Ssd1 and Gcn2 suppress global translational efficiency in replicatively aged yeast, while their activation in young cells extends lifespan

Using ribosome profiling, we find globally reduced translation efficiency during mitotic / replicative aging in budding yeast. Two mechanisms contribute to this: Firstly, the mRNA binding protein Ssd1 is induced during aging, sequestering mRNAs to P-bodies and stress granules that are abundant in old cells. Indeed, overexpression of Ssd1 reduced protein synthesis in young cells and extended lifespan, while loss of Ssd1 reduced the translational deficit of old cells and shortened lifespan. Secondly, the Gcn2 kinase is activated in old cells, phosphorylating and inactivating the translational initiation factor eIF2α. Accordingly, deletion of GCN2 reduced the translational defect of old cells. Furthermore, overexpressing an uncharged tRNA to fully activate Gcn2, or overexpression of its downstream mediator, Gcn4, extended replicative lifespan in a manner that was mostly dependent on autophagy without inhibiting the TOR pathway. As such, Ssd1 induction, activation of the integrated stress response or autophagy are favorable TOR-independent therapeutic targets for lifespan extension.本研究借助核糖体谱（ribosome profiling）技术，发现酿酒酵母在有丝分裂/复制性衰老过程中全局翻译效率显著降低。该现象由两种机制介导：其一，衰老过程中mRNA结合蛋白Ssd1的表达被诱导，其可将mRNA封存于老年细胞中富集的P小体与应激颗粒内。实验证实，过表达Ssd1可降低年轻细胞的蛋白质合成水平并延长其寿命；而缺失Ssd1则可缓解老年细胞的翻译缺陷并缩短寿命。其二，老年细胞中Gcn2激酶被激活，通过磷酸化修饰使翻译起始因子eIF2α失活。相应地，敲除GCN2可改善老年细胞的翻译缺陷。此外，过表达未负载tRNA以完全激活Gcn2，或过表达其下游介导因子Gcn4，均可在不抑制雷帕霉素靶蛋白（TOR）通路的前提下，主要依赖自噬途径延长酿酒酵母的复制性寿命。综上，Ssd1诱导、整合应激反应激活或自噬，均可作为不依赖TOR通路的理想寿命延长治疗靶点。