In its later stages atherosclerosis is a vicious cycle in which oxidized lipids and the remains of dead cells build up into deposits in blood vessel walls, growing because these deposits cause nearby healthy cells to signal for help. That produces an inflammatory response and attracts the immune cells called macrophages that try and fail to clean up the mess, adding their own remains to the disaster area. As a result of this process of ever-widening damage, blood vessels weaken, narrow, and are ultimately blocked, causing incapacity and death.
Inflammation in blood vessel walls is an important driver of atherosclerosis in its early stages as well. Levels of preexisting inflammation contribute to determining the tipping point between successful cleanup of a small deposit of oxidatively damaged lipids and failure of that cleanup, producing a persistent area of damage that will grow over time - the seed of atherosclerosis. An increasing level of chronic inflammation throughout the body is a characteristic feature of aging, caused by a combination of immune system dysfunction and various other factors. Here researchers discuss one of the mechanisms by which chronic inflammation contributes to the development of atherosclerosis:
Atherosclerosis in the aging population has well surpassed other age-associated diseases such as susceptibility to infection, chronic lung disease, and cancer as a cause of morbidity and mortality in older people. The strongest independent risk factor for the development of atherosclerosis is aging. This risk is greater than the additive risk of hypertension, hypercholesterolemia, and genetics accrued over time. Despite the ongoing threat of atherosclerosis in older people, our understanding of the mechanisms by which aging enhances atherosclerosis remains unclear and under investigated especially in relevant experimental disease models.
Aging may affect atherosclerosis through several mechanisms in hematopoietic cells, vascular cells, or both. For example, aging induces cellular senescence, which leads to DNA damage and impaired antioxidant responses resulting in vascular inflammation that contributes to atherosclerosis. In addition, studies in disease-free animals have found that vascular aging induces oxidative stress in endothelial cells, and leads to medial vessel wall thickening, increased collagen, and extracellular matrix deposition. Endothelial cells (ECs) and vascular smooth muscle cells (VSMC) from disease-free animals exhibit enhanced secretion of inflammatory mediators with aging. Hence, these studies indicate that vascular aging may predispose to diseases such as atherosclerosis, yet whether such age-related vascular changes occur during atherosclerosis remains unclear.
Monocytes and their macrophage descendants are critical immune cells for atherosclerosis. Monocyte recruitment into aortas is critical during atherogenesis, whereas macrophage proliferation in the tissue enhances atherosclerotic lesion progression. Monocytes can be categorized into 'inflammatory' monocytes and 'patrolling' monocytes. Inflammatory monocytes are typically the initial cells recruited into inflammatory sites of the aorta that develop atherosclerosis. After recruitment, the cells engulf lipid particles, become 'foam cell' macrophages, and accumulate within atherosclerotic lesions. It is not known, however, whether aging enhances monocyte intrinsic function or whether aging impacts monocytes indirectly via the vasculature during chronic inflammatory diseases such as atherosclerosis.
Here, we examined how aging impacts atherosclerosis using Ldlr-/- mice, an established murine model of atherosclerosis. We found that aged atherosclerotic Ldlr-/- mice exhibited enhanced atherogenesis within the aorta. Aging also led to increased LDL levels, elevated blood pressure on a low-fat diet, and insulin resistance after a high-fat diet. On a high-fat diet, aging increased a monocytosis in the peripheral blood and enhanced macrophage accumulation within the aorta. When we conducted bone marrow transplant experiments, we found that stromal factors contributed to age-enhanced atherosclerosis. To delineate these stromal factors, we determined that the vasculature exhibited an age-enhanced inflammatory response consisting of elevated production of CCL-2, osteopontin, and IL-6 during atherogenesis. In addition, in vitro cultures showed that aging enhanced the production of osteopontin by vascular smooth muscle cells. Functionally, aged atherosclerotic aortas displayed higher monocyte chemotaxis than young aortas. Hence, our study has revealed that aging induces metabolic dysfunction and enhances vascular inflammation to promote a peripheral monocytosis and macrophage accumulation within the atherosclerotic aorta.