Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
Ageing Res Rev. 2012 Apr;11(2):230-41. doi: 10.1016/j.arr.2011.12.005. Epub 2011 Dec 15.
Efficient control of energy metabolic homeostasis, enhanced stress resistance, and qualified cellular housekeeping are the hallmarks of improved healthspan and extended lifespan. AMPK signaling is involved in the regulation of all these characteristics via an integrated signaling network. Many studies with lower organisms have revealed that increased AMPK activity can extend the lifespan. Experiments in mammals have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling which augment the quality of cellular housekeeping. Moreover, AMPK-induced stimulation of FoxO/DAF-16, Nrf2/SKN-1, and SIRT1 signaling pathways improves cellular stress resistance. Furthermore, inhibition of NF-κB signaling by AMPK suppresses inflammatory responses. Emerging studies indicate that the responsiveness of AMPK signaling clearly declines with aging. The loss of sensitivity of AMPK activation to cellular stress impairs metabolic regulation, increases oxidative stress and reduces autophagic clearance. These age-related changes activate innate immunity defence, triggering a low-grade inflammation and metabolic disorders. We will review in detail the signaling pathways of this integrated network through which AMPK controls energy metabolism, autophagic degradation and stress resistance and ultimately the aging process.
有效的能量代谢稳态控制、增强的应激抗性和合格的细胞维护是改善健康寿命和延长寿命的标志。AMPK 信号通过一个整合的信号网络参与调节所有这些特征。许多低等生物的研究表明，增加 AMPK 活性可以延长寿命。在哺乳动物中的实验表明，AMPK 通过 mTOR 和 ULK1 信号来控制自噬，从而提高细胞维护的质量。此外，AMPK 诱导的 FoxO/DAF-16、Nrf2/SKN-1 和 SIRT1 信号通路的刺激增强了细胞的应激抗性。此外，AMPK 抑制 NF-κB 信号转导抑制炎症反应。新出现的研究表明，AMPK 信号的反应性随着衰老而明显下降。AMPK 激活对细胞应激的敏感性丧失会损害代谢调节，增加氧化应激并减少自噬清除。这些与年龄相关的变化激活先天免疫防御，引发低度炎症和代谢紊乱。我们将详细回顾这个整合网络的信号通路，AMPK 通过这些信号通路控制能量代谢、自噬降解和应激抗性，最终控制衰老过程。
