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

Abstract

SummaryCutaneous 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.

Health benefits of resveratrol: Evidence from clinical studies

“…Resveratrol treatment has been shown to increase the healing rate and to reduce foot ulcer size . The general wound healing promoting effects of resveratrol is presumably mediated through AMPK activation leading to improved vascularization, or neovascularization, of wound beds along with increased granular tissue …”

“…34 The general wound healing promoting effects of resveratrol is presumably mediated through AMPK activation leading to improved vascularization, or neovascularization, of wound beds along with increased granular tissue. 35,36 Resveratrol is reported to reduce the glycemic index in a rodent model in response to upregulated glucagon like peptide-1 (GLP-1), which is known to stimulate insulin and suppress glucagon production. 37 There are some studies which do not report any antidiabetic effects of resveratrol in humans.…”

Sirtuins in wound healing

“…SIRTs activators have been found in nature and synthesized such as RSV and its derivatives [60] . The effect of RSV on wound healing and chronic diseases has been evaluated not only in animal model and human EpiDerm full thickness model, but also in clinical applications [61][62][63] . Taken together, SIRTs are involved in orchestrated wound healing processes and its activation provides an approach for acceleration of wound therapy.…”

Biological approaches for hypertrophic scars

“…And fibroblast dysfunction is linked to the overproduction of free ROS . Application of antioxidant or drugs with antioxidant properties could relieve the microenvironment of chronic inflammation, accelerate wound healing and alleviate scar formation on wounds . Similarly, classical traditional medicine, arsenic trioxide, could effectively inhibit the formation of rabbit ear scars through the overexpression of antioxidant genes …”