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

Bjedov, I. et al. (2020) Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in drosophila. PLoS Genetics, 16(11), e1009083. (doi: 10.1371/journal.pgen.1009083) (PMID:33253201) (PMCID:PMC7738165)

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.

• Item Type: Articles
• Additional Information: This work was supported by Research into Ageing (Age UK), the Wellcome Trust and the Max Planck Society (L.P.). I.B. acknowledges funding from the European Research Council (ERC StG 311331 and ERC PoC 842174), Cancer Research UK (CRUK-UCL Centre Award [C416/ A25145]), Royal Society Research Grant (RSG/R1/180431), and The Bill Lyons foundation (I.B.). F.C. acknowledges funding from the Wellcome Trust/ Royal Society (102532/Z/12/Z and 102531/Z/13/A) and Medical Research Council (MC-A654-5QC80). H.M.C. is funded by the Medical Research Council UK (MC-A654-5QB90). N.S.W. is funded by the Alzheimer’s Society AS-JF-17b-011. K.J.K. acknowledges funding from the Rosetree Trust and The Wellcome Trust (214589/Z/18/Z).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Woodling, Dr Nathan

Creator Roles

Woodling, N.: Formal analysis, Investigation, Writing – review and editing

• Authors: Bjedov, I., Cochemé, H. M., Foley, A., Wieser, D., Woodling, N. S., Castillo-Quan, J. I., Norvaisas, P., Lujan, C., Regan, J. C., Toivonen, J. M., Murphy, M. P., Thornton, J., Kinghorn, K. J., Neufeld, T. P., Cabreiro, F., and Partridge, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: PLoS Genetics
• Publisher: Public Library of Science
• ISSN: 1553-7390
• ISSN (Online): 1553-7404
• Copyright Holders: Copyright: © 2020 Bjedov et al.
• First Published: First published in PLoS Genetics 16(11): e1009083
• Publisher Policy: Reproduced under a Creative Commons licence

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