Role of melatonin in senescence/aging of human skin

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Cellular senescence is an irreversible growth arrest that occurs as a result of different damaging intrinsic and extrinsic stimuli, including DNA damage, telomere shortening and dysfunction or oncogenic stress. Senescent cells exert a pleiotropic effect on development, tissue aging and regeneration, inflammation, wound healing and tumour suppression. Strategies to remove senescent cells from aging tissues can delay tissue dysfunction and lead to increased health span. Human skin is the largest organ of the body and consists of different cell types and compartments. Skin provides a physical barrier against harmful microbes, toxins, and protect us from ultraviolet radiation (UVR). Increasing evidence suggests that senescent cells accumulate in chronologically aged and photoaged skin; and may contribute to age-related skin changes and pathologies. Because skin health is considered one of the principal factors representing overall “well-being” and the perception of “health” in humans, enclosed research project is tempting to evaluate melatonin’s modulatory activity on cellular senescence of the skin. Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. It regulates circadian rhythmicity and exerts anti-oxidative, anti-inflammatory, immunomodulatory, and anti-tumor capacities. To the best of our knowledge, almost nothing is known on the precise impact of melatonin on cellular senescence of keratinocytes, fibroblasts and melanocytes. It is also unknown whether the melatonin pathway is impaired during skin aging, e.g. by reduced generation of melatonin and reduced expression of melatonin receptors in skin. Based on preliminary results, melatonin is hypothesized to act as an anti-aging agent in human skin, especially in the context of extrinsic UV-induced skin aging. To address this question, a combination of experimental approaches have been designed consisting of a) in vitro experiments on key cell types of the skin, i.e. epidermal keratinocytes and dermal fibroblasts, b) mechanistic studies on the mode of action of melatonin, c) ex vivo experiments on UV-exposed and not-UV-exposed skin samples derived from young and old donors in order to determine the levels/expression of melatonin and its receptor, and d) ex vivo experiments on human skin organ culture assessing the relevance of in vitro experiments. This proposal will improve our knowledge about changes within skin aging, research advances on the molecular mechanisms leading to these changes, and the impact of the melatoninergic anti-oxidative system controlled by melatonin, targeting the prevention or reversal of skin aging.