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Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila

Published version
Peer-reviewed

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Authors

Cochemé, Helena M.  ORCID logo  https://orcid.org/0000-0001-8637-0042
Wieser, Daniela 
Woodling, Nathaniel S.  ORCID logo  https://orcid.org/0000-0002-0298-3800

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.

Description

Keywords

Research Article, Biology and life sciences, Medicine and health sciences

Journal Title

PLOS Genetics

Conference Name

Journal ISSN

1553-7390
1553-7404

Volume Title

16

Publisher

Public Library of Science