Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk.,Nature Communications

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Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-16 , DOI: 10.1038/s41467-019-14187-x
Liam D Cassidy ₁ , Andrew R J Young ₁ , Christopher N J Young ₂ , Elizabeth J Soilleux ₃ , Edward Fielder ₄ , Bettina M Weigand _{4,

5,

6} , Anthony Lagnado _{5,

6} , Rebecca Brais ₇ , Nicholas T Ktistakis ₈ , Kimberley A Wiggins ₉ , Katerina Pyrillou ₉ , Murray C H Clarke ₉ , Diana Jurk _{5,

6} , Joao F Passos _{4,

5,

6} , Masashi Narita _{1,

10}

Affiliation

University of Cambridge, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK.
Leicester School of Allied Health Sciences, Faculty of Health & Life Sciences, De Montfort University, Leicester, LE1 5RR, UK.
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Signalling Programme, Babraham Institute, Babraham, Cambridge, UK.
Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
Tokyo Tech World Research Hub Initiative (WRHI), Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan.

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.

中文翻译：

自噬的暂时抑制揭示了衰老的节段性逆转，并增加了癌症风险。

自噬是一种重要的细胞降解途径，在新陈代谢和基本质量控制中发挥着核心作用，这两个过程与衰老有着千丝万缕的联系。自噬的减少与年龄的增长有关，但尚不清楚这是否是衰老过程的原因，以及自噬的恢复是否可以抵消这些衰老效应。在这里，我们证明系统性自噬抑制会导致哺乳动物过早获得与年龄相关的表型和病理学。值得注意的是，自噬恢复使发病率几乎完全恢复，并显着延长寿命。然而，在分子水平上，这种拯救似乎并不完整。重要的是，由于自发肿瘤形成的增加，自噬恢复的小鼠仍然会更早死亡。因此，我们的数据表明，慢性自噬抑制会导致癌症风险不可逆转地增加，并揭示自噬在癌症发展中的双相作用，依次是肿瘤抑制和致癌。

更新日期：2020-01-16

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