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.
Nat Commun. 2020 Jan 16;11(1):307. 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.
自噬是一种重要的细胞降解途径，在代谢以及基本的质量控制中起着核心作用，这两个过程与衰老密不可分。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中的因果关系，以及自噬的恢复是否可以对抗这些衰老效应。在这里，我们证明全身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。值得注意的是，自噬的恢复几乎完全恢复了发病率并显著延长了寿命；然而，在分子水平上，这种挽救似乎并不完全。重要的是，自噬恢复的小鼠由于自发性肿瘤形成的增加而更早死亡。因此，我们的数据表明，慢性自噬抑制会导致癌症风险的不可逆增加，并揭示了自噬在癌症发展中的双重作用，既有肿瘤抑制作用，也有致癌作用，顺序发生。
