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

• Published in: Nature communications Vol. 11; no. 1; p. 307
• Main Authors: Cassidy, Liam D., Young, Andrew R. J., Young, Christopher N. J., Soilleux, Elizabeth J., Fielder, Edward, Weigand, Bettina M., Lagnado, Anthony, Brais, Rebecca, Ktistakis, Nicholas T., Wiggins, Kimberley A., Pyrillou, Katerina, Clarke, Murray C. H., Jurk, Diana, Passos, Joao F., Narita, Masashi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/51; 13/89; 631/67; 631/80/39/2346; 64/60; 692/308/1426; Age; Aging; Aging (artificial); Aging - genetics; Aging - physiology; Animal models; Animals; Autophagy; Autophagy - drug effects; Autophagy - genetics; Autophagy - physiology; Autophagy-Related Protein 5 - genetics; Bone Marrow Transplantation; Cancer; Disease Models, Animal; Female; Health risks; Humanities and Social Sciences; Inflammation; Life span; Longevity - genetics; Longevity - physiology; Male; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Morbidity; multidisciplinary; Muscles; Neoplasms; Phagocytosis; Phenotype; Phenotypes; Quality control; Restoration; Science; Science (multidisciplinary); Sequestosome-1 Protein - metabolism; Skin - pathology; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14187-x

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.