Experimental and clinical investigations suggest the hypothesis that dehydroepiandrosterone sulfate (DHEAS) can positively influence natural killer (NK) immunity via locally produced insulin-like growth factor I (IGF-I) from NK cells. In the present study, the NK cell cytotoxicity (NKCC) and IGF-I levels in the supernatant of NK cells were studied at baseline and after exposure to various molar concentrations of DHEAS (from 10(-5)-10(-8) mol/L x mL/7.75 x 10(6) NK cells) in healthy subjects of young and old age. DHEAS-induced NKCC was also determined after DHEAS coincubation with somatostatin-14 (10-6) mol/L x mL/7.75 x 10(6) NK cells) and with interleukin-2 (IL-2; 100 IU/mL x 7.75 x 10(6) NK cells). NK cells were previously isolated by Ficoll-Hypaque density gradient and then by immunomagnetic procedure; the purity obtained was 97 +/- 1%. NKCC was determined against K562 tumoral targets. We observed that the increase in NKCC after DHEAS exposure was dose dependent and was correlated with the amount of IGF-I released in the supernatant of cultured NK cells. NKCC and IGF-I generation from NK cells were more elevated in healthy elder subjects than in healthy young subjects. The coincubation of DHEAS with somatostatin-14 significantly suppressed NKCC and IGF-I release from NK in both groups, whereas higher NKCC was found after DHEAS plus IL-2 exposure than after incubation with DHEAS alone. Taken together, this study suggests a role for NK-generated IGF-I in the modulation of NKCC by DHEAS in humans. Although DHEAS may contribute to the IL-2-mediated NKCC, its activity on NK cytolytic function can be dependent on a autocrine mechanism (IGF-I-mediated), probably independent of cytokine activation. The higher NKCC response to DHEAS found in old subjects than in younger might counterbalance the age-dependent decline in circulating DHEAS, thus contributing to maintain the pattern of NK immunity during aging.