Inhibition of the master growth regulator mTORC1 (mechanistic target of rapamycin complex 1) slows ageing across phyla, in part by reducing protein synthesis. Various stresses globally suppress protein synthesis through the integrated stress response (ISR), resulting in preferential translation of the transcription factor ATF-4. Here we show in C. elegans that inhibition of translation or mTORC1 increases ATF-4 expression, and that ATF-4 mediates longevity under these conditions independently of ISR signalling. ATF-4 promotes longevity by activating canonical anti-ageing mechanisms, but also by elevating expression of the transsulfuration enzyme CTH-2 to increase hydrogen sulfide (H₂S) production. This H₂S boost increases protein persulfidation, a protective modification of redox-reactive cysteines. The ATF-4/CTH-2/H₂S pathway also mediates longevity and increased stress resistance from mTORC1 suppression. Increasing H₂S levels, or enhancing mechanisms that H₂S influences through persulfidation, may represent promising strategies for mobilising therapeutic benefits of the ISR, translation suppression, or mTORC1 inhibition.

中文翻译：

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ATF-4 和硫化氢信号通过抑制翻译或 mTORC1 介导长寿

抑制主生长调节剂 mTORC1（雷帕霉素复合物 1 的机制目标）可减缓整个门的衰老，部分原因是减少蛋白质合成。各种压力通过综合压力反应 (ISR) 全局抑制蛋白质合成，导致转录因子 ATF-4 的优先翻译。在这里，我们在秀丽隐杆线虫中表明，抑制翻译或 mTORC1 会增加 ATF-4 表达，并且 ATF-4 在这些条件下独立于 ISR 信号传导介导寿命。ATF-4 通过激活经典的抗衰老机制，以及通过提高转硫酶 CTH-2 的表达来增加硫化氢 (H ₂ S) 的产生来延长寿命。这 H ₂S boost 增加了蛋白质过硫化，这是一种对氧化还原反应性半胱氨酸的保护性修饰。ATF-4/CTH-2/H ₂ S 通路还介导了 mTORC1 抑制导致的寿命和增加的抗压性。增加 H ₂ S 水平，或增强 H ₂ S 通过过硫化作用影响的机制，可能代表调动 ISR、翻译抑制或 mTORC1 抑制的治疗益处的有希望的策略。