Previous studies indicated that natural killer (NK) activity in mice declined with age. In this report, we investigated the basis for the decreased activity of NK cells in older mice. Our results demonstrated that phorbol myristate acetate (PMA)--an activator of protein kinase C (PKC)--corrects the impaired NK function of older animals. The per cent increase of NK activity post treatment with PMA is 226-261% at effector:target (E:T) ratio = 100:1 compared with control untreated cells. The effect of PMA was shown to be dose dependent. A maximum increase in NK activity was achieved at approximately 10-15 nM PMA. Treatment with PMA does not result in increased binding of NK cells to YAC-1 targets as demonstrated by single-cell assay. In addition, treatment of young NK cells with 1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride (H-7), a very potent PKC inhibitor, significantly suppressed NK activity (65% of control). Therefore, we conclude that the age-related decline in murine NK activity may reside in the early signalling events leading to triggering of PKC.