Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Madrid, Spain.
Aging (Albany NY). 2021 Apr 26;13(8):10989-11009. doi: 10.18632/aging.203018.
Although the stress response in eukaryotes depends on early events triggered in cells by environmental insults, long-term processes such as aging are also affected. The loss of cellular proteostasis greatly impacts aging, which is regulated by the balancing of protein synthesis and degradation systems. As translation is the input event in proteostasis, we decided to study the role of translational activity on cell lifespan. Our hypothesis was that a reduction on translational activity or specific changes in translation may increase cellular longevity. Using mutant strains of and various stress conditions, we showed that translational reduction caused by phosphorylation of eukaryotic translation initiation factor 2 (eIF2) during the exponential growth phase enhances chronological lifespan (CLS). Furthermore, through next-generation sequence analysis, we found eIF2α phosphorylation-dependent translational activation of some specific genes, especially those involved in autophagy. This fact, together with the observed regulation of autophagy, points to a conserved mechanism involving general and specific control of translation and autophagy as mediators of the role of eIF2α phosphorylation in aging.
尽管真核生物的应激反应依赖于环境刺激引发的细胞早期事件，但衰老等长期过程也会受到影响。细胞蛋白质稳态的丧失对衰老有很大影响，而衰老受蛋白质合成和降解系统平衡的调节。由于翻译是蛋白质稳态的输入事件，我们决定研究翻译活性对细胞寿命的作用。我们的假设是，翻译活性的降低或翻译的特定变化可能会增加细胞的寿命。通过使用和各种应激条件的突变株，我们表明，在指数生长阶段通过磷酸化真核翻译起始因子 2（eIF2）引起的翻译减少会增强时序寿命（CLS）。此外，通过下一代序列分析，我们发现 eIF2α 磷酸化依赖性的一些特定基因的翻译激活，特别是那些参与自噬的基因。这一事实，加上对自噬的观察调控，表明存在一种保守机制，涉及到翻译和自噬的普遍和特定控制，作为 eIF2α 磷酸化在衰老过程中作用的介质。
