Grant: Project Grant

During aging, the human mortality rate rises exponentially as a result of a loss of normal organ functions. Of those, age-related cardiovascular diseases are of particular clinical concern because they represent 50% of premature deaths. By 2030, 1 billion individuals are projected to be over 65 years old. Today, 38% of people age 40 to 60 years, and 83% of those over 85 years have cardiovascular diseases. The main cause of premature death is atherosclerosis, plaques of fat (atheroma) that form with time in the arteries and eventually clog them, preventing blood flow to the organs, the heart being the first target. In this project, we propose that the inner layer of cells in the main arteries, the endothelium, becomes senescent with age, a process that could favour the development of the atheroma. Indeed, senescent cells accumulate and produce factors responsible for inflammation that contribute to change the structure of the vessel wall. This deleterious inflammatory environment could also affect the organ cells, promoting their senescence and therefore the dysfunction of the organ with time. We have discovered in old patients with cardiovascular diseases a protein produced by these senescent endothelial cells. We now have preliminary data showing that if we inactivate this protein in mice with atheroma, it improves the function of the arteries, it reduces the amount of senescent endothelial cells in the aorta, it decreases the level of inflammation in the aorta and reduces the growth rate of the atheroma plaque formation in the aorta. In addition, it increases health-span, that is, increases median mouse lifespan. We almost know nothing about the impact of senescence of endothelial cells on vascular function. Our aim is to demonstrate that by eliminating these senescent vascular cells, atheroma plaque growth will be reduced and this will maintain an adequate blood flow to the organ to maintain their function with age.