Enhancing autophagy by redox regulation extends lifespan in Drosophila

Claudia Lennicke, Ivana Bjedov, Sebastian Grönke, Katja E. Menger, Andrew M. James, Jorge Iván Castillo-Quan, Lucie A. G. Leeuwen, Andrea Foley, Marcela Buricova, Jennifer Adcott, Alex Montoya, Holger B. Kramer, Pavel V. Shliaha, Angela Logan, Filipe Cabreiro, Michael P. Murphy, Linda Partridge () and Helena M. Cochemé ()
Additional contact information
Claudia Lennicke: MRC Laboratory of Medical Sciences (LMS)
Ivana Bjedov: UCL Cancer Institute
Sebastian Grönke: Max Planck Institute for Biology of Ageing
Katja E. Menger: University of Cambridge, Cambridge Biomedical Campus
Andrew M. James: University of Cambridge, Cambridge Biomedical Campus
Jorge Iván Castillo-Quan: University College London
Lucie A. G. Leeuwen: MRC Laboratory of Medical Sciences (LMS)
Andrea Foley: MRC Laboratory of Medical Sciences (LMS)
Marcela Buricova: MRC Laboratory of Medical Sciences (LMS)
Jennifer Adcott: University College London
Alex Montoya: MRC Laboratory of Medical Sciences (LMS)
Holger B. Kramer: MRC Laboratory of Medical Sciences (LMS)
Pavel V. Shliaha: MRC Laboratory of Medical Sciences (LMS)
Angela Logan: University of Cambridge, Cambridge Biomedical Campus
Filipe Cabreiro: Institute of Clinical Sciences, Imperial College London, Hammersmith Hospital Campus
Michael P. Murphy: University of Cambridge, Cambridge Biomedical Campus
Linda Partridge: Max Planck Institute for Biology of Ageing
Helena M. Cochemé: MRC Laboratory of Medical Sciences (LMS)

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Dysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H2O2 in vivo, we established a redox-shifted model by manipulating levels of the H2O2-degrading enzyme catalase in Drosophila. Here we report that ubiquitous over-expression of catalase robustly extends lifespan in females. As anticipated, these flies are strongly resistant to a range of oxidative stress challenges, but interestingly are sensitive to starvation, which could not be explained by differences in levels of energy reserves. This led us to explore the contribution of autophagy, which is an important mechanism for organismal survival in response to starvation. We show that autophagy is essential for the increased lifespan by catalase upregulation, as the survival benefits are completely abolished upon global autophagy knock-down. Furthermore, using a specific redox-inactive knock-in mutant, we highlight the in vivo role of a key regulatory cysteine residue in Atg4a, which is required for the lifespan extension in our catalase model. Altogether, these findings confirm the redox regulation of autophagy in vivo as an important modulator of longevity.

Date: 2025
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DOI: 10.1038/s41467-025-60603-w

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