Understanding how ageing impacts on vascular regeneration through the endothelial senescence associated secretory phenotype

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Ageing is the greatest risk factor for poor health and chronic diseases. While life expectancy continues to rise, health span is not improving at the same pace, and therefore there is a real need to increase the quality of life in the elderly population. Ageing impacts on every tissue in our body, and our lab is particularly interested in ageing of blood vessels. The idea of ageing in the vasculature is not new as there is an English saying from the 1600s stating, "A man is only as old as his arteries"; however, recent technological advances in science have opened new opportunities to understand the ageing of blood vessels at the molecular level.This study will employ state-of-the-art technology to investigate ageing in stem cells from blood vessels. These cells known as vascular stem cells or endothelial progenitor cells are responsible for repairing and maintaining a healthy vasculature. There is a theory of ageing suggesting that there is a loss of stem cells with age, while others propose that stem cells become dysfunctional or senescent. Here, we will elucidate how stem cells in blood vessels change during the ageing process.The ageing process in cells is called cellular senescence, and there is evidence to indicate that senescent cells adopt an inflammatory phenotype. The secretion of these inflammatory proteins is called SASP and reinforces the senescence programme. While this idea was demonstrated in human skin fibroblasts, it is not known if this applies to other tissues and cells. Here, we will investigate if inflammation and SASP drives cellular senescence in endothelial progenitors. Importantly, we aim to inhibit this SASP as a strategy to enhance vascular health.A multidisciplinary team comprising of stem cell biologists, vascular biologists, and inflammation biologists designed this project. Working together, we will investigate vascular ageing and endothelial senescence in vascular stem cells using state-of-the-art technologies. We will provide the first detailed molecular characterisation of SASP in endothelial progenitors. Furthermore, we will identify components of the SASP that could be modulated to promote vascular health. In addition, we will use a unique animal model to test the role of inflammation driving vascular ageing and vascular stem cell exhaustion. In summary, outcomes of this project will provide critical information in relation to how vascular ageing is driven by cellular senescence and inflammation in vascular stem cells.