The old guard: Age-related changes in microglia and their consequences.

Among all major organs, the brain is one of the most susceptible to the inexorable effects of aging. Throughout the last decades, several studies in human cohorts and animal models have revealed a plethora of age-related changes in the brain, including reduced neurogenesis, oxidative damage, mitochondrial dysfunction and cell senescence. As the main immune effectors and first responders of the nervous tissue, microglia are at the center of these events. These cells experience irrevocable changes as a result from cumulative exposure to environmental triggers, such as stress, infection and metabolic dysregulation. The age-related immunosenescent phenotype acquired by microglia is characterized by profound modifications in their transcriptomic profile, secretome, morphology and phagocytic activity, which compromise both their housekeeping and defensive functions. As a result, aged microglia are no longer capable of establishing effective immune responses and sustaining normal synaptic activity, directly contributing to age-associated cognitive decline and neurodegeneration. This review discusses how lifestyle and environmental factors drive microglia dysfunction at the molecular and functional level, also highlighting possible interventions to reverse aging-associated damage to the nervous and immune systems.