Abstract
Down-regulation of insulin/insulin-like growth factor signaling (IIS) can increase lifespan in C. elegans, Drosophila and mice. In C. elegans, reduced IIS results in down-regulation of translation, which itself can extend lifespan. However, the effect of reduced IIS on translation has yet to be determined in other multicellular organisms. Using two long-lived IIS models, namely Drosophila lacking three insulin-like peptides (dilp2-3,5−/−) and mice lacking insulin receptor substrate 1 (Irs1−/−), and two independent translation assays, polysome profiling and radiolabeled amino acid incorporation, we show that reduced IIS lowers translation in these organisms. In Drosophila, reduced IIS decreased polysome levels in fat body and gut, but reduced the rate of protein synthesis only in the fat body. Reduced IIS in mice decreased protein synthesis rate only in skeletal muscle, without reducing polysomes in any tissue. This lowered translation in muscle was independent of Irs1 loss in the muscle itself, but a secondary effect of Irs1 loss in the liver. In conclusion, down-regulation of translation is an evolutionarily conserved response to reduced IIS, but the tissues in which it occurs can vary between organisms. Furthermore, the mechanisms underlying lowered translation may differ in mice, possibly associated with the complexity of the regulatory processes.
Highlights
Lifespan in C. elegans[11,12]
To determine if the translational response to reduced IIS observed in C. elegans is evolutionarily conserved, we first assayed translational activity in long-lived Drosophila dilp[2,3,5] mutants
To determine if the tissue-specific response of translation to reduced IIS is evolutionarily conserved beyond Drosophila and C. elegans, we examined polysome profiles in Irs[1] knockout mice
Summary
Lifespan in C. elegans[11,12]. Tellingly, the lifespan of daf-2 mutants could not be further extended by depletion of translation-related proteins[11], suggesting that the role of decreased translation in extension of lifespan was already maximized in the daf-2 mutant worms. In Drosophila, loss of translation initiation factor 5C13, as well as inhibition of ribosomal protein S6-kinase and TOR14, two regulators of translation, increase lifespan. We used both polysome profiling and 35S-incorporation to measure translational activity in multiple tissues from both Drosophila and mouse IIS mutants, to determine whether the decrease in protein translation observed upon lowered IIS in C. elegans is conserved in Drosophila and mice. We used long-lived flies lacking three of the seven Drosophila insulin-like peptides, 2, 3 and 5 ( forth referred to as dilp2-3,5), and long-lived mice which lack the insulin receptor substrate 1 (Irs[1]) In both the Drosophila dilp[2,3,5] mutants and Irs1−/− mice we found evidence of tissue-specific reductions in translation activity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
