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eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans


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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Figure 1: eIF4E deficiency in somatic tissues extends C. elegans lifespan.
Figure 2: IFE-2 and genes influencing ageing in C. elegans.
Figure 3: Effects of regulatory kinase and IFE-2 removal on ageing.
Figure 4: eIF4E deficiency in the soma reduces protein synthesis and increases oxidative stress resistance in C. elegans.

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  1. Ward, W. F. The relentless effects of the aging process on protein turnover. Biogerontology 1, 195–199 (2000)

    Article  CAS  Google Scholar 

  2. Gebauer, F. & Hentze, M. W. Molecular mechanisms of translational control. Nature Rev. Mol. Cell Biol. 5, 827–835 (2004)

    Article  CAS  Google Scholar 

  3. Gingras, A. C., Raught, B. & Sonenberg, N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68, 913–963 (1999)

    Article  CAS  Google Scholar 

  4. Keiper, B. D. et al. Functional characterization of five eIF4E isoforms in Caenorhabditis elegans. J. Biol. Chem. 275, 10590–10596 (2000)

    Article  CAS  Google Scholar 

  5. Amiri, A. et al. An isoform of eIF4E is a component of germ granules and is required for spermatogenesis in C. elegans. Development 128, 3899–3912 (2001)

    MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  6. Beanan, M. J. & Strome, S. Characterization of a germ-line proliferation mutation in C. elegans. Development 116, 755–766 (1992)

    CAS  PubMed  Google Scholar 

  7. Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005)

    Article  CAS  Google Scholar 

  8. Lakowski, B. & Hekimi, S. Determination of life-span in Caenorhabditis elegans by four clock genes. Science 272, 1010–1013 (1996)

    Article  ADS  CAS  Google Scholar 

  9. Lakowski, B. & Hekimi, S. The genetics of caloric restriction in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 95, 13091–13096 (1998)

    Article  ADS  CAS  Google Scholar 

  10. Waskiewicz, A. J. et al. Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnk1 in vivo. Mol. Cell. Biol. 19, 1871–1880 (1999)

    Article  CAS  Google Scholar 

  11. Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620 (2003)

    Article  ADS  CAS  Google Scholar 

  12. Ruvinsky, I. & Meyuhas, O. Ribosomal protein S6 phosphorylation: from protein synthesis to cell size. Trends Biochem. Sci. 31, 342–348 (2006)

    Article  CAS  Google Scholar 

  13. Arquier, N., Bourouis, M., Colombani, J. & Leopold, P. Drosophila Lk6 kinase controls phosphorylation of eukaryotic translation initiation factor 4E and promotes normal growth and development. Curr. Biol. 15, 19–23 (2005)

    Article  CAS  Google Scholar 

  14. Reiling, J. H., Doepfner, K. T., Hafen, E. & Stocker, H. Diet-dependent effects of the Drosophila Mnk1/Mnk2 homolog Lk6 on growth via eIF4E. Curr. Biol. 15, 24–30 (2005)

    Article  CAS  Google Scholar 

  15. Jia, K., Chen, D. & Riddle, D. L. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897–3906 (2004)

    Article  CAS  Google Scholar 

  16. Proud, C. G. Regulation of mammalian translation factors by nutrients. Eur. J. Biochem. 269, 5338–5349 (2002)

    Article  CAS  Google Scholar 

  17. Martin, G. M., Austad, S. N. & Johnson, T. E. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nature Genet. 13, 25–34 (1996)

    Article  CAS  Google Scholar 

  18. Stadtman, E. R. Protein oxidation and aging. Science 257, 1220–1224 (1992)

    Article  ADS  CAS  Google Scholar 

  19. Lin, S. J. & Culotta, V. C. The ATX1 gene of Saccharomyces cerevisiae encodes a small metal homeostasis factor that protects cells against reactive oxygen toxicity. Proc. Natl Acad. Sci. USA 92, 3784–3788 (1995)

    Article  ADS  CAS  Google Scholar 

  20. Yoshikawa, S. et al. Redox-coupled crystal structural changes in bovine heart cytochrome c oxidase. Science 280, 1723–1729 (1998)

    Article  ADS  CAS  Google Scholar 

  21. Vanfleteren, J. R. Oxidative stress and ageing in Caenorhabditis elegans. Biochem. J. 292, 605–608 (1993)

    Article  CAS  Google Scholar 

  22. Sohal, R. S. & Weindruch, R. Oxidative stress, caloric restriction, and aging. Science 273, 59–63 (1996)

    Article  ADS  CAS  Google Scholar 

  23. Ishii, N. et al. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 394, 694–697 (1998)

    Article  ADS  CAS  Google Scholar 

  24. Tavernarakis, N., Wang, S. L., Dorovkov, M., Ryazanov, A. & Driscoll, M. Heritable and inducible genetic interference by double-stranded RNA encoded by transgenes. Nature Genet. 24, 180–183 (2000)

    Article  CAS  Google Scholar 

  25. Makrides, S. C. Protein synthesis and degradation during aging and senescence. Biol. Rev. Camb. Philos. Soc. 58, 343–422 (1983)

    Article  CAS  Google Scholar 

  26. Rattan, S. I. Synthesis, modifications, and turnover of proteins during aging. Exp. Gerontol. 31, 33–47 (1996)

    Article  CAS  Google Scholar 

  27. Tavernarakis, N. & Driscoll, M. Caloric restriction and lifespan: a role for protein turnover? Mech. Ageing Dev. 123, 215–229 (2002)

    Article  CAS  Google Scholar 

  28. Ruggero, D. et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nature Med. 10, 484–486 (2004)

    Article  CAS  Google Scholar 

  29. Ahmed, S. & Hodgkin, J. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans. Nature 403, 159–164 (2000)

    Article  ADS  CAS  Google Scholar 

  30. Kirkwood, T. B. & Austad, S. N. Why do we age? Nature 408, 233–238 (2000)

    Article  ADS  CAS  Google Scholar 

  31. Pan, K. Z. et al. Inhibition of mRNA translation extends lifespan in C. elegans. Ageing Cell doi:10.1111/j.1474-9726.2006.00266.x (5 December 2006).

  32. Hansen, M. et al. Lifespan extension by conditions that inhibit translation in C. elegans. Ageing Cell doi:10.1111/j.1474-9726.2006.00267.x (5 December 2006).

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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 (, 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.

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Correspondence to Nektarios Tavernarakis.

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Syntichaki, P., Troulinaki, K. & Tavernarakis, N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature 445, 922–926 (2007).

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