['The process of aging has recently been shown to substantially affect the ability of cells to respond to inflammatory challenges. We demonstrate that aging leads to hepatic hyperresponsiveness to interleukin 1beta (IL-1beta), and we examine the factors that could be responsible for this phenomenon. IL-1beta-induced phosphorylation of c-jun N-terminal kinase (JNK) in hepatocytes isolated from aged rats was 3 times more potent than that in hepatocytes from young rats. Moreover, JNK was activated by substantially lower doses of IL-1beta. These age-related changes in JNK phosphorylation correlated with diminished IL-1beta-induced degradation of interleukin-1 receptor-associated kinase-1 (IRAK-1). Expression levels of IL1beta receptor I, total JNK, IRAK-1, and transforming growth factor-beta-activated kinase-1 (TAK-1) were not affected by aging. However, increased neutral sphingomyelinase activity was observed in hepatocytes from old animals, which we show is caused by induction of the plasma membrane localized neutral sphingomyelinase-2 (NSMase-2). We provide evidence that NSMase-2 is both required and sufficient for the onset of IL-1beta hyperresponsiveness during aging. Overexpression of NSMase-2 in hepatocytes from young rats leads both to a reduction in IRAK-1 degradation and potentiation of JNK phosphorylation, mimicking that seen in hepatocytes from old animals. More importantly, inhibition of NSMase activity in hepatocytes from aged rats using either scyphostatin or short interfering ribonucleic acid (siRNA) leads to reversion to the "young" phenotype of IL-1beta response.'] Does aging in rat cause hepatic hyperresposiveness to interleukin-1beta which is mediated by neutral sphingomyelinase-2?