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Aging is the main risk factor for Alzheimer's disease. Among other characteristics, it shows changes in inflammatory signaling that could affect the regulation of glial cell activation. We have shown that astrocytes prevent microglial cell cytotoxicity by mechanisms mediated by TGFβ1. However, whereas TGFβ1 is increased, glial cell activation persists in aging. To understand this apparent contradiction, we studied TGFβ1-Smad3 signaling during aging and their effect on microglial cell function. TGFβ1 induction and activation of Smad3 signaling in the hippocampus by inflammatory stimulation was greatly reduced in adult mice. We evaluated the effect of TGFβ1-Smad3 pathway on the regulation of nitric oxide (NO) and reactive oxygen species (ROS) secretion, and phagocytosis of microglia from mice at different ages with and without in vivo treatment with lipopolysaccharide (LPS) to induce an inflammatory status. NO secretion was only induced on microglia from young mice exposed to LPS, and was potentiated by inflammatory preconditioning, whereas in adult mice the induction of ROS was predominant. TGFβ1 modulated induction of NO and ROS production in young and adult microglia, respectively. Modulation was partially dependent on Smad3 pathway and was impaired by inflammatory preconditioning. Phagocytosis was induced by inflammation and TGFβ1 only in microglia cultures from young mice. Induction by TGFβ1 was also prevented by Smad3 inhibition. Our findings suggest that activation of the TGFβ1-Smad3 pathway is impaired in aging. Age-related impairment of TGFβ1-Smad3 can reduce protective activation while facilitating cytotoxic activation of microglia, potentiating microglia-mediated neurodegeneration., (Copyright © 2013 Elsevier Inc. All rights reserved.)