title: Resveratrol prevents oxidative stress-induced senescence and proliferative dysfunction by activating the AMPK-FOXO3 cascade in cultured primary human keratinocytes.
abstract: The aging process is perceived as resulting from a combination of intrinsic factors such as changes in intracellular signaling and extrinsic factors, most notably environmental stressors. In skin, the relationship between intrinsic changes and keratinocyte function is not clearly understood. Previously, we found that increasing the activity of AMP-activated protein kinase (AMPK) suppressed senescence in hydrogen peroxide (H2O2)-treated human primary keratinocytes, a model of oxidative stress-induced cellular aging. Using this model in the present study, we observed that resveratrol, an agent that increases the activities of both AMPK and sirtuins, ameliorated two age-associated phenotypes: cellular senescence and proliferative dysfunction. In addition, we found that treatment of keratinocytes with Ex527, a specific inhibitor of sirtuin 1 (SIRT1), attenuated the ability of resveratrol to suppress senescence. In keeping with the latter observation, we noted that compared to non-senescent keratinocytes, senescent cells lacked SIRT1. In addition to these effects on H2O2-induced senescence, resveratrol also prevented the H2O2-induced decrease in proliferation (as indicated by 3H-thymidine incorporation) in the presence of insulin. This effect was abrogated by inhibition of AMPK but not SIRT1. Compared to endothelium, we found that human keratinocytes expressed relatively high levels of Forkhead box O3 (FOXO3), a downstream target of both AMPK and SIRT1. Treatment of keratinocytes with resveratrol transactivated FOXO3 and increased the expression of its target genes including catalase. Resveratrol's effects on both senescence and proliferation disappeared when FOXO3 was knocked down. Finally, we performed an exploratory study which showed that skin from humans over 50 years old had lower AMPK activity than skin from individuals under age 20. Collectively, these findings suggest that the effects of resveratrol on keratinocyte senescence and proliferation are regulated by the AMPK-FOXO3 pathway and in some situations, but not all, by SIRT1.
authors: Diabetes and Metabolism Unit, Boston University Medical Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Yasuo
authors: Y
authors: Ido
authors: L'OREAL Research and Innovation, Aulnay sous bois, France.
authors: Albert
authors: A
authors: Duranton
authors: Endocrinology, Second Affiliated Hospital Chongqing Medical University, Chongqing, China.
authors: Fan
authors: F
authors: Lan
authors: Diabetes and Metabolism Unit, Boston University Medical Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Karen A
authors: KA
authors: Weikel
authors: L'OREAL Research and Innovation, Aulnay sous bois, France.
authors: Lionel
authors: L
authors: Breton
authors: Diabetes and Metabolism Unit, Boston University Medical Center, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors: Neil B
authors: NB
authors: Ruderman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007223:Infant; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D013267:Stilbenes; D006861:Hydrogen Peroxide; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000077185:Resveratrol
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