Infant microglial programming as the earliest determinant of brain aging: A roadmap for microglial age-trajectory mapping

Microglia, the resident immune cells of the brain, undergo profound and highly plastic developmental transitions during the first 12–24 months of life. During this critical window, environmental stimuli, infections, metabolic and nutritional factors, and the broader neurodevelopmental milieu shape microglial functional set-points that may determine the lifelong trajectory of brain immuno-aging. Although microglial aging and its contribution to neurodegeneration have been extensively studied in adulthood, the early-life determinants of these trajectories remain incompletely defined. In this narrative review, we integrate evidence from developmental neuroimmunology, early-life immune activation models, microglial transcriptomics, and aging neuroscience to propose that infant microglial programming constitutes a foundational—and potentially modifiable—determinant of later-life brain aging and vulnerability to age-related neurological disorders. Building on emerging concepts of developmental-geriatric continuity, we introduce microglial age-trajectory mapping, a lifespan framework linking early microglial states to future resilience or susceptibility. We summarize key elements of microglial ontogeny and early postnatal maturation, outline molecular and cellular mechanisms through which early microglial programming is established, review evidence connecting these early influences to later immuno-aging, and discuss clinical, paediatric neurology, and ethical implications. Finally, we propose a research roadmap aimed at early identification of at-risk infants and at designing targeted early-life strategies capable of steering microglial aging trajectories toward long-term brain health.