PMID- 30555576 OWN - NLM STAT- MEDLINE DCOM- 20190904 LR - 20220716 IS - 1838-7640 (Electronic) IS - 1838-7640 (Linking) VI - 8 IP - 20 DP - 2018 TI - Caffeine Protects Skin from Oxidative Stress-Induced Senescence through the Activation of Autophagy. PG - 5713-5730 LID - 10.7150/thno.28778 [doi] AB - Skin cells are vulnerable to oxidative stress-induced senescence, which may lead to abnormal aging or aging-related disorders. Therefore, strategies that can ameliorate oxidative stress-induced senescence are expected to protect skin from damage, holding the promise of treating skin diseases in the clinic. This study aims to investigate whether caffeine, a well-known purine alkaloid, is able to prevent skin from oxidative stress-induced senescence, and to explore the underlying molecular mechanisms. Methods: A free radical inducer 2,2'-Azobis (2-amidinopropane) dihydrochloride (AAPH) was used to induce oxidative stress and cellular senescence in both transformed skin cells and in normal human epidermal keratinocytes (NHEKs). Ultraviolet (UV) irradiation was established as the in vivo oxidative stress model in mouse skin tissues. Cellular senescence was determined by SA beta-galactosidase staining, immunofluorescence and western blotting. Activation of autophagy was confirmed by western blotting, immunofluorescence, and transmission electron microscopy. Reactive oxygen species (ROS) detection by commercial kits, gene knockdown by RNA interference (RNAi) and receptor activation/inactivation by agonist/antagonist treatment were applied in mechanistic experiments. Results: We report that AAPH induced senescence in both transformed skin cells and in NHEKs. Similarly, UV irradiation induced senescence in mouse skin tissues. Remarkably, low dose of caffeine (<10 muM) suppressed cellular senescence and skin damage induced by AAPH or UV. Mechanistically, caffeine facilitated the elimination of ROS by activating autophagy. Using a combination of RNAi and chemical treatment, we demonstrate that caffeine activates autophagy through a series of sequential events, starting from the inhibition of its primary cellular target adenosine A2a receptor (A2AR) to an increase in the protein level of Sirtuin 3 (SIRT3) and to the activation of 5' adenosine monophosphate-activated protein kinase (AMPK). Oral administration of caffeine increased the protein level of SIRT3, induced autophagy, and reduced senescence and tissue damage in UV-irradiated mouse skin. On the other hand, co-administration with autophagy inhibitors attenuated the protective effect of caffeine on UV-induced skin damage in mice. Conclusion: The results reveal that caffeine protects skin from oxidative stress-induced senescence through activating the A2AR/SIRT3/AMPK-mediated autophagy. Our study not only demonstrated the beneficial effect of caffeine using both in vitro and in vivo models, but also systematically investigated the underlying molecular mechanisms. These discoveries implicate the potential of caffeine in the protection of skin disease. FAU - Li, Yi-Fang AU - Li YF AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. FAU - Ouyang, Shu-Hua AU - Ouyang SH AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. FAU - Tu, Long-Fang AU - Tu LF AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. FAU - Wang, Xi AU - Wang X AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. FAU - Yuan, Wei-Lin AU - Yuan WL AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. FAU - Wang, Guo-En AU - Wang GE AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. FAU - Wu, Yan-Ping AU - Wu YP AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. FAU - Duan, Wen-Jun AU - Duan WJ AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. FAU - Yu, Hong-Min AU - Yu HM AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. FAU - Fang, Zhong-Ze AU - Fang ZZ AD - Department of Toxicology, School of Public Health, Tianjin Medical University, Heping District, Tianjin, China. FAU - Kurihara, Hiroshi AU - Kurihara H AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. FAU - Zhang, Youwei AU - Zhang Y AD - Department of Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. FAU - He, Rong-Rong AU - He RR AD - Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China. LA - eng GR - R01 CA230453/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20181110 PL - Australia TA - Theranostics JT - Theranostics JID - 101552395 RN - 0 (Amidines) RN - 0 (Antioxidants) RN - 0 (Oxidants) RN - 3G6A5W338E (Caffeine) RN - 7381JDR72F (2,2'-azobis(2-amidinopropane)) SB - IM MH - Aging/pathology MH - Amidines/toxicity MH - Animals MH - Antioxidants/administration & dosage MH - Autophagy/*drug effects MH - Caffeine/*administration & dosage MH - Cells, Cultured MH - Disease Models, Animal MH - Humans MH - Mice MH - Models, Theoretical MH - Oxidants/*toxicity MH - *Oxidative Stress MH - Skin/drug effects/radiation effects MH - Skin Diseases/pathology/*prevention & control MH - Treatment Outcome MH - *Ultraviolet Rays PMC - PMC6276298 OTO - NOTNLM OT - UV radiation OT - autophagy OT - caffeine OT - cellular senescence OT - skin aging COIS- Competing Interests: The authors have declared that no competing interest exists. EDAT- 2018/12/18 06:00 MHDA- 2019/09/05 06:00 PMCR- 2018/01/01 CRDT- 2018/12/18 06:00 PHST- 2018/07/26 00:00 [received] PHST- 2018/10/04 00:00 [accepted] PHST- 2018/12/18 06:00 [entrez] PHST- 2018/12/18 06:00 [pubmed] PHST- 2019/09/05 06:00 [medline] PHST- 2018/01/01 00:00 [pmc-release] AID - thnov08p5713 [pii] AID - 10.7150/thno.28778 [doi] PST - epublish SO - Theranostics. 2018 Nov 10;8(20):5713-5730. doi: 10.7150/thno.28778. eCollection 2018.