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Aging Cell. 2017 Oct;16(5):1083-1093. doi: 10.1111/acel.12635. Epub 2017 Jul 5.

Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application.

Zhao P1,2, Sui BD1,3, Liu N1,3,4, Lv YJ1,5, Zheng CX1,3, Lu YB2, Huang WT2, Zhou CH1,2, Chen J1, Pang DL1,3, Fei DD1, Xuan K1,3, Hu CH1,2, Jin Y1,3.

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State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China.
Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
Department of Periodontology, Stomatological Hospital, Zunyi Medical College, Zunyi, Guizhou, 563003, China.
Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710069, China.


Cutaneous wounds are among the most common soft tissue injuries and are particularly hard to heal in aging. Caloric restriction (CR) is well documented to extend longevity; pharmacologically, profound rejuvenative effects of CR mimetics have been uncovered, especially metformin (MET), resveratrol (RSV), and rapamycin (RAPA). However, locally applied impacts and functional differences of these agents on wound healing remain to be established. Here, we discovered that chronic topical administration of MET and RSV, but not RAPA, accelerated wound healing with improved epidermis, hair follicles, and collagen deposition in young rodents, and MET exerted more profound effects. Furthermore, locally applied MET and RSV improved vascularization of the wound beds, which were attributed to stimulation of adenosine monophosphate-activated protein kinase (AMPK) pathway, the key mediator of wound healing. Notably, in aged skin, AMPK pathway was inhibited, correlated with impaired vasculature and reduced healing ability. As therapeutic approaches, local treatments of MET and RSV prevented age-related AMPK suppression and angiogenic inhibition in wound beds. Moreover, in aged rats, rejuvenative effects of topically applied MET and RSV on cell viability of wound beds were confirmed, of which MET showed more prominent anti-aging effects. We further verified that only MET promoted wound healing and cutaneous integrity in aged skin. These findings clarified differential effects of CR-based anti-aging pharmacology in wound healing, identified critical angiogenic and rejuvenative mechanisms through AMPK pathway in both young and aged skin, and unraveled chronic local application of MET as the optimal and promising regenerative agent in treating cutaneous wound defects.


AMPK pathway; aged skin; anti-aging pharmacology; metformin; vascularization; wound healing

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