Changing Functional Signatures of Microglia along the Axis of Brain Aging

Microglia, the innate immune cells of the brain, are commonly perceived as resident macrophages of the central nervous system (CNS). This definition, however, requires further specification, as under healthy homeostatic conditions, neither morphological nor functional properties of
microglia mirror those of classical macrophages. Indeed, microglia adapt exceptionally well to their
microenvironment, becoming a legitimate member of the cellular brain architecture. The ramified
or surveillant microglia in the young adult brain are characterized by specific morphology (small
cell body and long, thin motile processes) and physiology (a unique pattern of Ca2+ signaling, responsiveness to various neurotransmitters and hormones, in addition to classic “immune” stimuli).
Their numerous physiological functions far exceed and complement their immune capabilities. As
the brain ages, the respective changes in the microglial microenvironment impact the functional
properties of microglia, triggering further rounds of adaptation. In this review, we discuss the recent
data showing how functional properties of microglia adapt to age-related changes in brain parenchyma in a sex-specific manner, with a specific focus on early changes occurring at middle age as
well as some strategies counteracting the aging of microglia.