Enhancing autophagy by redox regulation extends lifespan in <i>Drosophila</i>



Cochemé, Helena M ORCID: 0000-0001-8637-0042, Bjedov, Ivana, Grönke, Sebastian, Menger, Katja E, James, Andrew M, Quan, Jorge Ivan Castillo, Foley, Andrea, Lennicke, Claudia, Buricova, Marcela, Adcott, Jennifer ORCID: 0000-0001-9146-3171
et al (show 3 more authors) (2019) Enhancing autophagy by redox regulation extends lifespan in <i>Drosophila</i>. bioRXiv. 790378-.

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Abstract

<jats:p>Redox signalling is an important modulator of diverse biological pathways and processes, and operates through specific post-translational modification of redox-sensitive thiols on cysteine residues <jats:sup>1–4</jats:sup>. Critically, redox signalling is distinct from irreversible oxidative damage and functions as a reversible ‘redox switch’ to regulate target proteins. H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> acts as the major effector of redox signalling, both directly and through intracellular thiol redox relays <jats:sup>5,6</jats:sup>. Dysregulation of redox homeostasis has long been implicated in the pathophysiology of many age-related diseases, as well as in the ageing process itself, however the underlying mechanisms remain largely unclear <jats:sup>7,8</jats:sup>. To study redox signalling by H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub><jats:italic>in vivo</jats:italic> and explore its involvement in metabolic health and longevity, we used the fruit fly <jats:italic>Drosophila</jats:italic> as a model organism, with its tractable lifespan and strong evolutionary conservation with mammals <jats:sup>9</jats:sup>. Here we report that inducing an endogenous redox-shift, by manipulating levels of the H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>-degrading enzyme catalase, improves health and robustly extends lifespan in flies, independently of oxidative stress resistance and dietary restriction. We find that the catalase redox-shifted flies are acutely sensitive to starvation stress, which relies on autophagy as a vital survival mechanism. Importantly, we show that autophagy is essential for the lifespan extension of the catalase flies. Furthermore, using redox-inactive knock-in mutants of Atg4a, a major effector of autophagy, we show that the lifespan extension in response to catalase requires a key redox-regulatory cysteine residue, Cys102 in Atg4a. These findings demonstrate that redox regulation of autophagy can extend lifespan, confirming the importance of redox signalling in ageing and as a potential pro-longevity target.</jats:p>

Item Type: Article
Uncontrolled Keywords: Aging, 1.1 Normal biological development and functioning, 1 Underpinning research, Generic health relevance
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Tech, Infrastructure and Environmental Directorate
Depositing User: Symplectic Admin
Date Deposited: 27 Aug 2021 08:56
Last Modified: 17 Mar 2024 12:34
DOI: 10.1101/790378
Open Access URL: https://www.biorxiv.org/content/10.1101/790378v1
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3134918