Gram-negative bacterial infection is a common cause of septic shock in the older population in the U.S. We employed an experimental model of sepsis to study the cause of increased lethality due to LPS in older animals. Three ages of male B6JC3J/Nia mice, young (2 mo old), mature (12 mo old), and senescent (24 mo old), were treated with bacterial LPS, and the older mice were found to be 10 times more sensitive to LPS lethality. Increased sensitivity to LPS in senescent mice correlated with significantly elevated plasma TNF-alpha and nitric oxide levels. Abs to TNF-alpha afforded aged animals passive protection against a supralethal dose of LPS, establishing a central role for TNF in the increased sensitivity to LPS seen in the aged animals. Other cytokines, such as IL-1 and IFN-gamma, appeared secondary to TNF and nitric oxide in the age-associated sensitivity to LPS. Plasma corticosterone levels were increased by LPS at a time when maximal levels of plasma TNF-alpha were observed in both age groups, although the kinetics of hormone production and the magnitude of TNF-alpha release varied among the age groups. Exogenously administered dexamethasone protected senescent animals given a high dose of LPS, by decreasing cytokine levels. The increased sensitivity to LPS observed in aged animals, therefore, seems to be due to excessive TNF and nitric oxide production, resulting from perturbed endogenous hormonal control of cytokine production.