Elderly humans demonstrate decreased responsiveness in several hormone-receptor systems, including adrenergic receptors. Studies of the beta-adrenergic receptor (beta-AR) system have shown that reduced beta-adrenergic sensitivity in the elderly may be due to reduced beta-AR affinity for agonists. To determine the mechanisms underlying altered alpha-adrenergic sensitivity in the elderly, we assessed the relationships between age and platelet membrane alpha 2-adrenergic receptor (alpha 2-AR)-binding properties, receptor-linked adenylate cyclase (AC) activity, and the affinity of the alpha 2-AR-AC complex for agonists in 18 young (mean age, 24 yr; range 19-34) and 13 elderly (mean age, 69 yr; range, 63-85) normal subjects. In platelet membrane preparations from elderly compared to young subjects, we found similar antagonist-binding properties and similar activity of the catalytic unit of platelet AC, as indicated by the cAMP response to sodium fluoride stimulation. However, mean epinephrine-mediated inhibition of sodium fluoride-stimulated platelet AC activity was less in the elderly [20 +/- 4% (+/- SEM) vs. 31 +/- 2% inhibition; P less than 0.005). In addition, platelet alpha 2-AR affinity for agonist was lower in the elderly, as indicated by the higher concentration of epinephrine needed to inhibit 50% of specific [3H]yohimbine binding (IC50, 3.2 +/- 0.6 vs. 1.4 +/- 0.3 microM; P less than 0.02). These data provide evidence that platelet membranes from elderly humans have decreased responsiveness to alpha-adrenergic stimulation, which can be attributed to reduced alpha 2-AR-AC affinity for agonists. Similarly to reported age-related alterations in beta-adrenergic receptor function, these results suggest that there is also functional uncoupling of the alpha 2-AR-AC complex in elderly humans.