Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2020-11-30
Date Acceptance
2020-08-26
Citation
PLoS Genetics, 2020, 16 (11), pp.1-33
ISSN
1553-7390
Publisher
Public Library of Science (PLoS)
Start Page
1
End Page
33
Journal / Book Title
PLoS Genetics
Volume
16
Issue
11
Copyright Statement
© 2020 Bjedov et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Sponsor
Wellcome Trust
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000595960400005&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
102531/Z/13/A
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
MASS-SPECTROMETRY DATA
IMMUNE-RESPONSE
CELL
METABOLOMICS
LONGEVITY
SYSTEM
RESISTANCE
INHIBITION
RECEPTOR
STRESS
Publication Status
Published
Article Number
ARTN e1009083
Date Publish Online
2020-11-30