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)
Summary
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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