title: AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation.
abstract: 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.
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Han
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Tai
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Xiawei
authors.initials: X
authors.lastname: Wei
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Chunfen
authors.initials: C
authors.lastname: Mo
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Jianqiong
authors.initials: J
authors.lastname: Qin
authors.affiliation: Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Yuanji
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.affiliation: Department of Clinical Medicine, Medical School of Nankai University, Tianjin, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xiang
authors.affiliation: Lab for Aging Research, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
authors.forename: Hengyi
authors.initials: H
authors.lastname: Xiao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D042541:Intracellular Space / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009243:NAD / Q000378:metabolism*; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C484068:Tcfeb protein, mouse; D009243:NAD; D006861:Hydrogen Peroxide; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; NAD+; autophagy; oxidative stress; senescence