Although inhibition of translation initiation extends lifespan from yeast to mammals, the mechanism remains unknown. We showed that one of the most robust lifespan extension comes from suppression of ifg-1, the C. elegans ortholog of eukaryotic translation initiation factor (eIF)-4G, a factor that positively regulates translation. Previous studies have analyzed changes in total mRNA expression to investigate causes of lifespan changes under a number of different genetic and environmental conditions. However, other studies have shown large discrepancies between the transcriptome and proteome. I used translation state array analysis (TSAA), which accounts for post-transcriptional processing, to investigate changes upon direct modulation of translation by inhibiting ifg-1 expression. A large number of differentially translated mRNAs were found and ontological analysis revealed that upregulated genes included stress response genes and aging genes that are positive regulators of aging. Preliminary sequence analysis suggests that genes with preferentially maintained expression contain conserved characteristics known to modulate translation. qRT- PCR and quantitative mass spectroscopy corroborate TSAA results. Hypothesis: in addition to reducing global rates of translation, suppression of ifg-1 results in preferential translation of mRNA associated with stress response and somatic maintenance based on mRNA composition. An epistasis screen of 50 translationally enhanced stress response genes showed 10 that are required for maximal lifespan extension when ifg-1 is inhibited. I intend to a) directly determine translation changes and the impact of overexpression for these seven genes using in vivo reporter constructs, b) analyze sequences for known or novel cis- regulatory elements and isolate microRNAs (miRNAs) associated with differentially translated mRNAs, and c) characterize the miRNA and cis-regulatory elements for their effects between conditions as well as their roles in lifespan modulation 7.
Inhibition of translation extends lifespan across species. Simple model organisms like the nematode C. elegans provide powerful tools to uncover biological mechanisms that determine the beneficial effects of translation inhibition. Using C. elegans, I will examine how post-transcriptional processing is remodeled upon inhibition of translation initiation through the C. elegans ortholog of eukaryotic translation initiation factor 4G. Given the role played by deregulation of translation in age-related diseases including diabetes, cancer and neurodegeneration, this research has important implications for human health.
|Rogers, Aric N; Chen, Di; McColl, Gawain et al. (2011) Life span extension via eIF4G inhibition is mediated by posttranscriptional remodeling of stress response gene expression in C. elegans. Cell Metab 14:55-66|