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A proteomic atlas of insulin signaling reveals tissue-specific mechanisms of longevity-assurance

ABSTRACT: Lowered activity of the insulin/IGF signaling (IIS) network can ameliorate the effects of ageing in model organisms and, possibly, humans. Remodelling of the RNA transcriptome of long-lived IIS mutants has been extensively documented, but is only weakly predictive of consequent changes in protein expression, and the causal mechanisms at work, particularly in specific tissues, remain unclear. We have characterised changes in the proteomes of four key insulin-sensitive tissues of a long-lived Drosophila IIS mutant. We identified with high confidence ~6000 proteins, constituting 44% of the predicted proteome, which were mainly tissue-specific in expression. Lowered IIS resulted in robust, highly reproducible and tissue-specific responses, particularly pronounced in the brain and intestine, 60% of which were not detected in previous profiles of changes in RNA expression. Lowered IIS resulted in reduced expression of ribosome-associated proteins in the fat body, and a corresponding, tissue-specific reduction in translation. Mitochondrial electron transport chain proteins were increased in the fat body, leading to increased respiration, and the increase was both necessary for IIS-mediated lifespan extension and sufficient alone to mediate it. Proteosomal subunits were differentially regulated in IIS mutant gut, and directed expression of a single proteosomal subunit, RPN6, in the gut was sufficient to increase assembly and activity of the proteasome and to extend lifespan. Inhibition of proteasome activity specifically abolished IIS-mediated longevity. Tissue-specific proteomic profiling has thus deconstructed the diverse responses to reduced IIS, and demonstrated that they act in concert to ameliorate ageing.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

SUBMITTER: Robert Sehlke

LAB HEAD: Linda Partridge

PROVIDER: PXD006225 | Pride | 2017-09-13

REPOSITORIES: Pride

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A proteomic atlas of insulin signalling reveals tissue-specific mechanisms of longevity assurance.

Tain Luke S LS Sehlke Robert R Jain Chirag C Chokkalingam Manopriya M Nagaraj Nagarjuna N Essers Paul P Rassner Mark M Grönke Sebastian S Froelich Jenny J Dieterich Christoph C Mann Matthias M Alic Nazif N Beyer Andreas A Partridge Linda L

Molecular systems biology 20170915 9

Lowered activity of the insulin/IGF signalling (IIS) network can ameliorate the effects of ageing in laboratory animals and, possibly, humans. Although transcriptome remodelling in long-lived IIS mutants has been extensively documented, the causal mechanisms contributing to extended lifespan, particularly in specific tissues, remain unclear. We have characterized the proteomes of four key insulin-sensitive tissues in a long-lived <i>Drosophila</i> IIS mutant and control, and detected 44% of the ...[more]

PMID: 28916541

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Project description:Analysis of gene expression in two long-lived daf-2 mutant (mutation in the insulin/IGF-1 receptor) and eat-2 mutant (caloric restriction model), comparison of gene expression profiles of two long-lived mutants provide novel insight into longevity Impaired insulin/IGF-1 signaling (IIS) pathway and caloric restriction (CR) are two well-established interventions to prolong lifespan in worm C. elegans. Although many studies using “-omics” approaches have gained informative knowledges on key longevity regulators in either IIS or CR models, few of those investigated the shared regulators between these two longevity interventions and integrated the messages from different –omics studies. In this study, we aimed to identify key pathways and metabolite fingerprints of longevity shared between the two interventions in worms using a multi-omics integration approach. We collected transcriptomics and metabolomics data from two long-lived mutant worm strains, i.e. daf-2 (impaired IIS pathway) and eat-2 (CR model) and compared with N2 strain. We detected many key pathways that were upregulated at the gene expression level in both long-lived mutants, such as defense response and lipid storage, while synthesis of macromolecules and developmental processes were downregulated at the transcript level. From our polar metabolite analysis, we discovered several shared metabolic features between the two long-lived mutants, including glycerol-3P, adenine, xanthine and AMP. In addition, we detected a lowered amino acid pool and two fatty acid species, C18:0 and C17:1, that behaved similarly in both long-lived mutants. After we integrated transcriptomics and metabolomics data based on the annotations in KEGG, our results highlighted a downregulation of pyrimidine metabolism and upregulation of purine metabolism in both long-lived mutants compared to N2 worms. Overall, our findings point towards the existence of shared metabolic pathways that are important for lifespan extension and provide novel insight of potential regulators and metabolic fingerprints for longevity.

Dataset Information

A proteomic atlas of insulin signaling reveals tissue-specific mechanisms of longevity-assurance

Publications

A proteomic atlas of insulin signalling reveals tissue-specific mechanisms of longevity assurance.

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