Role of melatonin in senescence/aging of human skin

褪黑激素在人体皮肤衰老中的作用

• 批准号: 516216077
• 负责人: Privatdozent Dr. Konrad Kleszczynski, Ph.D.
• 金额: --
• 依托单位: Klinik für Hautkrankheiten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/516216077?language=en
• 关键词: Role; melatonin; senescence; aging; human

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.

细胞衰老是由于不同的损伤性内在和外在刺激（包括DNA损伤、端粒缩短和功能障碍或致癌应激）而发生的不可逆的生长停滞。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方面发挥多效性作用。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增加健康寿命。 人体皮肤是人体最大的器官，由不同的细胞类型和隔室组成。皮肤提供了一个物理屏障，防止有害微生物，毒素，并保护我们免受紫外线辐射（UVR）。越来越多的证据表明，衰老细胞在时间老化和光老化皮肤中积累;并且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“健康”和“健康”感知的主要因素之一，因此封闭的研究项目很有吸引力，以评估褪黑激素对皮肤细胞衰老的调节活性。褪黑激素是一种具有激素性质的5-羟色胺的古老衍生物，是松果体的主要神经内分泌产物。它调节昼夜节律并发挥抗氧化、抗炎、免疫调节和抗肿瘤能力。据我们所知，几乎没有什么是已知的确切影响褪黑激素对角质形成细胞，成纤维细胞和黑素细胞的细胞衰老。还不知道褪黑激素途径是否在皮肤老化期间受损，例如通过皮肤中褪黑激素的产生减少和褪黑激素受体的表达减少。基于初步结果，假设褪黑激素在人类皮肤中充当抗衰老剂，特别是在外源性UV诱导的皮肤老化的背景下。为了解决这个问题，设计了实验方法的组合，包括a）对皮肤的关键细胞类型，即表皮角质形成细胞和真皮成纤维细胞的体外实验，B）对褪黑激素作用模式的机理研究，c）对来自年轻和老年供体的UV暴露和非UV暴露皮肤样品进行离体实验，以确定褪黑激素及其受体的表达，和d）对人皮肤器官培养物的离体实验，评估体外实验的相关性。这一建议将提高我们对皮肤衰老变化的认识，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能抗氧化系统的影响，旨在预防或逆转皮肤衰老。