image: Shown is a cross section through an atherosclerotic plaque of an LDLR knockout mouse fed a high fat diet for 12 weeks. The plaque is stained for senescence-associated beta galactosidase to visualize senescent (often referred to as "zombie") cells. Our research shows that these cells are present throughout plaque development. We find that at the earliest stages of disease, senescent cells propel plaque emlargement through the secretion of factors that attract circulating monocytes to the plaque. At advanced disease stages, senescent cells produce enzymes that dissolve the fibrous cap that overlays the plaque to give it stability, thereby promoting plaque rupture, coagulation of platelets at the site of rupture, full arterial occlusion and myocardial infarction. We show that drugs that eliminate senescent cells (referred to senolytics) inhibit plaque expansion and preserve the cap, giving plaques long-term stability. view more
Credit: Jan van Deursen and Bennett Childs
Aging macrophages contribute to both early and late stages of atherosclerosis, the most common driver of cardiovascular disease, a new study in mice reveals. At early stages of the disease, removing these old or "senescent" cells caused regression of the atherosclerotic lesions, and at advanced stages, it limited disease progression, hinting at a potential cellular target for therapy. Atherosclerosis is the buildup of plaque within the arteries, which can restrict blood flow. If plaques rupture, they can cause blood clots that lead to a heart attack or other cardiovascular complications. Previous studies had linked plaque buildup with markers of cell senescence -- a state whereby cells stop dividing but do not die - but it was unclear whether and when senescent cells actively contribute to the disease. To explore the role of senescent cells in more detail, Bennett Childs and colleagues studied atherosclerosis-prone mice that were genetically engineered in a way that allowed researchers to selectively eliminate senescent cells by administering a certain drug. When these mice were fed a high-fat diet and treated with the drug to remove senescent cells, they exhibited 60% less plaque compared to controls, despite similar feeding habits and blood lipids. By looking closely at the arteries of mice very shortly after starting a high-fat diet, the researchers observed fatty streaks containing lipid-filled "foamy" macrophages along the interior, which drove the expression of inflammatory cytokines. In mice with suppressed senescence, by contrast, these fatty streaks were reduced. Advanced atherosclerosis is characterized by unstable plaques that are prone to rupture; when the researchers studied mice with this advanced stage of disease, they found that markers of plaque instability were reduced in the mice with suppressed senescence compared to controls. These results suggest that blocking senescence could have beneficial effects at both early and late stages of atherosclerosis.
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Journal
Science