Abstract

Reduced activity of the insulin/IGF signalling network increases health during ageing in multiple species. Diverse and tissue-specific mechanisms drive the health improvement. Here, we performed tissue-specific transcriptional and proteomic profiling of long-lived Drosophila dilp2-3,5 mutants, and identified tissue-specific regulation of >3600 transcripts and >3700 proteins. Most expression changes were regulated post-transcriptionally in the fat body, and only in mutants infected with the endosymbiotic bacteria, Wolbachia pipientis, which increases their lifespan. Bioinformatic analysis identified reduced co-translational ER targeting of secreted and membrane-associated proteins and increased DNA damage/repair response proteins. Accordingly, age-related DNA damage and genome instability were lower in fat body of the mutant, and overexpression of a minichromosome maintenance protein subunit extended lifespan. Proteins involved in carbohydrate metabolism showed altered expression in the mutant intestine, and gut-specific overexpression of a lysosomal mannosidase increased autophagy, gut homeostasis, and lifespan. These processes are candidates for combatting ageing-related decline in other organisms.

Highlights

  • Human life expectancy is increasing (Oeppen and Demography, 2002) and is predicted to continue to do so (Kontis et al, 2017)

  • We identified novel functional signatures of reduced endoplasmic reticulum (ER)-protein targeting and an increased DNA damage/repair response that require Wolbachia and that were specific to the fat body of dilp2-3,5 mutants

  • We reproducibly identified a total of 11331 transcripts and 7234 proteins (Appendix 1A-C), of which 3683 transcripts and 3738 proteins showed significantly altered expression in at least one tissue of dilp2-3,5 mutant flies (Appendix 1D, Supplementary file 1–2)

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Summary

Introduction

Human life expectancy is increasing (Oeppen and Demography, 2002) and is predicted to continue to do so (Kontis et al, 2017). Lowered activity of the insulin and IGF-1-like signalling (IIS) network can extend lifespan in laboratory model organisms (Kenyon, 2011; Partridge et al, 2011), and possibly humans through specific mutations (Flachsbart et al, 2009; Study of Osteoporotic Fractures et al, 2009), and can reduce the incidence of age-related impairments and diseases (Mannick et al, 2014; Mannick et al, 2018). Identifying the molecular mechanisms and understanding exactly how reducing IIS activity prolongs longevity may lead to interventions that ameliorate the effects of ageing and prevent age-related pathology. Gene expression profiling in whole organisms has identified genes and molecular mechanisms that ameliorate ageing in IIS mutants in C. elegans

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