RRC ID 64507
Author Bjedov I, Cochemé HM, Foley A, Wieser D, Woodling NS, Castillo-Quan JI, Norvaisas P, Lujan C, Regan JC, Toivonen JM, Murphy MP, Thornton J, Kinghorn KJ, Neufeld TP, Cabreiro F, Partridge L.
Title Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila.
Journal PLoS Genet
Abstract Increased cellular degradation by autophagy is a feature of many interventions that delay ageing. We report here that increased autophagy is necessary for reduced insulin-like signalling (IIS) to extend lifespan in Drosophila and is sufficient on its own to increase lifespan. We first established that the well-characterised lifespan extension associated with deletion of the insulin receptor substrate chico was completely abrogated by downregulation of the essential autophagy gene Atg5. We next directly induced autophagy by over-expressing the major autophagy kinase Atg1 and found that a mild increase in autophagy extended lifespan. Interestingly, strong Atg1 up-regulation was detrimental to lifespan. Transcriptomic and metabolomic approaches identified specific signatures mediated by varying levels of autophagy in flies. Transcriptional upregulation of mitochondrial-related genes was the signature most specifically associated with mild Atg1 upregulation and extended lifespan, whereas short-lived flies, possessing strong Atg1 overexpression, showed reduced mitochondrial metabolism and up-regulated immune system pathways. Increased proteasomal activity and reduced triacylglycerol levels were features shared by both moderate and high Atg1 overexpression conditions. These contrasting effects of autophagy on ageing and differential metabolic profiles highlight the importance of fine-tuning autophagy levels to achieve optimal healthspan and disease prevention.
Volume 16(11)
Pages e1009083
Published 2020-11-1
DOI 10.1371/journal.pgen.1009083
PMID 33253201
PMC PMC7738165
MeSH Aging / genetics Animals Autophagy / genetics* Autophagy-Related Protein-1 Homolog / genetics Autophagy-Related Protein-1 Homolog / metabolism Drosophila Proteins / genetics Drosophila Proteins / metabolism Drosophila melanogaster / genetics Gene Expression / genetics Gene Expression Regulation / genetics Genes, Mitochondrial / genetics Insulin Receptor Substrate Proteins / genetics Insulin Receptor Substrate Proteins / metabolism Longevity / genetics* Mitochondria / genetics* Protein Serine-Threonine Kinases / genetics Receptor, Insulin / genetics Signal Transduction
IF 5.175
Drosophila DGRC#112001