Atherosclerosis and Aging

There are two explanations for the increased prevalence of vascular disease in the elderly: (1) the increased risk represents a longer duration of exposure to conditions that promote atherosclerosis (i.e., the time-dose product of the risk factors); and (2) atherosclerosis is a specific aging-associated process. It is important to note that these possibilities are not mutually exclusive and that from the perspective of a given elderly individual at risk for vascular disease, this distinction may not matter much. However, discrimination between these hypotheses has important implications for prevention of vascular disease, particularly at the population level. In the former case, preventive therapies should focus on early interventions on established risk factors such as hypercholesterolemia, hypertension, diabetes, obesity, and smoking; in the latter case, specific therapies may be required to target the aging-associated mechanisms that accelerate atherosclerosis in the elderly.

The possibility that atherosclerosis has a specific aging-associated pathogenesis can be explored at the epidemio-logic and pathophysiologic levels. The Framingham study still provides the best data for understanding the epidemiologic impact of aging on cardiovascular disease. One way that this data set can be used to address the role of aging per se as a risk factor for atherosclerosis is to examine the age-dependence of established cardiovascular risk factors. Indeed, the combined effect of all cardiovascular risk factors together, or of each risk factor individually (with the exception of hypertension), decreases with age, in spite of the age-associated increase in prevalence of cardiovascular disease, suggesting that aging itself is the critical factor (Kannel and Gordon, 1980). More to the point, multivariate analysis demonstrates that aging is a risk factor for atherosclerosis independent of cholesterol level, blood pressure, diabetes, or smoking.

Well-described physiologic changes in the cardiovascular system occur with aging that may predispose the vasculature to accelerate the development of atherosclerosis. A variety of studies have shown that older animals have an increased susceptibility and responsiveness to vascular insults (Weingand et al., 1986; Spagnoli et al., 1991; McCaffrey and Falcone, 1993). With aging, there is progressive dilation of large vessels with associated intimal thickening (Michel et al., 1994). Collagen content is increased but elastin content is decreased, resulting in decreased compliance of large arteries (Fornieri et al., 1992). In fact, the change in matrix composition is the primary determinant of intimal thickening associated with aging, as total cellularity remains constant or even decreases (Fornieri et al., 1992; Michel et al., 1994; Lopez-Candales et al., 1997). Bilato and Crow term these aging-associated vascular changes ''the vasculopathy of aging,'' and argue that they provide the soil for atherosclerosis in elderly individuals (Bilato and Crow, 1996). Strongly supporting the hypothesis that atherogenesis is an intrinsically age-related process, accelerated atherosclerosis is seen in diseases associated with premature senescence, such as Werner's syndrome and progeria (Cohen et al., 1987).

At present, we know in significant detail the molecular and cellular events that link important cardiovascular risk factors (increased cholesterol, hypertension, diabetes, and smoking) with atherosclerotic lesion progression, and in many cases we have effective therapies that have been extensively documented to modify the risk of cardiovascular events. In comparison with these other risk factors, we know almost nothing about the molecular events that link aging and atherosclerosis, and consequently we have no therapies aimed at modulating the cardiovascular risk inherent to aging. This gap in our knowledge provides the fundamental rationale for the application of animal models of atherosclerosis to delineate the age-associated pathogenetic mechanisms of this disease.

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