Age-Related Elevation of Plasma Catecholamine Concentration and Reduced Responsiveness of Lymphocyte Adenylate Cyclase*

Abstract

Plasma catecholamine (norepinephrine) concentration during upright posture and lymphocyte adenylate cyclase response to the β-adrenergic catecholamine isoproterenol were compared in two age groups of healthy subjects. Compared to subjects between the ages of 19-38 yr, those between 65-88 yr had higher plasma norepinephrine concentrations (353 ± 42 vs. 577 ± 65 pg⁄ml) and reduced lymphocyte adenylate cyclase responsiveness to NaF, isoproterenol, guanyl nucleotide, and isoproterenol in the presence of guanylyl nucleotide. There were important differences between the properties of adenylate cyclase in cells from the aged subjects and those from younger subjects pretreated with norepinephrine in vitro. Pretreated cells had diminished responsiveness to isoproterenol (desensitization), but not to guanylyl nucleotide. Moreover, guanylyl nucleotide restored isoproterenol responsiveness to the desensitized enzyme. Thus, reduced responsiveness of lymphocyte adenylate cyclase from aged subjects was not attributable solely to acutely elevated plasma plasma catecholamine levels The interactions between the guanylyl nucleotide-requiring coupling factors and the catalytic subunits of adenylate cyclase were similar in the two age groups, as evidenced by similar Km values of activation by the nonhydrolyzable GTP analog Gpp[NH]p (guanyl-5-yl imidodiphosphate) and by Hill coefficients of activation near unity. The initial velocity of product formation by adenylate cyclase from the older group was only about half that from the younger group in the presence of Gpp[NH]p. These differences could not be attributed to age-related changes in the distribution of cell types in the leukocyte population. The results suggest that decreases in the concentration of either the guanylyl nucleotide-requiring coupling factors or the catalytic subunits of adenylate cyclase may accompany aging and contribute to the diminished responsiveness of the lymphocyte enzyme. Similar decreases could occur in less accessible catecholamine target tissues as a consequence of human aging.