Aged monocytes, that is, monocytes purified from the blood of donors > or =65 years of age, when compared with young monocytes, that is, monocytes purified from the blood of young donors 25 years of age, display a decrease in interleukin-6 (IL-6) and tumor necrosis factor (TNF) production after activation by lipopolysaccharide (LPS). The LPS concentration required to obtain IL-6 and TNF production is much higher for aged monocytes than for young monocytes. Furthermore, the intensity of TNF and IL-6 production was much weaker for LPS-activated aged monocytes than for LPS-activated young monocytes. In addition, deficient protein kinase C (PKC)-alpha, PKC-/betaI, and PKC-betaII activation, deficient mitogen-activated protein kinase (MAP-Kinase) activation, and deficient expression of c-Fos and c-Jun was observed in LPS-activated aged monocytes when compared with LPS-activated young monocytes. These data suggest that age induces human monocyte immune deficiencies that could be observed not only at the functional level but also in the signal transduction pathways.