Developing multi-level pipelines for senolytics discoveries

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Accumulation of senescent cells has been shown in recent years as a driver of most, if not all age-associated conditions. Drugs that selectively kill senescent cells (senolytics) emerged as novel therapeutic modalities for a wide range of age-associated diseases in pre-clinical studies, and first generation senolytics are now in about a dozen of clinical trials. The main limitations for translation are frequent side effects, limited specificity of first-generation senolytics, and importantly the lack of rigorous evaluations of the administration protocols.Lead supervisor's lab has been engaged in the discovery of novel safer and more effective senolytics using knowledge and expertise in cell senescence and cellular energetics. The lab has developed a novel senolytics screening platform with an in vitro model using human dermal fibroblasts, and one promising candidate has been selected for pre-clinical tests using an in vivo mouse model. The candidate treatment was shown to be safe and able to bring about excellent anti-ageing properties assessed by frailty index, cognitive and neuromuscular function, and a patent application is in process. Its application to clinical setting is also being planned.The project aims to further advancing a pipeline for discovery of novel senolytics and other agents with anti-ageing properties by developing a multi-level testing platform, based on the systems established at the lead supervisor's lab. Specifically, the project will (1) expand the in vitro screening platform, using different cell types, growth conditions, and treatment schedules (2) establish an in vitro 3D model testing platform, using 3D skin models and human skin explants and (3) refine the pre-clinical assessment protocols for ageing phenotype in mouse models. The multi-level platforms will benefit not only the ability to more rigorously and specifically assess the effects of novel agents, but also increase our understanding of the biological impact of senescent cells in mammalian ageing.The project will test and validate compounds derived in-house using bioinformatic and hypothesis driven approaches as well as those provided by our industry partner (Novos Labs). The student will obtain knowledge and experiences in a wide range of skills associated with ageing and senescence research. The supervisor is closely associated with the Alliance for Healthy Ageing, an international consortium of world-leading ageing institutes; there are a variety of workshop, summer schools, seminars and meetings for the student to attend and to be exposed to highly stimulating learning environments.