The mTOR pathway is necessary for survival of mice with short telomeres
The mTOR pathway is necessary for survival of mice with short telomeres
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DOI：
10.1038/s41467-020-14962-1
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发表时间：
2020-03-03
影响因子：
16.6
通讯作者：
Blasco, Maria A.
中科院分区：
文献类型：
--
作者：
Ferrara-Romeo, Iole;Martinez, Paula;Blasco, Maria A.
端粒酶缺乏导致与年龄相关的疾病和寿命缩短。抑制雷帕霉素（mTOR）的机制靶点可以延缓衰老和年龄相关的病理。在这里，我们发现，端粒酶缺陷小鼠与短端粒（G2-Terc（-/-））有一个超活化的mTOR通路与增加水平的磷酸化核糖体S6蛋白在肝脏，骨骼肌和心脏，一个目标的mTORC 1。转录谱确认了G2-Terc（-/-）肝脏中的mTOR活化。用雷帕霉素（mTORC 1的抑制剂）治疗G2-Terc（-/-）小鼠，与野生型对照组的寿命延长相反，存活率降低。与单个S6 K1（-/-）雌性小鼠的寿命延长相反，G3-Terc（-/-）小鼠中mTORC 1下游S6激酶1的缺失也会降低寿命。这些发现表明，在短端粒的情况下，mTOR对于生存是重要的，并且在这种情况下，其抑制是有害的。这些结果是临床意义上的人类综合征的情况下，其特征在于严重短端粒。端粒酶缺乏导致与年龄相关的疾病和寿命缩短，而mTOR通路的抑制延缓衰老。在这里，作者表明mTORC 1信号的抑制缩短了端粒酶缺陷小鼠的寿命。
Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc(-/-)) have an hyper-activated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc(-/-) livers. Treatment of G2-Terc(-/-) mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1in G3-Terc(-/-) mice also decreases longevity, in contrast to lifespan extension in single S6K1(-/-) female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres. Telomerase deficiency leads to age-related diseases and shortened lifespan, while inhibition of the mTOR pathway delays aging. Here, the authors show that inhibition of mTORC1 signaling shortens the lifespan of telomerase deficient mice.