具有增加的肥胖和降低的血糖控制水平，但仍具有改善的生存能力。此外，出乎意料的是，卵巢切除术促进了缺乏肝脏 mTORC2 的雌性小鼠的中年生存，显著增加了那些没有发生癌症的小鼠的生存能力。除了确定肝脏 mTORC2 在雌性长寿中的性别依赖性作用外，我们的结果还表明，在哺乳动物中，代谢健康与寿命并非不可分割地联系在一起，并强调了在哺乳动物长寿研究中评估寿命的重要性。
