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

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

Abstract

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.

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

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Acetyl-CoA Carboxylase / genetics
  • Acetyl-CoA Carboxylase / metabolism
  • Administration, Cutaneous
  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Enzyme Activation
  • Female
  • Gene Expression Regulation
  • Metformin / pharmacology*
  • Mice
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Resveratrol
  • Ribosomal Protein S6 Kinases / genetics
  • Ribosomal Protein S6 Kinases / metabolism
  • Sirolimus / pharmacology*
  • Skin / blood supply
  • Skin / drug effects
  • Skin / enzymology
  • Skin / injuries
  • Skin Aging / drug effects*
  • Stilbenes / pharmacology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Wound Healing / drug effects*
  • Wound Healing / physiology
  • Wounds, Nonpenetrating / drug therapy*
  • Wounds, Nonpenetrating / enzymology
  • Wounds, Nonpenetrating / genetics
  • Wounds, Nonpenetrating / pathology

Substances

  • Ccnd1 protein, rat
  • Cyclin-Dependent Kinase Inhibitor p16
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • Stilbenes
  • Tumor Suppressor Protein p53
  • Cyclin D1
  • Metformin
  • Ribosomal Protein S6 Kinases
  • Rps6kb1 protein, rat
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase
  • Resveratrol
  • Sirolimus