Age-Dependent Changes in the Activation and Regulation of Microglia.

As we age, a large number of physiological and molecular changes affect the normal functioning of cells, tissues, and the organism as a whole. One of the main changes is the establishment of a state of systemic inflammatory activation, which has been termed "inflamm-aging"; a mild chronic inflammation of the aging organism that reduces the ability to generate an efficient response against stressor stimuli. As any other system, the nervous system undergoes these aging-related changes; the neuroinflammatory state depends mainly on the dysregulated activation of microglia, the innate immune cells of the central nervous system (CNS) and the principal producers of reactive oxygen species. As the brain ages, microglia acquire a phenotype that is increasingly inflammatory and cytotoxic, generating a hostile environment for neurons. There is mounting evidence that this process facilitates development of neurodegenerative diseases, for which the greatest risk factor is age. In this chapter, we will review key aging-associated changes occurring in the central nervous system, focusing primarily on the changes that occur in aging microglia, the inflammatory and oxidative stressful environment they establish, and their impaired regulation. In addition, we will discuss the effects of aged microglia on neuronal function and their participation in the development of neurodegenerative pathologies such as Parkinson's and Alzheimer's diseases.