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

Ivana Bjedov, Helena M. Cochemé, Andrea Foley, Daniela Wieser, Nathaniel S. Woodling, Jorge Iván Castillo-Quan, Povilas Norvaisas, Celia Lujan, Jenny Regan, Janne M. Toivonen, Michael P. Murphy, Janet Thornton, Kerri J. Kinghorn, Thomas P. Neufeld, Filipe Cabreiro, Linda Partridge

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere1009083
JournalPLoS genetics
Volume16
Issue number11
DOIs
StatePublished - Nov 30 2020

Bibliographical note

Funding Information:
This work was supported by Research into Ageing (Age UK), the Wellcome Trust and the Max Planck Society (L.P.). The work was also funded by European Research Council Starting Grant, Cancer Research UK and The Bill Lyons foundation (I.B.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 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.

Fingerprint Dive into the research topics of 'Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila'. Together they form a unique fingerprint.

Cite this