AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation.
AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation.
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AMPK 激活通过恢复自噬通量和细胞内 NAD() 升高来保护细胞免受氧化应激诱导的衰老。
DOI：
10.1111/acel.12446
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发表时间：
2016-06
期刊：
影响因子：
7.8
通讯作者：
Xiao H
中科院分区：
文献类型：
--
作者：
Han X;Tai H;Wang X;Wang Z;Zhou J;Wei X;Ding Y;Gong H;Mo C;Zhang J;Qin J;Ma Y;Huang N;Xiang R;Xiao H
激活AMPK有利于细胞稳态和预防衰老。然而，参与AMPK激活的分子事件并没有很好地定义。在这项研究中，我们探讨了AMPK对氧化应激诱导的衰老的保护作用的机制。结果表明，AMPK在衰老细胞中失活。然而，二甲双胍和小檗碱对AMPK的药理激活显著阻止了衰老的发展，因此，化合物C对AMPK的抑制作用加快。重要的是，AMPK的激活阻止了过氧化氢诱导的衰老细胞自噬通量的损伤，p62降解、GFP - RFP - LC3取消和溶酶体水解酶活性的降低证明了这一点。我们还发现，AMPK的激活恢复了衰老细胞中NAD +的水平，其机制主要涉及NAD +合成的挽救途径。此外，我们还评估了自噬通量与NAD +合成的机制关系以及mTOR和Sirt1活性的参与。综上所述，我们的研究结果表明AMPK通过改善自噬通量和NAD +稳态来防止氧化应激诱导的衰老。该研究为探索衰老、自噬和NAD +稳态的机制提供了新的视角，对开发抗衰老的创新策略也有价值。
AMPK activation is beneficial for cellular homeostasis and senescence prevention. However, the molecular events involved in AMPK activation are not well defined. In this study, we addressed the mechanism underlying the protective effect of AMPK on oxidative stress‐induced senescence. The results showed that AMPK was inactivated in senescent cells. However, pharmacological activation of AMPK by metformin and berberine significantly prevented the development of senescence and, accordingly, inhibition of AMPK by Compound C was accelerated. Importantly, AMPK activation prevented hydrogen peroxide‐induced impairment of the autophagic flux in senescent cells, evidenced by the decreased p62 degradation, GFP‐RFP‐LC3 cancellation, and activity of lysosomal hydrolases. We also found that AMPK activation restored the NAD + levels in the senescent cells via a mechanism involving mostly the salvage pathway for NAD + synthesis. In addition, the mechanistic relationship of autophagic flux and NAD + synthesis and the involvement of mTOR and Sirt1 activities were assessed. In summary, our results suggest that AMPK prevents oxidative stress‐induced senescence by improving autophagic flux and NAD + homeostasis. This study provides a new insight for exploring the mechanisms of aging, autophagy and NAD + homeostasis, and it is also valuable in the development of innovative strategies to combat aging.