Max Planck Institute for Biology of Ageing, Cologne, Germany.
CECAD - Cluster of Excellence, University of Cologne, Cologne, Germany.
Nat Commun. 2021 Mar 15;12(1):1678. doi: 10.1038/s41467-021-21743-x.
Protein homeostasis is modulated by stress response pathways and its deficiency is a hallmark of aging. The integrated stress response (ISR) is a conserved stress-signaling pathway that tunes mRNA translation via phosphorylation of the translation initiation factor eIF2. ISR activation and translation initiation are finely balanced by eIF2 kinases and by the eIF2 guanine nucleotide exchange factor eIF2B. However, the role of the ISR during aging remains poorly understood. Using a genomic mutagenesis screen for longevity in Caenorhabditis elegans, we define a role of eIF2 modulation in aging. By inhibiting the ISR, dominant mutations in eIF2B enhance protein homeostasis and increase lifespan. Consistently, full ISR inhibition using phosphorylation-defective eIF2α or pharmacological ISR inhibition prolong lifespan. Lifespan extension through impeding the ISR occurs without a reduction in overall protein synthesis. Instead, we observe changes in the translational efficiency of a subset of mRNAs, of which the putative kinase kin-35 is required for lifespan extension. Evidently, lifespan is limited by the ISR and its inhibition may provide an intervention in aging.
蛋白质动态平衡受应激反应途径调节，其缺乏是衰老的标志。整合应激反应（ISR）是一种保守的应激信号通路，通过磷酸化翻译起始因子 eIF2 来调节 mRNA 翻译。ISR 激活和翻译起始通过 eIF2 激酶和 eIF2 鸟嘌呤核苷酸交换因子 eIF2B 精细平衡。然而，ISR 在衰老过程中的作用仍知之甚少。我们通过在秀丽隐杆线虫中进行基因组诱变筛选长寿，定义了 eIF2 调节在衰老过程中的作用。通过抑制 ISR，eIF2B 的显性突变增强蛋白质动态平衡并延长寿命。通过使用磷酸化缺陷型 eIF2α 或药理学 ISR 抑制完全抑制 ISR 一致地延长寿命。通过阻碍 ISR 延长寿命的发生并没有降低整体蛋白质合成。相反，我们观察到一部分 mRNA 的翻译效率发生变化，其中假定的激酶 kin-35 对于延长寿命是必需的。显然，寿命受到 ISR 的限制，其抑制可能为衰老干预提供了一种方法。
