On the Aging of Microglia

Microglia are innate immune cells of the brain. They are analogous to macrophages elsewhere in the body, responsible for clearing up debris, destroying pathogens and problem cells, and participating in regeneration. They also undertake an arguably larger portfolio of tissue maintenance tasks that are related to neural function and synaptic connections.

With advancing age, the microglial population of the brain becomes more activated and inflammatory in response to a tissue environment that contains more signs of damage and cell stress. As is true of senescent cells, this microglial contribution to the chronic inflammation of aging appears to be a significant aspect of age-related neurodegeneration. There is thus an increasing interest in the research community in targeting microglia as a basis for therapies to treat neurodegenerative conditions.

Aging microglia

Microglia are the resident immune cells of the central nervous system (CNS), a tissue-resident macrophage population with specific characteristics to support the CNS environment and health. Microglia have a mesodermal origin and originate from yolk-sac progenitors during embryogenesis; after their early migration and proliferation, they colonize the CNS and self-renew throughout the lifespan.

Microglia perform a variety of critical functions; (a) they support neurogenesis and ensure correct neuronal circuitry by pruning synapses; (b) phagocytose apoptotic neurons; (c) defend against infectious and non-infectious insults; (d) produce extracellular matrix (ECM) components and control its remodeling by secreting ECM-degrading enzymes; (e) maintain myelin health; (f) and remove extracellular protein aggregates, which accumulate in neurodegenerative diseases. Homeostatic adult microglia have a highly ramified morphology, with extended and arborized processes and a small body. However, when responding to stimulation or during aging and CNS pathology, their morphology changes.

With age, microglia alter their function, morphology and phenotype; however, there are still many gaps in our knowledge of how microglia age. Both rodent and human aging microglia are characterized by alterations in morphology, phagocytosis, metabolism, and inflammatory phenotype, which appear to play protective and detrimental roles in maintaining brain homeostasis and preserving their ability to respond to non-sterile and sterile insults.

Furthermore, more recent evidence indicates that environmental factors, such as meningeal lymphatics health and production of metabolites from the gut microbiome, can affect brain homeostasis by affecting microglia reactivity and phenotype. Recent single cell RNA-seq studies suggest that different subsets of microglia already exist in young adults; however, they expand in aging and even more so in neurodegeneration. Nonetheless, we still do not know the full extent of microglia plasticity and how firm these phenotypes are.