Aging can impair functional interaction that occurs between the brain and the immune system. Recent findings indicate that microglia and astrocytes, innate immune cells of the brain, become more reactive during normal aging. This age-associated increase in innate immune reactivity sets the stage for an exaggerated inflammatory cytokine response in the brain after activation of the peripheral innate immune system. This elevated neuroinflammatory response may lead to more severe long-lasting behavioral and cognitive deficits. This article discusses new evidence that aging creates a brain environment that is permissive to the occurrence of mental health complications following innate immune activation.