Theranostics 2018; 8(20):5713-5730. doi:10.7150/thno.28778 This issue

Research Paper

Caffeine Protects Skin from Oxidative Stress-Induced Senescence through the Activation of Autophagy

Yi-Fang Li1*, Shu-Hua Ouyang1*, Long-Fang Tu1, Xi Wang1, Wei-Lin Yuan1, Guo-En Wang1, Yan-Ping Wu1, Wen-Jun Duan1, Hong-Min Yu1, Zhong-Ze Fang2, Hiroshi Kurihara1, Youwei Zhang3✉, Rong-Rong He1✉

1. Anti-Stress and Health Research Center, College of Pharmacy, Jinan University, Guangzhou, Guangdong 510632, China
2. Department of Toxicology, School of Public Health, Tianjin Medical University, Heping District, Tianjin, China
3. Department of Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
*These authors contributed equally to this work

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Li YF, Ouyang SH, Tu LF, Wang X, Yuan WL, Wang GE, Wu YP, Duan WJ, Yu HM, Fang ZZ, Kurihara H, Zhang Y, He RR. Caffeine Protects Skin from Oxidative Stress-Induced Senescence through the Activation of Autophagy. Theranostics 2018; 8(20):5713-5730. doi:10.7150/thno.28778. Available from

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Graphic abstract

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 β-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 μM) 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.

Keywords: autophagy, caffeine, cellular senescence, skin aging, UV radiation