IgE production declines with age, and allergic symptoms tend to improve. Aging therefore represents an in vivo model to study IgE regulation. We compared IgE production in older (> or = 60 years old) and young (15 to 30 years old) nonatopic individuals. Addition of exogenous interleukin-4 (IL-4) to mononuclear cells from older and young subjects induced equivalent amounts of IgE, indicating that IL-4 responsiveness is preserved in aging. After surface receptor stimulation with concanavalin A, IL-4 production by mononuclear cells from older subjects was approximately 50% as compared with the young, whereas interferon-gamma (IFN-gamma) production was reduced threefold (p = 0.008). By contrast, stimulation with phorbol esters and ionophore, which bypass surface receptor signaling, induced comparable amounts of IL-4 and IFN-gamma in older and young subjects. These data point to an impairment in T-cell membrane signal transduction in older individuals. This hypothesis was directly confirmed by showing that Ca+2 fluxes after CD3 crosslinking were significantly (p = 0.014) decreased in the older population. Our findings altogether suggest that an age-dependent T-cell activation defect may result in decreased availability of IL-4 and in the waning of IgE responses.