Identifying the impact of skin senescence through the lifecourse

细胞衰老是组织和有机体衰老的公认驱动因素。虽然衰老作为肿瘤抑制机制是有益的，但包括皮肤在内的许多组织中衰老细胞的年龄相关积累导致组织功能、完整性和再生能力下降。衰老被定义为从细胞周期中不可逆地退出，并且响应于潜在的转化细胞应激（例如癌基因激活和DNA损伤）而发生。尽管不能分裂，但生长和代谢途径在衰老中仍然活跃，导致特征性标志，例如增加的氧化应激和产生一组极端炎症的分泌因子，包括细胞因子，生长因子和细胞外基质组分。这个博士项目将扩展我们以前的出版物，并在体外和体内研究不同皮肤相关细胞类型衰老的代谢途径，以确定靶向这些途径是否具有衰老潜力并改善皮肤健康和功能。最终，目的是开发和验证一种局部衰老清除化合物，我们假设它将改善皮肤衰老的许多方面，包括减少炎症，减少氧化应激和改善ECM网络。

Cellular senescence is a well-established driver of tissue and organismal ageing. While senescence is beneficial as a tumour suppressor mechanism, age-related accumulation of senescent cells in many tissues, including skin leads to a decline in tissue function, integrity and regeneration capacity. Senescence is defined as an irreversible exit from the cell cycle and occurs in response to potentially transformative cell stress such as oncogene activation and DNA damage. Despite not being able to divide, growth and metabolic pathways are still active in senescence, leading to the characteristic hallmarks such as increased oxidative stress and production of an extremely inflammatory set of secretory factors, including cytokines, growth factors and extracellular matrix components. This PhD project will expand on our previous publications and investigate metabolic pathways in senescence of different skin-associated cell types in vitro and in vivo to determine whether targeting these pathways has senolytic potential and improves skin health and function. Ultimately, the aim is to develop and validate a topical senolytic compound which we hypothesise will improve many aspects of skin ageing including reduced inflammation, reduced oxidative stress and improved ECM networks.