Grant: Project Grant

Aging alone or in combination with risk factors for cardiovascular diseases such as high blood pressure, high levels of fat and sugar in the blood, is associated with a decline in memory that can lead to dementia in some of us. The mechanisms underlying dementia are not clear and so far, no drug treatment has been successful. In this project, we propose that the inner layer of cells in the brain arteries, the endothelium, becomes senescent with age; this could cause damage to our neurons (brain cells) and promote memory loss. Indeed, although senescent cells do no divide anymore, they produce factors responsible for inflammation, destruction of the structures that maintain the architecture of the vessels and lead to lower cerebral perfusion. This deleterious inflammatory environment could also affect the neurons, promote neuronal death and therefore loss of memory and cognitive decline. 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, it improves the function of the cerebral arteries, reduces the amount of senescent endothelial cells in the aorta, decreases the level of inflammation in the aorta, reduces atheroma plaque formation in the aorta, and increases healthspan, that is, increases median mouse lifespan. Nothing is known about the impact of senescence of the endothelial cells specifically in the brain. Our aim is to demonstrate that by eliminating these senescent vascular cells, brain structure, perfusion and function will be preserved, slowing the loss of memory and delay the onset of age-related dementia.