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Recently, we demonstrated that β2AR and several other Gαs-coupled receptors in human atria also couple to Gαi, a G protein that inhibits adenylyl cyclase (AC). The present study was undertaken to determine whether age increases expression of Gαi in human atrium, and more specifically whether it results in an increase in receptor-mediated activation of Gαi. Right atrial appendages were obtained from 14 mature adult (40–55 years) and 14 elderly (71–79 years) patients undergoing cardiac surgery. Immunoblotting of atrial membranes indicates that elderly atria have 82 ± 18% more Gαi2 than atria from mature adults (P < 0.002); this increase in Gαi with age is confirmed by pertussis toxin-catalyzed ADP-ribosylation as well as by photoaffinity labeling with [32P]azidoanilido-GTP. We also find that receptor-mediated activation of Gαi is greater in elderly atria and that both basal and receptor-mediated AC activities decrease in elderly atria. These decreases in AC activity can be reversed by disabling Gαi with pertussis toxin, indicating that the age-dependent increases in Gαi expression and activation have functional consequences. Because β2ARs in human atria mediate contractility through cAMP-mediated phosphorylation of phospholamban, we conclude that an age-induced increase in Gαi may have a role in depressing cardiac function in aged human atria.