CRH acts within the brain to activate the sympathetic nervous system and reduce cellular immune function. To determine the effects of age on CRH-induced elevations of sympathetic activity and suppression of immunity, we examined the responses of plasma catecholamines, neuropeptide-Y (NPY), corticosterone, and splenic natural killer (NK) activity after microinjection of rat CRH (200 pmol) into the lateral ventricle of aged (24-month-old) Fischer 344 (F344) rats compared to those in young (4-month-old) F344 rats. Basal concentrations of plasma norepinephrine and NPY were higher in the aged than in the young animals. In addition, CRH produced a greater elevation of plasma levels of catecholamines and NPY, which persisted for a longer period of time in the aged rats compared to responses in the young animals. Splenic NK activity showed an age-related decrement at baseline, and CRH induced a further significant (P less than 0.01) reduction of lytic activity in the aged rats, but did not alter cytotoxicity in the young rats. Corticosterone basal levels and responses were similar in the aged and young rats. These results show an age-related increase in autonomic outflow and suppression of NK activity after central CRH administration. In aged animals, the central nervous system may have a role in abnormal regulation of sympathetic activity and suppression of natural cytotoxicity in vivo.