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Mol Syst Biol. 2017 Sep 15;13(9):939. doi: 10.15252/msb.20177663.

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

Author information

1
Max-Planck Institute for Biology of Ageing, Cologne, Germany.
2
CECAD Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany.
3
Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
4
Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, Heidelberg, Germany.
5
DZHK (German Centre for Cardiovascular Research), Partner site Heidelberg/Mannheim, Heidelberg, Germany.
6
Institute of Healthy Ageing, and GEE, UCL, London, UK.
7
CECAD Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany andreas.beyer@uni-koeln.de partridge@age.mpg.de.
8
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
9
Max-Planck Institute for Biology of Ageing, Cologne, Germany andreas.beyer@uni-koeln.de partridge@age.mpg.de.

Abstract

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 Drosophila IIS mutant and control, and detected 44% of the predicted proteome (6,085 proteins). Expression of ribosome-associated proteins in the fat body was reduced in the mutant, with a corresponding, tissue-specific reduction in translation. Expression of mitochondrial electron transport chain proteins in fat body was increased, leading to increased respiration, which was necessary for IIS-mediated lifespan extension, and alone sufficient to mediate it. Proteasomal subunits showed altered expression in IIS mutant gut, and gut-specific over-expression of the RPN6 proteasomal subunit, was sufficient to increase proteasomal activity and extend lifespan, whilst inhibition of proteasome activity abolished IIS-mediated longevity. Our study thus uncovered strikingly tissue-specific responses of cellular processes to lowered IIS acting in concert to ameliorate ageing.

KEYWORDS:

ageing; insulin/IGF; mitochondria; proteasome; proteome

PMID:
28916541
PMCID:
PMC5615923
DOI:
10.15252/msb.20177663
[Indexed for MEDLINE]
Free PMC Article

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