Aging brain immune cells shift identity toward chronic inflammation

Brain aging involves a radical transformation of its immune landscape: embryonically derived resident microglia are progressively replaced by a population of circulating monocyte-derived cells with profoundly inflammatory properties. This discovery, revealed through high-resolution epigenetic analysis (DNA methylation, chromatin accessibility, and three-dimensional genome organization), represents a fundamental shift in understanding neuroinflammation during aging. Notably, this cellular replacement occurs during a nonlinear transition around midlife and was undetectable using conventional gene expression alone; only the epigenetic signature preserved in DNA methylation patterns revealed this lineage substitution. The new microglia-like cells exhibit transcriptional programs and three-dimensional genomic features associated with chronic inflammation, positioning them as potential drivers of age-related neuronal degeneration. For longevity readers, this finding suggests that therapeutic approaches targeting microglial dysfunction may prove insufficient if they fail to address the fundamental nature of this replacement cell population.