{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:07:42Z","timestamp":1791324462430,"version":"4.3.1"},"reference-count":152,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T00:00:00Z","timestamp":1699056000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Monat Global"},{"name":"CUTANEON"},{"name":"Endowed Frost Scholarship from the Dept. of Dermatology, University of Miami"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human skin aging is associated with functional deterioration on multiple levels of physiology, necessitating the development of effective skin senotherapeutics. The well-tolerated neurohormone melatonin unfolds anti-aging properties in vitro and in vivo, but it remains unclear whether these effects translate to aged human skin ex vivo. We tested this in organ-cultured, full-thickness human eyelid skin (5\u20136 donors; 49\u201377 years) by adding melatonin to the culture medium, followed by the assessment of core aging biomarkers via quantitative immunohistochemistry. Over 6 days, 200 \u00b5M melatonin significantly downregulated the intraepidermal activity of the aging-promoting mTORC1 pathway (as visualized by reduced S6 phosphorylation) and MMP-1 protein expression in the epidermis compared to vehicle-treated control skin. Conversely, the transmembrane collagen 17A1, a key stem cell niche matrix molecule that declines with aging, and mitochondrial markers (e.g., TFAM, MTCO-1, and VDAC\/porin) were significantly upregulated. Interestingly, 100 \u00b5M melatonin also significantly increased the epidermal expression of VEGF-A protein, which is required and sufficient for inducing human skin rejuvenation. In aged human dermis, melatonin significantly increased fibrillin-1 protein expression and improved fibrillin structural organization, indicating an improved collagen and elastic fiber network. In contrast, other key aging biomarkers (SIRT-1, lamin-B1, p16INK4, collagen I) remained unchanged. This ex vivo study provides proof of principle that melatonin indeed exerts long-suspected but never conclusively demonstrated and surprisingly differential anti-aging effects in aged human epidermis and dermis.<\/jats:p>","DOI":"10.3390\/ijms242115963","type":"journal-article","created":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T14:51:01Z","timestamp":1699109461000},"page":"15963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Melatonin Exerts Prominent, Differential Epidermal and Dermal Anti-Aging Properties in Aged Human Eyelid Skin Ex Vivo"],"prefix":"10.3390","volume":"24","author":[{"given":"Tara","family":"Samra","sequence":"first","affiliation":[{"name":"Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8624-509X","authenticated-orcid":false,"given":"Tatiana","family":"Gomez-Gomez","sequence":"additional","affiliation":[{"name":"Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7029-2657","authenticated-orcid":false,"given":"Kinga","family":"Linowiecka","sequence":"additional","affiliation":[{"name":"Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA"},{"name":"Department of Human Biology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1, 87-100 Torun, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysun","family":"Akhundlu","sequence":"additional","affiliation":[{"name":"Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Lopez de Mendoza","sequence":"additional","affiliation":[{"name":"Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Gompels","sequence":"additional","affiliation":[{"name":"Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy W.","family":"Lee","sequence":"additional","affiliation":[{"name":"Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Gherardini","sequence":"additional","affiliation":[{"name":"Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1901-0551","authenticated-orcid":false,"given":"J\u00e9r\u00e9my","family":"Ch\u00e9ret","sequence":"additional","affiliation":[{"name":"Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Paus","sequence":"additional","affiliation":[{"name":"Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA"},{"name":"Monasterium Laboratory, 48149 Muenster, Germany"},{"name":"CUTANEON\u2014Skin & Hair Innovations, 22335 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"110780","DOI":"10.1016\/j.exger.2019.110780","article-title":"Cell Aging and Cellular Senescence in Skin Aging\u2014Recent Advances in Fibroblast and Keratinocyte Biology","volume":"130","author":"Gruber","year":"2020","journal-title":"Exp. 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