Fig. 6: Direct ISR inhibition through phospho-defective eIF2αS51A mutations extends lifespan via eIF2B.

a Western blot of day 1 WT animals and eIF2αS51A mutants using anti-phospho-eIF2α (Ser51) and anti-α-tubulin antibodies. b Developmental tunicamycin (TM) resistance assay of WT animals and eIF2αS51A mutants treated with tunicamycin at the indicated concentrations (error bars represent means + SEM, two-way ANOVA Sidak’s post hoc test, ***p < 0.001 vs. WT at respective tunicamycin concentration; n = 4 independent experiments with ≥20 animals each). c Survival of eIF2αS51A mutants compared to WT control animals (representative data from n = 4 independent experiments). d Thermotolerance assays of eIF2αS51A mutants compared to WT animals (error bars represent means ± SD, two-way ANOVA Sidak’s post hoc test with ***p < 0.001 vs. WT controls; n = 4 independent experiments with 50 animals each). e, f Polysome profiling and quantification of day 1 WT worms and eIF2αS51A mutants (error bars represent means + SD, two-way ANOVA Dunnett’s post hoc test; n = 4 independent experiments). g Survival of WT worms and eIF2αS51A mutants upon RNAi treatment targeting kin-35 or control luciferase (representative data from n = 4 independent experiments). h Survival of WT animals and eIF2αS51A mutants upon RNAi treatment targeting ppp-1 or control luciferase (representative data from n = 2 independent experiments). i Survival of heterozygous phospho-mimic eIF2αS51D/+ mutants compared to WT control animals (representative data from n = 2 independent experiments). See Supplementary Dataset 1 for survival statistics. See Supplementary Table 1 for statistics on thermotolerance assays. Source data are provided as a Source Data file.