PMID- 28677234 OWN - NLM STAT- MEDLINE DCOM- 20180515 LR - 20220330 IS - 1474-9726 (Electronic) IS - 1474-9718 (Print) IS - 1474-9718 (Linking) VI - 16 IP - 5 DP - 2017 Oct TI - Anti-aging pharmacology in cutaneous wound healing: effects of metformin, resveratrol, and rapamycin by local application. PG - 1083-1093 LID - 10.1111/acel.12635 [doi] AB - 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. CI - (c) 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. FAU - Zhao, Pan AU - Zhao P AD - 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. AD - Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China. FAU - Sui, Bing-Dong AU - Sui BD AD - 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. AD - Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. FAU - Liu, Nu AU - Liu N AD - 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. AD - Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. AD - Department of Periodontology, Stomatological Hospital, Zunyi Medical College, Zunyi, Guizhou, 563003, China. FAU - Lv, Ya-Jie AU - Lv YJ AD - 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. AD - Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710069, China. FAU - Zheng, Chen-Xi AU - Zheng CX AD - 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. AD - Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. FAU - Lu, Yong-Bo AU - Lu YB AD - Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China. FAU - Huang, Wen-Tao AU - Huang WT AD - Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China. FAU - Zhou, Cui-Hong AU - Zhou CH AD - 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. AD - Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China. FAU - Chen, Ji AU - Chen J AD - 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. FAU - Pang, Dan-Lin AU - Pang DL AD - 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. AD - Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. FAU - Fei, Dong-Dong AU - Fei DD AD - 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. FAU - Xuan, Kun AU - Xuan K AD - 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. AD - Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. FAU - Hu, Cheng-Hu AU - Hu CH AD - 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. AD - Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi, 710032, China. FAU - Jin, Yan AU - Jin Y AD - 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. AD - Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. LA - eng PT - Journal Article DEP - 20170705 PL - England TA - Aging Cell JT - Aging cell JID - 101130839 RN - 0 (Ccnd1 protein, rat) RN - 0 (Cyclin-Dependent Kinase Inhibitor p16) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Ppargc1a protein, rat) RN - 0 (Stilbenes) RN - 0 (Tumor Suppressor Protein p53) RN - 136601-57-5 (Cyclin D1) RN - 9100L32L2N (Metformin) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases) RN - EC 2.7.11.1 (Rps6kb1 protein, rat) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 6.4.1.2 (Acetyl-CoA Carboxylase) RN - Q369O8926L (Resveratrol) RN - W36ZG6FT64 (Sirolimus) SB - IM EIN - Aging Cell. 2022 Feb;21(2):e13561. PMID: 35112450 MH - AMP-Activated Protein Kinases/genetics/metabolism MH - Acetyl-CoA Carboxylase/genetics/metabolism MH - Administration, Cutaneous MH - Aging/genetics/*metabolism MH - Animals MH - Cyclin D1/genetics/metabolism MH - Cyclin-Dependent Kinase Inhibitor p16/genetics/metabolism MH - Enzyme Activation MH - Female MH - Gene Expression Regulation MH - Metformin/*pharmacology MH - Mice MH - Neovascularization, Physiologic/drug effects/physiology MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Resveratrol MH - Ribosomal Protein S6 Kinases/genetics/metabolism MH - Sirolimus/*pharmacology MH - Skin/blood supply/drug effects/enzymology/injuries MH - Skin Aging/*drug effects MH - Stilbenes/*pharmacology MH - Tumor Suppressor Protein p53/genetics/metabolism MH - Wound Healing/*drug effects/physiology MH - Wounds, Nonpenetrating/*drug therapy/enzymology/genetics/pathology PMC - PMC5595695 OTO - NOTNLM OT - AMPK pathway OT - aged skin OT - anti-aging pharmacology OT - metformin OT - vascularization OT - wound healing EDAT- 2017/07/06 06:00 MHDA- 2018/05/16 06:00 PMCR- 2017/10/01 CRDT- 2017/07/06 06:00 PHST- 2017/06/01 00:00 [accepted] PHST- 2017/07/06 06:00 [pubmed] PHST- 2018/05/16 06:00 [medline] PHST- 2017/07/06 06:00 [entrez] PHST- 2017/10/01 00:00 [pmc-release] AID - ACEL12635 [pii] AID - 10.1111/acel.12635 [doi] PST - ppublish SO - Aging Cell. 2017 Oct;16(5):1083-1093. doi: 10.1111/acel.12635. Epub 2017 Jul 5.