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Melatonin Exerts Prominent, Differential Epidermal and Dermal Anti-Aging Properties in Aged Human Eyelid Skin Ex Vivo
Tara Samra1, Tatiana Gomez-Gomez1, Kinga Linowiecka1,2
1Dr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33125, USA.
Abstract:
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 (5-6 donors; 49-77 years) by adding melatonin to the culture medium, followed by the assessment of core aging biomarkers via quantitative immunohistochemistry. Over 6 days, 200 µM 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 µM 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.
Insights
Melatonin demonstrates anti-aging effects on aged human skin ex vivo. It downregulates aging pathways and boosts collagen and mitochondrial markers, suggesting potential for skin rejuvenation therapies.
Area of Science:
- Dermatology
- Gerontology
- Molecular Biology
Background:
- Human skin aging involves physiological decline, necessitating senotherapeutics.
- Melatonin shows in vitro and in vivo anti-aging potential, but its ex vivo effects on aged human skin are unproven.
- Understanding melatonin's impact on aged skin biomarkers is crucial for developing effective anti-aging strategies.
Purpose of the Study:
- To investigate the anti-aging effects of melatonin on organ-cultured aged human eyelid skin ex vivo.
- To assess melatonin's impact on key aging biomarkers in both the epidermis and dermis.
- To determine if melatonin can reverse or mitigate signs of aging in human skin.
Main Methods:
- Organ-cultured, full-thickness human eyelid skin from aged donors (49-77 years) was treated with melatonin (100-200 µM) or vehicle for 6 days.
- Quantitative immunohistochemistry was employed to assess core aging biomarkers, including pathway activity, protein expression, and structural organization.
- Specific markers analyzed included mTORC1 activity (S6 phosphorylation), MMP-1, collagen 17A1, mitochondrial proteins (TFAM, MTCO-1, VDAC), VEGF-A, fibrillin-1, SIRT-1, lamin-B1, p16INK4, and collagen I.
Main Results:
- Melatonin (200 µM) significantly downregulated epidermal mTORC1 pathway activity and MMP-1 expression.
- Transmembrane collagen 17A1 and mitochondrial markers (TFAM, MTCO-1, VDAC) were significantly upregulated by melatonin.
- Melatonin (100 µM) increased epidermal VEGF-A expression, and in the dermis, it enhanced fibrillin-1 expression and organization, improving the extracellular matrix.
Conclusions:
- This ex vivo study provides proof of principle for melatonin's anti-aging effects in aged human skin.
- Melatonin exerts differential effects on aged epidermis and dermis, downregulating some aging markers while upregulating others beneficial for skin health.
- The findings suggest melatonin's potential as a senotherapeutic agent for human skin rejuvenation.
