BackgroundAging decreases cardiac β–adrenergic responsiveness in model systems and in humans in vivo. The purpose of this study was to comprehensively evaluate the age-related changes in the β-receptor-G protein-adenylyl cyclase complex in nonfailing human hearts.Methods and ResultsTwenty-six nonfailing explanted human hearts aged 1 to 71 years were obtained from organ donors and subjected to pharmacological investigation of β-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total β-receptor density assessed by maximum [125I]ICYP binding (βmax) was reduced in older hearts by 37% in left ventricles and 31 % in right ventricles (bothP<.05), and the downregulation was confined to the β1subtype (r= −.78 left ventricle β1density versus donor age). Older donor hearts exhibited a 3- to 4-fold rightward shift of ICYP-isoproterenol (ISO) competition curves and demonstrated 43% fewer receptors in a high-affinity agonist binding state (P<.05). Older hearts exhibited decreased adenylyl cyclase stimulation by ISO, by zinterol (β2-agonist), and by the G protein–sensitive probes forskolin, Gpp(NH)p, and NaF. In contrast, there was no change in response to manganese, a specific activator of the adenylyl cyclase catalytic subunit. Toxin-catalyzed ADP ribosylation in membranes prepared from older versus younger hearts revealed a 29% to 30% reduction (P<.05) with cholera toxin (Gβs) but no difference with pertussis toxin (Gβi). The systolic contractile response of isolated right ventricular trabeculae to ISO was decreased by 46%, with a 10-fold increase in ISO EC50in older relative to younger donor hearts.ConclusionsThere is a profound decrease in cardiac β-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of β1-receptors, uncoupling of β2-receptors, and abnormal G protein-mediated signal transduction.