Senescence is the process of biological ageing that takes place in living cells and the abundance of senescent cells increase in our bodies as we age. As many people will be aware, age is one of the biggest risk factors for a number of diseases, and it is thought that senescent cells and the factors that they secrete may drive the ageing process. Controlled and targeted clearance of the senescent cell burden may have considerable health benefits and is an attractive strategy for extending our healthspan. This research programme seeks to identify new gene that can be targeted for clearance of senescent cells and identify novel compounds to achieve this aim. Until very recently it was not possible to perform targeted gene knockdown in senescent cells. However, the applicant has successfully developed a technique to turn individual genes off in senescent cells. This has enabled us to screen for genes that senescent cells have become 'addicted to' and find those that can be targeted to specifically kill these aged cells. Using this strategy, we have identified 16 such genes. Excitingly, these genes appear to be functionally related, interact with key drivers of senescence and are observed to increase their expression in a range of cells and tissues with biological ageing. Our bodies are made up of lots of different cell types, and an important first step will be to determine if turning these genes off in different cell types also results in the specific clearance of senescent cells. This will involve the culture of epithelial cells and fibroblasts from two different tissues, breast and skin. These cells have already been grown and aged in our laboratory. We will also validate the reported increase in expression with age using skin biopsies. Throughout this work, we will examine a range of known senescence markers, determine the precise cell death pathways that are engaged and check that our approaches are well tolerated by 'healthy' young cells. We will use a mixture of sophisticated, automated microscopy techniques coupled with molecular biology and others assays to achieve these aims. It is anticipated that future strategies for the targeted removal of senescent cells (so call senolytic therapies) will involve intermittent administration during periods of good health. We will test a range of different regimes to model the optimal treatment strategy for human senescent cell clearance. In addition to turning off our selected genes, we will perform a small-scale compound screen to see if we can identify senolytic compounds which inhibit our genes of interest. Next, we will use state of the art 3D co-culture systems to generate 'skin in a dish' and determine the impact of senescent cell clearance on skin ageing phenotypes. Finally, we will perform a high-throughput compound screen to identify novel compounds that can achieve targeted senescent cell clearance in cells in a dish and in our 3D models. Results of this research programme will therefore provide much needed information about the route to senescent cell clearance, identify novel senolytic compounds and bespoke treatment regimes. We hope our research will pave the way for the development of future treatments for senescent cell clearance.