Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk.
Weigand, Bettina M
Ktistakis, Nicholas T
Wiggins, Kimberley A
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Cassidy, L. D., Young, A., Young, C. N., Soilleux, E., Fielder, E., Weigand, B. M., Lagnado, A., et al. (2020). Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk.. Nature communications, 11 (1), 307. https://doi.org/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.
Muscles, Skin, Animals, Mice, Inbred C57BL, Mice, Knockout, Mice, Neoplasms, Disease Models, Animal, Inflammation, Bone Marrow Transplantation, Aging, Longevity, Phenotype, Autophagy, Female, Male, Sequestosome-1 Protein, Autophagy-Related Protein 5
This work was supported by the University of Cambridge, Cancer Research UK and Hutchison Whampoa. The M.N. lab was supported by a Cancer Research UK Cambridge Institute Core Grant [C14303/A17197]. M.N. is also supported by The CRUK Early Detection Pump Priming Awards [C20/A20976] and Medical Research Council [MR/M013049/1]. C.N.J.Y. is supported by a DMU Early Career Fellowship. M.C.H.C is supported by grants from The British Heart Foundation [FS/13/3/30038], [FS/18/19/33371], and [RG/16/8/32388]. D.J. is funded by a Newcastle University Faculty of Medical Sciences Fellowship and The Academy of Medical Sciences. J.P. was supported by the BBSRC [BB/H022384/1] and [BB/K017314/1].
Cancer Research UK (C14303_do not transfer)
Cancer Research UK (C20/A20976)
Medical Research Council (MR/M013049/1)
British Heart Foundation (FS/18/19/33371)
British Heart Foundation (RG/16/8/32388)
British Heart Foundation (FS/13/3/30038)
British Heart Foundation (BHF-FS/18/19/33371)
Embargo Lift Date
External DOI: https://doi.org/10.1038/s41467-019-14187-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/300207
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