eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans

Abstract

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 synthesis. 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 initiation. 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 synthesis. Here we show that loss of a specific eIF4E isoform (IFE-2) that functions in somatic tissues 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.

Autophagy and ageing: Insights from invertebrate model organisms

“…Under reduced nutrient conditions, such as amino acid limitation, TOR activity is quenched, the TOR effectors S6K and 4E-BP are dephosphorylated and consequently protein synthesis decreases. Reduction of mRNA translation by conditions that shift cells from states of nutrient utilization and growth to states of cell maintenance has been shown to increase lifespan of yeast, worm, flies and mice (Hansen et al, 2007;Harrison et al, 2009;Kapahi et al, 2004;Pan et al, 2007;Syntichaki et al, 2007).…”

“…Worms bearing mutations in S6K (RSKS-1) and components of the translational machinery such as ribosomal proteins and translation initiation factors, live longer (Hansen et al, 2007;Kaeberlein and Kennedy, 2008;Syntichaki et al, 2007). Recently, TORC2 has been implicated in regulation of worm longevity (Soukas et al, 2009).…”

“…However, the long-lived phenotype of let-363 RNAi worms is not suppressed by mutations in daf-16, indicating that TOR may be acting downstream or independently of DAF-16 (Jia et al, 2004;Vellai et al, 2003). Importantly, knockout of ife-2, one of five C. elegans eIF4E isoforms (ife-1 to ife-5), extends lifespan, and enhances resistance to oxidative stress, UV irradiation and heat shock independently of DAF-16/FoxO (Syntichaki et al, 2007).…”

Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan

“…Dominant negative forms of TOR or its downstream effector S6K1 or overexpression of the upstream inhibitors of TOR, TSC1 and TSC2, extend lifespan in Drosophila (Kapahi et al, 2004). Similarly, deletion of TOR1 and many of its downstream targets in yeast (Kaeberlein et al, 2005) or deletion of the downstream TOR target e1F4E in worms confers longevity (Syntichaki et al, 2007).…”

Caenorhabditis elegans 2007: The premier model for the study of aging

“…Similarly, Pan et al (2007) showed that mRNA translation exerts pleiotropic effects on growth, reproduction, stress resistance and lifespan in C. elegans. The Tavernarakis lab (Syntichaki et al, 2007) showed that loss of a specific eIF4E isoform (IFE-2) functions in somatic tissues, reduces global protein synthesis, protects from oxidative stress and extends lifespan (the eukaryotic initiation factor 4E (eIF4E) is a principal regulator of protein synthesis). Lifespan extension is independent of the forkhead transcription factor DAF-16.…”