The purpose of the present study was to investigate the effect of aging on silica-induced lung toxicity. In young animals silica induced a significant increase in bronchoalveolar lavage tumor necrosis factor-alpha (TNF), lactate dehydrogenase as well as in cell numbers, which correlate with increased collagen deposition and silicotic nodules formations. In old rats, however, no changes in bronchoalveolar lavage or lung parameters were observed following silica instillation. These in vivo results were also confirmed in vitro, where silica failed to induce TNF release in alveolar macrophages obtained from old animals. This defective response to silica could be explained with defective protein kinase C translocation, due to a reduction in its anchoring protein RACK-1 with aging. Overall, these data indicate that the understanding of the molecular mechanisms undelaying toxicity is crucial to define the influence of age on the toxic response and progression of the disease.