Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice.
Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice.
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DOI：
10.1111/acel.12425
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发表时间：
2016-02
期刊：
影响因子：
7.8
通讯作者：
Lamming DW
中科院分区：
文献类型：
--
作者：
Baar EL;Carbajal KA;Ong IM;Lamming DW
抑制 mTOR（雷帕霉素的机械靶标）信号通路可有效延长包括小鼠在内的模型生物体的寿命。雷帕霉素有益作用背后的精确分子机制和生理效应是一个令人兴奋的研究领域。令人惊讶的是，虽然一些数据表明 mTOR 信号传导通常随着小鼠年龄的增长而增加，但年龄对 mTOR 信号传导的影响从未得到全面评估。在这里，我们确定了 C57BL/6J.Nia 小鼠肝脏、肌肉、脂肪和心脏中 mTORC1（mTOR 复合物 1）和 mTORC2（mTOR 复合物 2）信号传导与年龄相关的变化，雷帕霉素治疗可以延长其寿命。我们发现，在 C57BL/6J.Nia 小鼠中，年龄对 mTORC1 和 mTORC2 活性的几种不同读数的影响因组织和性别而异。有趣的是，我们观察到与同龄雄性小鼠相比，年轻雌性小鼠的肝脏和心脏组织中 mTORC1 活性增加。在 HET3 和 DBA/2 小鼠品系的肝脏以及 F344 大鼠的肝脏、肌肉和脂肪组织中观察到了组织和底物特异性结果。我们的结果表明，衰老不会导致大多数组织中 mTOR 信号传导增加，并且表明雷帕霉素不会通过逆转或减弱这种效应来延长寿命。
Inhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age‐associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate‐specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.