IGF-1 Induced Longevity Accompanied by Reduced Protein Translation and Increased Autophagy

Enhanced longevity associated with changes in the insulin/IGF-1 pathway is one of the most studied areas of the genetics of longevity in laboratory animals. Metabolism is complex enough that researchers are still building the picture of how alterations like this work to extend life. The open access research quoted below suggests that broad reductions in rate of creation of proteins from DNA blueprints are involved, and thus a related boost in the level of autophagy as the body seeks to recycle more proteins.

This shows up elsewhere in processes related to longevity - for example in dietary methionine restriction, as methionine is required for the assembly of all proteins. Increased levels of the housekeeping processes of autophagy appear in many forms of metabolic alteration that extend life, and most likely work by consistently reducing the levels of cellular damage that contribute to degenerative aging over the long term.

To date, the biological processes underlying Insulin/IGF-1-mediated longevity remain studied predominantly at the gene level. However, organismal phenotypes are far more dependent on protein function. An initial quantitative proteomics study of Insulin/IGF-1 pathway confirmed the role of stress-protective pathways during longevity signalling. Additionally, it uncovered several compensatory pathways involved in longevity, underscoring the potential of this approach to identify novel longevity pathways. However, this analysis was restricted to a subset of the nematode proteome, involving mainly cytoplasmic and non-membrane bound proteins.

In this study, a more stringent and non-biased proteomics approach of the whole nematode using TMT proteomics was employed. This recently developed quantification method was used to identify novel processes and pathways involved in Insulin/IGF-1-mediated longevity. The obtained results confirmed the previously reported alteration of several proteins in daf-2(e1370) nematodes, including an increased representation of stress-resistance enzymes and a decrease in chaperone proteins. However, our results go on to reveal a severe and previously overlooked reduction in ribosomal proteins and concomitant translational activity. In addition, reduced expression of proteins involved in mRNA processing, translation, and the ubiquitin-proteasome system (UPS) was observed. Functional assays confirmed reduced mRNA levels and 20S proteasomal activity while at the same time total protein content of the mutants compared with wild-type nematodes remained unchanged. Moreover, the importance of these processes for lifespan extension is demonstrated using RNA interference (RNAi)-mediated knockdown of identified candidates.

All together, we propose a model for Insulin/IGF-1-mediated longevity that, in addition to an enhanced stress response, relies on protein metabolism coupled to the reduction in de novo protein synthesis and a shift from the UPS of degradation to recycling of proteins via autophagy.

Link: http://dx.doi.org/10.1038/msb.2013.35


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