Inhibition of a eukaryotic initiation factor (eIF2Bδ/F11A3.2) during adulthood extends lifespan in Caenorhabditis elegans

The critical role of protein synthesis in regulating lifespan has been evidenced. This study shows that adult-onset RNAi inactivation of eukaryotic initiation factor 2B delta (eIF2B delta/F11A3.2), a subunit of eIF2B, extends the mean lifespan of Caenorhabditis elegans. eIF2B is a GDP-GTP exchange factor for eIF2-a rate-limiting factor for protein synthesis initiation. S-35-methionine incorporation assay showed that global protein synthesis is reduced by eIF2B delta/F11A3.2 RNAi. Inhibition of eIF2B delta/F11A3.2 during adulthood conferred thermal and oxidative stress resistance and reduced the fecundity and fat storage, suggesting the possible trade-offs of resources between reproduction and somatic maintenance. Lifespan extension by adult-onset eIF2B delta/F11A3.2 RNAi is suppressed in FOXO transcription factor daf-16 deletion mutants. Adult-onset eIF2B delta/F11A3.2 RNAi increases the expression of stress-resistant genes, including hsp-16.2, hsp-70, hsp90, and sod-3, some of which are reported to be targets of DAF-16. Adult-onset eIF2B delta/F11A3.2 RNAi in daf-16 mutants reduced fecundity, but did not extend lifespan. Furthermore, adult-onset eIF2B delta/F11A3.2 RNAi did not extend the lifespan of germline-defective glp-4 organisms. Thus, it is possible that eIF2B delta/F11A3.2 RNAi during adulthood prolongs lifespan via daf-16, which induces stress resistance in organisms. This might be the mechanism, at least in part, for trade-offs of resources between reproduction and somatic maintenance.-Tohyama, D., Yamaguchi, A., Yamashita, T. Inhibition of a eukaryotic initiation factor (eIF2B delta/F11A3.2) during adulthood extends lifespan in Caenorhabditis elegans. FASEB J. 22, 4327-4337 ( 2008)