Regulation of protein synthesis is critical for cell growth and maintenance. Ageing in many organisms, including humans, is accompanied by marked alterations in both general and specific protein synthesis1. Whether these alterations are simply a corollary of the ageing process or have a causative role in senescent decline remains unclear. An array of protein factors facilitates the tight control of messenger RNA translation initiation2. The eukaryotic initiation factor 4E (eIF4E), which binds the 7-monomethyl guanosine cap at the 5′ end of all nuclear mRNAs, is a principal regulator of protein synthesis3. Here we show that loss of a specific eIF4E isoform (IFE-2) that functions in somatic tissues4 reduces global protein synthesis, protects from oxidative stress and extends lifespan in Caenorhabditis elegans. Lifespan extension is independent of the forkhead transcription factor DAF-16, which mediates the effects of the insulin-like signalling pathway on ageing. Furthermore, IFE-2 deficiency further extends the lifespan of long-lived age and daf nematode mutants. Similarly, lack of IFE-2 enhances the long-lived phenotype of clk and dietary-restricted eat mutant animals. Knockdown of target of rapamycin (TOR), a phosphatidylinositol kinase-related kinase that controls protein synthesis in response to nutrient cues, further increases the longevity of ife-2 mutants. Thus, signalling via eIF4E in the soma is a newly discovered pathway influencing ageing in C. elegans.
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We are grateful to A. Pasparaki, H. Kontaki, N. Kourtis and M. Papadakis for help with experiments. We thank M. Artal-Sanz and G. Thireos for comments on the manuscript. Some nematode strains used in this work were provided by the C. elegans Gene Knockout Project at OMRF (http://www.mutantfactory.ouhsc.edu/), which is part of the International C. elegans Gene Knockout Consortium, and the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). We thank A. Fire for plasmid vectors. This work was funded by grants from EMBO and the EU sixth Framework Programme to N.T. N.T. is an EMBO Young Investigator.
Author Contributions P.S., K.T and N.T. performed experiments; N.T designed experiments, analysed data and wrote the manuscript. All authors discussed the results and commented on the manuscript.
This file contains Supplementary Materials and Methods, Supplementary Tables 1-2, Supplementary Figures 1-4 with Legends and additional references.
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Journal of Experimental Botany (2019)