Microglia are innate immune cells of the brain, very similar to the macrophages found elsewhere in the body outside the central nervous system. Both microglia and macrophages do much more than defend against pathogens; both are deeply involved in tissue maintenance, function, and regeneration. It is by now well established that microglia become inappropriately inflammatory in old age, and researchers increasingly see this as an important component of age-related neurodegeneration. Here, researchers present provocative data to argue that the microglia of old age are not the same cell type as the microglia of youth; they are instead more like macrophages, derived from circulating monocytes outside the brain. This is a sizable departure from the present understanding, a wrench thrown into the works for several possible therapeutic approaches to microglial dysfunction in old age, so one should probably wait for confirmation before taking it at face value.
Prior studies have identified age-related shifts in gene expression, including increased inflammatory signaling and reduced synaptic function, implicating transcriptional dysregulation in brain aging. However, gene expression alone provides an incomplete view. To address this, we profiled gene expression and multiple layers of epigenetic regulation, including chromatin accessibility, DNA methylation, and three-dimensional (3D) genome organization at single-cell resolution across the adult lifespan.
Aging is associated with coordinated and often nonlinear changes in gene regulation across cell types, with a major transition occurring around midlife. A notable finding was a remodeling of the brain’s immune cell landscape. Microglia underwent a nonlinear transition in which embryonically derived, brain-resident microglial cells were progressively replaced by a population with epigenetic features resembling blood-circulating monocytes. This transition was not readily detectable using gene expression alone but was revealed by DNA methylation, which preserves cellular lineage. These monocyte-like microglia exhibited epigenetic, transcriptional, and 3D genome features associated with proinflammatory programs, suggesting a potential driver of age-related neuroinflammation.
