Cholesterol and Lipoprotein Metabolism in Aging

—Plasma cholesterol levels increase with age, as does the incidence of coronary heart disease. The mechanisms responsible for the age-related hypercholesterolemia are not well understood. An interesting hypothesis suggests that the relative deficiency in growth hormone (GH), which occurs with aging, contributes to the development of the age-related hypercholesterolemia, because GH has beneficial effects on cholesterol metabolism. In the present work, we tested this hypothesis by the administration of GH to normal rats of varying ages. Plasma lipids and hepatic cholesterol metabolism were characterized in 2-, 12-, and 18-month-old male Sprague-Dawley rats. In 2-month-old rats, GH specifically stimulated the hepatic low density lipoprotein (LDL) receptor expression in a dose-dependent way, both at the protein level and at the mRNA level. Concomitantly, plasma cholesterol increased by ≈30% within the large high density lipoprotein and LDL fractions. In 12-month-old animals, cholesterol 7α-hydroxylase (C7αOH) activity was reduced, whereas hepatic LDL receptors and plasma total cholesterol were unchanged. GH treatment (1 mg · kg−1 · d−1 ) normalized the activity of C7αOH and had effects on plasma cholesterol and LDL receptors similar to those seen in 2-month-old animals. In 18-month-old rats, plasma cholesterol was increased 2-fold, whereas hepatic LDL receptor expression and C7αOH activity were similar to those of the 12-month-old animals. Infusion of GH to 18-month-old rats had similar effects on hepatic C7αOH and LDL receptors as seen in 12-month-old rats. However, GH treatment strongly reduced the hypercholesterolemia in 18-month-old animals. We conclude that the age-dependent increase of plasma cholesterol in rats can be reversed by the administration of GH, presumably through the pleiotropic effects of this hormone on lipoprotein metabolism.