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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.
Autophagy declines with age, yet it is unclear if restoration of autophagy extends lifespan. Here, the authors demonstrate in murine models that the inhibition of Atg5 induces ageing phenotypes and reduces lifespan, whilst autophagy restoration partially reverses these phenotypes with accelerated tumorigenesis.
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1 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK (GRID:grid.470869.4) (ISNI:0000 0004 0634 2060)
2 De Montfort University, Leicester School of Allied Health Sciences, Faculty of Health & Life Sciences, Leicester, UK (GRID:grid.48815.30) (ISNI:0000 0001 2153 2936)
3 University of Cambridge, Department of Pathology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934)
4 Newcastle University Institute for Ageing, Newcastle University, Institute for Cell and Molecular Biosciences, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212)
5 Newcastle University Institute for Ageing, Newcastle University, Institute for Cell and Molecular Biosciences, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212) ; Mayo Clinic, Department of Physiology and Biomedical Engineering, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) ; Mayo Clinic, Robert and Arlene Kogod Center on Aging, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X)
6 Mayo Clinic, Department of Physiology and Biomedical Engineering, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) ; Mayo Clinic, Robert and Arlene Kogod Center on Aging, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X)
7 Cambridge University Hospitals NHS Foundation Trust, Department of Histopathology, Cambridge, UK (GRID:grid.24029.3d) (ISNI:0000 0004 0383 8386)
8 Babraham Institute, Signalling Programme, Cambridge, UK (GRID:grid.418195.0) (ISNI:0000 0001 0694 2777)
9 Addenbrookes Hospital, Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK (GRID:grid.120073.7) (ISNI:0000 0004 0622 5016)
10 Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK (GRID:grid.470869.4) (ISNI:0000 0004 0634 2060) ; Tokyo Institute of Technology, Tokyo Tech World Research Hub Initiative (WRHI), Institute of Innovative Research, Yokohama, Japan (GRID:grid.32197.3e) (ISNI:0000 0001 2179 2105)