Despite a wealth of clinical data showing an association between inflammation and degenerative disorders in the elderly, the immune sensors that causally link systemic inflammation to aging remain unclear. Here we detail a mechanism by which the Nlrp3 inflammasome controls systemic low-grade age-related "sterile" inflammation in both periphery and brain independently of the noncanonical caspase-11 inflammasome. Ablation of Nlrp3 inflammasome protectedmice from age-related increases in the innate immune activation, alterations in CNS transcriptome, and astrogliosis. Consistent with the hypothesis that systemic low-grade inflammationpromotesage-related degenerative changes, the deficient Nlrp3 inflammasome-mediatedcaspase-1 activity improvedglycemic control and attenuatedbone loss and thymic demise. Notably, IL-1mediated only Nlrp3 inflammasome-dependent improvement in cognitive function and motor performance in agemice. These studies reveal Nlrp3 inflammasome as an upstream target that controlsage-related inflammation and offer an innovative therapeutic strategy to lowerNlrp3 activity to delay multiple age-related chronic diseases.