Date Published: July 05, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Pan Zhao, Bing‐Dong Sui, Nu Liu, Ya‐Jie Lv, Chen‐Xi Zheng, Yong‐Bo Lu, Wen‐Tao Huang, Cui‐Hong Zhou, Ji Chen, Dan‐Lin Pang, Dong‐Dong Fei, Kun Xuan, Cheng‐Hu Hu, Yan Jin.
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.
Cutaneous wounds are among the most common soft tissue injuries that require long healing cycle during which severe structural and functional damages or further infection sometimes occur (Shaw & Martin, 2009). Particularly, aging is accompanied by an increasing risk of chronic nonhealing cutaneous wounds, resulting in severe clinical burdens but without effective therapeutics (Sgonc & Gruber, 2013). Currently, the only intervention shown conclusively to counteract aging is caloric restriction (CR) (Fontana & Partridge, 2015), which was also reported to improve wound healing in mammals (Reed et al., 1996). Pharmacologically, several CR mimetics have recently been discovered to retard aging and alleviate age‐related pathological changes in various experimental models (Vaiserman et al., 2016), particularly metformin (MET) (Barzilai et al., 2016), resveratrol (RSV) (Park et al., 2012), and rapamycin (RAPA) (Wilkinson et al., 2012). Among these anti‐aging agents, surprisingly, RAPA has been documented to inhibit wound healing (Mills et al., 2008), probably due to its immunosuppressive capability upon systemic administration (Mills et al., 2008; Lamming et al., 2013). However, the effects of other CR mimetics MET and RSV on cutaneous wound healing are less understood. Furthermore, considering that local application of agents on skin is more convenient and may exclude potential systemic side effects, elucidating and comparing topical effects of these anti‐aging pharmacological agents on wound healing are of significance to develop clinical relevant strategies for skin defects.
CR rescues impaired wound healing (Reed et al., 1996), but locally applied impacts and potential functional differences of CR mimetics MET, RSV, and RAPA (Park et al., 2012; Wilkinson et al., 2012; Vaiserman et al., 2016) on wound healing remain to be established. Here, we investigated and compared effects of these anti‐aging pharmacological agents on cutaneous wound healing by local application. We discovered that MET and RSV, but not RAPA, improved wound healing in young rodents. Particularly, MET exhibited more profound effects, and further exerted prominent regenerative effects in aged skin. We have also identified critical angiogenic and rejuvenative mechanisms through AMPK pathway in wound healing of both young and aged skin. These findings unraveled local application of MET as the promising therapeutic agent in wound defects.
This work was supported by The National Key Research and Development Program of China (2016YFC1102900 and 2016YFC1101400) and The General Program of National Natural Science Foundation of China (81570937 and 81470710).
P.Z., B.D.S., and N.L. contributed equally to the study design, experimental work, data analysis, data interpretation, and manuscript preparation. Y.J.L. and C.X.Z. contributed to the experimental work and revised the manuscript. Y.B.L. and W.T.H. contributed to the data interpretation. C.H.Z., J.C., D.L.P., D.D.F., and K.X. contributed to the data interpretation. C.H.H. and Y.J. conceived and supervised the study. All authors have reviewed and approved the final version of the manuscript.
The authors state no conflict of interest.