Although age is a strong risk factor for
atherosclerosis, it is unclear whether age may directly influence the process of
atherogenesis. We, therefore, performed several studies in young (2-4 months old), mature (10-14 months old), and old (20-22 months old) mice to determine if the rate of aortic lesion formation increases with age, and whether this is related to increases in oxidative stress or
vascular cell adhesion molecule (VCAM-1) expression in the aortic wall. In chow-fed
low-density lipoprotein receptor-deficient (LDLR-/-) mice, plasma total
cholesterol levels increased with age (250 +/- 52 mg/dl in young, 276 +/- 58 in mature, and 314 +/- 101 mg/dl in old mice). In contrast, the extent of
atherosclerosis rose more rapidly, increasing from 3.6 +/- 2.7% of the aortic surface in mature mice to 18.2 +/- 8% in old mice. Plasma and tissue levels of
antioxidant enzymes and molecules, as well as plasma
thiobarbituric acid reactive substances and
low-density lipoprotein susceptibility to oxidation, did not change with age. In a second study,
VCAM-1 expression in the aortic arch and the extent of
atherosclerosis in the aortic origin were significantly greater in old LDLR-/- mice than in young LDLR-/- mice. Additionally, after 1 month of a high-fat diet, which induced equally elevated plasma
cholesterol levels in both young and old LDLR-/- mice,
VCAM-1 expression and aortic lesion formation were still greater in old mice. The extent of
atherosclerosis correlated well (r = .65,p <.01) with the expression of
VCAM-1 in the aortic origin. In a final study, we measured
VCAM-1 expression and
atherosclerosis in young, mature, and old C57BL/6 mice, which have low plasma
cholesterol levels (< or =100 mg/dl) when fed a standard chow diet. Although plasma
cholesterol levels did not increase with age, old C57BL/6 mice had significantly more
VCAM-1 expression in the aortic arch than did young mice. However, no lesions were observed in the aortic origin in either group. These data demonstrate that plasma
cholesterol levels and
VCAM-1 expression increase with age and suggest that this may contribute to the increased rate of atherosclerotic lesion formation in LDLR-/- mice. Importantly, the age-dependent increase in
VCAM-1 expression does not appear to be related to plasma
cholesterol levels. This study also suggests that in the absence of elevated plasma
cholesterol, an increased expression of
VCAM-1 alone is not sufficient for lesion formation.