TY - JOUR
T1 - Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk
AU - Cassidy, Liam D.
AU - Young, Andrew R.J.
AU - Young, Christopher N.J.
AU - Soilleux, Elizabeth J.
AU - Fielder, Edward
AU - Weigand, Bettina M.
AU - Lagnado, Anthony
AU - Brais, Rebecca
AU - Ktistakis, Nicholas T.
AU - Wiggins, Kimberley A.
AU - Pyrillou, Katerina
AU - Clarke, Murray C.H.
AU - Jurk, Diana
AU - Passos, Joao F.
AU - Narita, Masashi
N1 - Funding Information:
We thank members of the Narita group, as well as K. Inoki of the University of Michigan, for their insights and suggestions. We are grateful to the following CRUK Cambridge Institute core facilities for advice and assistance: Histopathology, Light Microscopy (in particular H. Zecchini), PK/Bioanalytics core, and BRU. Cambridge Advanced Imaging Centre was used for EM specimen and processing facilities (in particular K.H. Muller). 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].
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-14187-x
DO - 10.1038/s41467-019-14187-x
M3 - Article
C2 - 31949142
AN - SCOPUS:85077940917
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 307
ER -