Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans
Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans
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DOI：
10.7554/elife.49158
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发表时间：
2019-08-14
期刊：
影响因子：
7.7
通讯作者：
Mair, William B.
中科院分区：
文献类型：
--
作者：
Zhang, Yue;Lanjuin, Anne;Mair, William B.
雷帕霉素复合物1（TORC 1）和AMP活化蛋白激酶（AMPK）的靶点拮抗性调节代谢和衰老。然而，它们如何协调以确定寿命以及它们是否通过可分离的机制起作用尚不清楚。在这里，我们表明，神经元AMPK是从TORC 1抑制寿命延长必不可少的，和TORC 1抑制增加寿命细胞非自主通过不同的机制从全球AMPK激活。通过编码raga-1（RagA）或rsks-1（S6 K）的基因中的无效突变延长寿命完全受到神经元特异性拯救的抑制。RAGA-1的缺失通过维持线粒体融合来增加寿命。神经元RAGA-1废除raga-1突变体寿命需要β-64/syntaxin，并促进线粒体分裂细胞非自主。最后，删除线粒体分裂因子DRP-1使动物对神经元RAGA-1的促衰老作用不敏感。我们的结果强调了神经元TORC 1在细胞非自主调节寿命中的新作用，并表明中枢神经系统中的TORC 1可能是促进健康衰老的目标。
Target of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK) antagonistically modulate metabolism and aging. However, how they coordinate to determine longevity and if they act via separable mechanisms is unclear. Here, we show that neuronal AMPK is essential for lifespan extension from TORC1 inhibition, and that TORC1 suppression increases lifespan cell non autonomously via distinct mechanisms from global AMPK activation. Lifespan extension by null mutations in genes encoding raga-1 (RagA) or rsks-1 (S6K) is fully suppressed by neuronal-specific rescues. Loss of RAGA-1 increases lifespan via maintaining mitochondrial fusion. Neuronal RAGA-1 abrogation of raga-1 mutant longevity requires UNC-64/syntaxin, and promotes mitochondrial fission cell nonautonomously. Finally, deleting the mitochondrial fission factor DRP-1 renders the animal refractory to the pro-aging effects of neuronal RAGA-1. Our results highlight a new role for neuronal TORC1 in cell nonautonomous regulation of longevity, and suggest TORC1 in the central nervous system might be targeted to promote healthy aging.