Lymphocyte Adenylate Cyclase and Human Aging

Abstract

Adenylate cyclase activity was determined by enzymatic conversion of [32P]ATP to [32P]cAMP using peripheral lymphocytes freshly isolated from human subjects. The lymphocyte enzyme was stimulated by the potent fl-adrenergic catecholamine agonist isoproterenol and by the nonhydrolyzable GTP-analog Gpp[NH]p.' The two activators had a synergistic effect, and agonistdependent enzyme activity followed simple Michaelis-Menten kinetics with respect to isoproterenol in the presence but not in the absence of Gpp[NH]p. Cyclic AMP production by intact lymphocytes, determined by protein binding assay, also followed simple Michaelis-Menten kinetics with respect to isoproterenol. Ke of isoproterenol was the same in intact cells and the broken cell assay in the presence of Gpp[NH]p, suggesting the indispensable role the GTPbinding coupling factors play in the intact lymphocyte. In 31 human subjects between the age of 21 and 103, adenylate cyclase activity in the presence of isoproterenol, Gpp[NH]p, or isoproterenol in the presence of Gpp[NH]p decreased with the increasing age of the subject. The sensitivity of the enzyme to stimulation by isoproterenol, defined as the Km and determined in the presence of Gpp[NH]p, was the same in lymphocytes from young (<45 years) or elderly (>75 years) subjects. These results suggest a deficiency in the lymphocyte adenylate cyclase system distal to the fl-adrenergic catecholamine receptor could account for deterioration of CAMPmediated components of the immune response which occur with age. 475

Age‐related changes in adenosine and beta‐adrenoceptor responsiveness of vascular smooth muscle in man.

“…There are no published studies of the influence of age on ,-adrenoceptor density in human vasculature, but the one study of 1-adrenoceptor density in a tissue other than the lymphocyte in man showed no ageing change in receptor density in human brain (Kalaria et al, 1989). Studies of human lymphocytes suggest that changes in receptor affinity, coupling of the receptor to the stimulatory G, protein, or a diminished ability of Gs to activate adenylate cyclase are the responsible mechanisms for the ageassociated decline in ,-adrenergic responsiveness, and our data are consistent with these findings (Abrass & Scarpace, 1981;Feldman et al, 1984;Krall et al, 1983). Studies of vascular responses in older animals confirming diminished 3-adrenergic induced vascular relaxation have reported diminished ,3-adrenergic mediated cAMP accumulation (Ericsson & Lundholm, 1975;Schoeffler & Stochet, 1982;Volicer et al, 1983) again consistent with findings in human lymphocytes.…”