Unveiling the Anti-Aging Potential of Topical Melatonin: A Systematic Review

Abstract

Introduction: Skin aging is a multifactorial process driven by intrinsic and extrinsic factors that lead to structural, functional, and biochemical deterioration. Reduced endogenous melatonin synthesis with age compromises cutaneous antioxidant defense and repair capacity. Topical melatonin, due to its amphiphilic nature and receptor-mediated as well as receptor-independent mechanisms, has shown potential to counteract oxidative stress, photoaging, mitochondrial dysfunction, and extracellular matrix degradation. Methods: A systematic search was performed in PubMed, Google Scholar, and Science Direct for studies published between 2015 and 2025 evaluating the effects of topical melatonin on skin aging. Inclusion criteria comprised clinical trials, in vivo, and ex vivo studies assessing anti-aging parameters such as wrinkle depth, hydration, skin firmness, pigmentation, oxidative stress biomarkers, and extracellular matrix integrity. Thirteen relevant studies met inclusion criteria and were qualitatively synthesized. Results: Clinical trials show topical melatonin, alone or combined, boosts skin hydration (+59.5%), firmness (+30%), and decreases wrinkle depth (−11% to −31%) and roughness (−13% to −26.5%). Ex vivo results reveal downregulated mTORC1 signaling, decreased MMP-1, and increased collagen 17A1, fibrillin-1, and mitochondrial markers (TFAM, MTCO-1, VDAC). The topical and oral combination approach further improved lipid profiles, notably ceramides and triglycerides. Animal studies confirmed increased angiogenesis (↑ VEGF) and collagen remodeling. All studies showed good tolerability with no serious effects. Discussion: The evidence supports topical melatonin as a safe, effective anti-aging treatment, functioning through antioxidant, mitochondrial, and extracellular matrix mechanisms. Most benefits are from short- to mid-term studies (4–12 weeks); longer-term and comparative trials are needed to confirm sustained efficacy and compare formulations and delivery methods. Conclusion: Topical melatonin demonstrates multi-targeted anti-aging effects in human skin, improving biomechanical, structural, and biochemical markers with an excellent safety profile. Its use in dermatology and cosmetic regimens offers a promising, evidence-based strategy for skin rejuvenation.

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