As cells age, they stop dividing and start leaking a toxic cocktail of inflammatory and clotting proteins into the bloodstream. This matters because the body’s blood vessels are lined with endothelial cells that normally store these dangerous proteins in tiny packets called Weibel-Palade bodies, releasing them only when needed to repair an injury. The researchers have discovered that senescent endothelial cells produce far more of these packets, and pack them with a more inflammatory cargo. This likely explains why older people have higher levels of clotting factors in their blood and are more prone to dangerous clots and chronic inflammation. But exactly how and why this storage system goes wrong during ageing is unknown. This project is fundamental science. It will map the molecular pathways that cause senescent cells to overproduce these storage granules, identify precisely which inflammatory and clotting proteins are being stockpiled, and test in mice whether blocking the release of these granules can reduce age-related clotting and inflammation. If successful, it could reveal new drug targets for preventing the blood-clotting disorders and frailty that plague older adults—conditions that currently have no treatment aimed at their root cause.
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Ageing is characterised by an ongoing process of cell and tissue dysfunction. This results in a number of phenotypes which include senescence (the stable arrest of cellular division) and chronic low-level inflammation1. One of the major hallmarks of senescence is a change in secretion, termed the senescence associated secretory phenotype (SASP)2 and this drastically effects cellular and tissue function. Many SASP proteins are associated with haemostasis3 and our previous research has demonstrated that upregulation of certain coagulation factors directly affects senescence4. More generally, dysregulation of coagulation is associated with frailty and thrombosis in the ageing population5,6. Here we seek to investigate the link between senescence, haemostasis, and inflammation by determining the impact of senescence pathways on regulated granule storage and release from the endothelium. Endothelial storage organelles (Weibel Palade Bodies) provide a rapidly mobilised pool of clotting factors (Von Willebrands Factor-VWF), inflammatory (P-selectin, IL-8) and vasoconstriction (endothelin, ECE) mediators that are essential for a normal response to vascular injury7. Our preliminary research indicates that during senescence, the number of storage organelles increases dramatically. In addition we show the arsenal of stored cargo changes, becoming markedly more pro-inflammatory. This is supported by other research which demonstrates increased levels of VWF are present in the circulation of both older individuals 8,9 and aged animals 10. However, the mechanism underlying the changes in biogenesis and storage are unclear, as are the likely functional effects on inflammation and haemostasis. As such we hypothesise: Senescent endothelial cells exhibit an altered regulated secretory pathway resulting in an increase in the number of endothelial storage organelles. This not only results in an increased secretion of VWF but also a bolus of release of other inflammatory mediators. Limiting storage organelle secretion will provide a way to limit the clotting and inflammatory abnormalities associated with ageing. To test this, we propose to address three interconnected aims. 1. To characterise the pathways that lead to an increase in WPB number in senescent cells. Using in vitro models to characterise the pathways that result in an increase in WPB number. 2. To determine how the contents of WPB vary in senescent compared to proliferating endothelial cells. Using a novel proximity proteomics strategy we will define the changes in WPB storage associated with senescence. 3. Using novel in vivo models, determine how senescent induced changes in WPB release and phenotype impact inflammation and haemostasis. Using an endothelial progerin mouse model that displays senescent phenotypes we will determine the impact of increased WPB number on inflammation and haemostasis and define the impact of the secretion of individual cargo. Overall this project will determine the importance of changes in endothelial storage organelle number and content on the phenotypes associated with senescence. It will also provide mechanistic insight into how this process is controlled and identify which cargo contents are the most important. In the long term this will allow new approaches for the therapeutic control of pathophysiology associated with aging.
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