Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk

Liam D. Cassidy, Andrew R. J. Young, Christopher N. J. Young, Elizabeth J. Soilleux, Edward Fielder, Bettina M. Weigand, Anthony Lagnado, Rebecca Brais, Nicholas T. Ktistakis, Kimberley A. Wiggins, Katerina Pyrillou, Murray C. H. Clarke, Diana Jurk, Joao F. Passos and Masashi Narita ()
Additional contact information
Liam D. Cassidy: Cancer Research UK Cambridge Institute
Andrew R. J. Young: Cancer Research UK Cambridge Institute
Christopher N. J. Young: De Montfort University
Elizabeth J. Soilleux: University of Cambridge
Edward Fielder: Newcastle University Institute for Ageing, Newcastle University
Bettina M. Weigand: Newcastle University Institute for Ageing, Newcastle University
Anthony Lagnado: Mayo Clinic
Rebecca Brais: Cambridge University Hospitals NHS Foundation Trust
Nicholas T. Ktistakis: Babraham Institute
Kimberley A. Wiggins: Addenbrookes Hospital
Katerina Pyrillou: Addenbrookes Hospital
Murray C. H. Clarke: Addenbrookes Hospital
Diana Jurk: Mayo Clinic
Joao F. Passos: Newcastle University Institute for Ageing, Newcastle University
Masashi Narita: Cancer Research UK Cambridge Institute

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Autophagy is an important cellular degradation pathway with a central role in metabolism as well as basic quality control, two processes inextricably linked to ageing. A decrease in autophagy is associated with increasing age, yet it is unknown if this is causal in the ageing process, and whether autophagy restoration can counteract these ageing effects. Here we demonstrate that systemic autophagy inhibition induces the premature acquisition of age-associated phenotypes and pathologies in mammals. Remarkably, autophagy restoration provides a near complete recovery of morbidity and a significant extension of lifespan; however, at the molecular level this rescue appears incomplete. Importantly autophagy-restored mice still succumb earlier due to an increase in spontaneous tumour formation. Thus, our data suggest that chronic autophagy inhibition confers an irreversible increase in cancer risk and uncovers a biphasic role of autophagy in cancer development being both tumour suppressive and oncogenic, sequentially.

Date: 2020
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DOI: 10.1038/s41467-019-14187-x

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