Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation

Maxime J Derisbourg,Martin S Denzel,Laura E Wester,Ruth Baddi

doi:10.1038/s41467-021-21743-x

Abstract

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.

Highlights

Protein homeostasis is modulated by stress response pathways and its deficiency is a hallmark of aging
We found that pharmacological integrated stress response (ISR) inhibition, as well as genetic ISR ablation by mutating serine 51 of eIF2α likewise results in lifespan extension
We identified two mutations in ifg-1 and two mutations in ife-2, genes linked to lifespan extension through reduced mRNA translation[25,26] (Supplementary Fig. 1e)

Summary

Introduction

Protein homeostasis is modulated by stress response pathways and its deficiency is a hallmark of aging. The activation of the ISR relies on the eukaryotic initiation factor 2 (eIF2) kinases: hemeregulated inhibitor (HRI), protein kinase R (PKR), general control nonderepressible 2 (GCN2), and PKR-like endoplasmic reticulum kinase (PERK). They are activated, respectively, by iron deficiency, viral infection, amino acid deprivation, and accumulation of misfolded proteins in the ER14. While the ISR and mRNA translation initiation are finely balanced to provide robustness during acute challenges to protein homeostasis, the role of this pathway during aging and in longevity remains largely unexplored

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Results

Conclusion