to attenuate carcinogenesis and possibly other pathological pro- cesses, including hyperproliferative/inflammatory conditions.2 Reduced melatonin levels have been linked to inflammation in psoriasis, suggesting a possible therapeutic role for melatonin supplementation.6 Topically applied melatonin has demonstrated positive effects for the management of androgenetic alopecia with a reduction in hair loss among women and a maintenance of current hair among men.7 The benefit has been attributed to melatonin’s indirect antioxidant and regenerative capacities.8 Melatonin may also have a role in barrier function and enhance wound healing by increasing proliferative activity of keratinocytes.9 The range of proposed cutaneous benefits associated with melatonin are certainly intriguing. However, its role as an anti-aging agent for topical application may have both greatest promise and potential utility. A careful assessment of the indirect or direct antioxidant and anti-inflammatory effects of melatonin is therefore warranted. Additionally, it is worthwhile to review the evidence for benefit attributed to topical application of melatonin.
Skin Aging and Antioxidants
Visible signs of skin aging are the result of various intrinsic and extrinsic factors. Genetic factors may direct the rate and extent of cell senescence, the depletion of collagen stores, and structur- al changes, including the shifting of fat and bone.10,11 However, extrinsic factors may significantly accelerate aging.The primary extrinsic driver of aging has been considered to be exposure to ultraviolet (UV) light. The predominant effects of UV exposure, such as sunburn, immunosuppression, skin aging, and carcino- genesis have been well-documented in the literature.12 Exposure to UVA has been directly correlated to a reduction of collagen in human dermal extracellular matrix.13 Relevant to both skin aging and photocarcinogenesis, the effects of UV exposure on the skin encompass DNA alterations, including induction of thy- mine-thymine dimers and loss of tumor suppressor gene p53.14 More recently, focus has shifted to other extrinsic contributors to skin aging, including visible and infrared (IR) light, as well as atmospheric pollutants, such as ozone.15-17 The oxidative stress theory of aging is relevant to skin aging, as evidence shows that irrespective of the extrinsic agent, either solar radiation (at multiple wavelengths) or atmospheric pollutants, oxidative stress mediated formation of reactive oxygen species (ROS)18 produces inflammation and cytotoxicity with resultant cell damage.19 Ozone induces oxidative stress on the skin's surface via formation of lipid peroxidation (LPO) products.17 Of note, research has shown that the mitochondria are responsible for producing 90% of ROS. Melatonin is shown to function as an indirect antioxidant in the skin, with several of its metabolites described as potent antioxi- dants.20 In addition, melatonin is also an indirect antioxidant and as such shown to stimulate the transcription factor, NRF2 and up-regulate gene expression and activity of several antioxidative enzymes, such as Cu⁄ Zn-superoxide dismutase (CuZn-SOD), Mn-superoxide dismutase (Mn-SOD), catalase and glutathione peroxidase (GPx) in human skin explants8,21 supporting an in- direct antioxidant action of melatonin. The levels of antioxidant enzymes have been reported to stay upregulated for several hours21 suggesting a sustained, long-lasting antioxidant protec- tion in the skin whose benefits last through the night.21 Its effects in supporting antioxidant activity are potent enough to inspire one group of researchers to suggest that melatonin “would improve the therapeutic ratio in radiation oncology and amelio- rate skin damage more effectively when administered in optimal and non-toxic doses.”22 While multiple antioxidants have been variously recommend- ed—either via oral supplementation or topical application for skin protection—melatonin presents distinct potential benefits for addressing oxidative stress in the skin. Melatonin is associated with stronger antioxidant effects than vitamins C and E. Mela- tonin is highly lipophilic and penetrates organic membranes to protect mitochondria and DNA from oxidative damage. Mamma- lian skin boasts high concentrations of precursor molecules that facilitate melatonin synthesis. Therefore, topical application of melatonin is expected to provide antioxidant benefits directly at the site where ROS form in response to exposure to UV light and pollution. Melatonin applied to the skin has been shown to elevate antioxidant enzymes mRNA levels for at least 24 hours.This suggests that the upregulation of gene expression and activity of the above-mentioned antioxidative enzymes and down-regulation of interstitial collagenase (MMP-1), stromelysin 1 (MMP-3), stromelysin 2 (MMP-10), and aldehyde dehydrogenase 3 type A1 would provide important activity for protecting and repairing the skin.21 In a randomized, split-face, assessor-blinded, prospective three- month study, involving 22 women (mean age, 55 years) with moderate-to-severe skin aging, topical application of a melatonin cream was associated with a significant 15% reduction in the appearance of crow's feet, compared with non-treatment, at three months. Skin tone and skin dryness were also improved.23 Melatonin absorbs UV light at a wavelength of 225-275 nm, which is below the UVA and UVB wavelengths of 290-390 nm.24 This has led researchers to speculate that the photoprotective benefits of melatonin are actually a direct consequence of its strong capacity to quench ROS produced as a result of radiation and of its ability to stimulate antioxidant enzymes in the skin. In order to show Melatonin’s impact as a direct and indirect antioxidant, researchers undertook a systematic database review, with 20 studies evaluating melatonin's protective effect against UVR-induced erythema in humans, with results indicating a