Analysing an unbiased forward genetic screen for longevity: Inhibiting the integrated stress response extends lifespan through selective mRNA translation

To conserve organismal fitness, the protein homeostasis network is maintained via cellular stress response pathways. The loss of protein homeostasis is a hallmark of ageing and its modulation can beneficially affect lifespan in model organisms. The evolutionary conserved integrated stress response (ISR) modulates mRNA translation by the phosphorylation of the translation initiation factor eIF2. Stress-sensing eIF2 kinases and the eIF2 guanine nucleotide exchange factor eIF2B are regulating ISR activation and therefore balance translation initiation. However, the role of the ISR during ageing and in longevity remains unexplored. We performed an unbiased genetic screen for the phenotype of longevity in Caenorhabditis elegans and discovered a role of eIF2B and the eIF2 kinases in longevity. We identified selected mutations in the respective genes to inhibit the ISR, enhancing protein homeostasis and increasing lifespan. Consistently, full inhibition of the ISR using phosphorylation-defective eIF2alpha or pharmacological ISR inhibition also prolonged lifespan. Lifespan extension through ISR inhibition occurred without changes in overall protein synthesis. Instead, we observed changes in translational efficiency of a defined subset of mRNAs. We could show that ISR-inhibition-mediated longevity depended on changed translational efficiency of the putative kinase KIN-35. Thus, ISR inhibition and a tuning of mRNA translation might be a viable option to promote healthy ageing