Role of melatonin in senescence/aging of human skin

细胞衰老是一种不可逆转的生长停滞，它是由不同的内在和外在损伤刺激引起的，包括DNA损伤、端粒缩短、功能障碍或致癌应激。衰老细胞在发育、组织老化和再生、炎症、伤口愈合和肿瘤抑制等方面发挥着多方面的作用。从衰老组织中去除衰老细胞的策略可以延缓组织功能障碍并延长健康寿命。人体皮肤是人体最大的器官，由不同类型的细胞和隔室组成。皮肤是抵御有害微生物和毒素的物理屏障，并保护我们免受紫外线辐射（UVR）。越来越多的证据表明，衰老细胞在年龄老化和光老化的皮肤中积累；并可能导致与年龄相关的皮肤变化和病理。由于皮肤健康被认为是代表人类整体“幸福”和“健康”感知的主要因素之一，因此封闭的研究项目很容易评估褪黑素对皮肤细胞衰老的调节活性。褪黑素是松果体的主要神经内分泌分泌产物，是一种具有激素特性的血清素衍生物。它调节昼夜节律，发挥抗氧化、抗炎、免疫调节和抗肿瘤能力。据我们所知，褪黑素对角质形成细胞、成纤维细胞和黑素细胞衰老的确切影响几乎一无所知。在皮肤老化过程中，褪黑激素通路是否受损，例如，皮肤中褪黑激素的生成减少和褪黑激素受体的表达减少，这也是未知的。根据初步结果，褪黑激素被假设为人类皮肤的抗衰老剂，特别是在外源性紫外线诱导的皮肤衰老的情况下。为了解决这个问题，我们设计了一系列实验方法，包括：a)皮肤关键细胞类型的体外实验，即表皮角质形成细胞和真皮成纤维细胞；b)褪黑激素作用模式的机制研究；c)来自年轻和年老供体的暴露于紫外线和未暴露于紫外线的皮肤样本的体外实验，以确定褪黑激素及其受体的水平/表达。d)人体皮肤器官培养的离体实验，评估体外实验的相关性。这一建议将提高我们对皮肤衰老内部变化的认识，对导致这些变化的分子机制的研究进展，以及褪黑激素控制的褪黑激素抗氧化系统的影响，以预防或逆转皮肤衰老为目标。

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.