Microglial Replacement Reverses Age-Associated Epigenetic Modifications Despite Accelerating Epigenetic Age.

Aging and disease 2025

Abstract

Microglial replacement is emerging as a promising concept for treating age-related disorders, but effects on epigenetic age remain unclear. Here, we examined DNA methylation dynamics in microglia from young and old mice and evaluated how ischemic stroke and microglial depletion/repopulation (D/R) influence their epigenetic landscape. Using epigenetic clocks, we confirmed that old microglia display an aged DNA methylation profile, consistent with functional decline. Both stroke and microglial D/R induced an acceleration of epigenetic age, likely reflecting proliferative stress associated with these conditions. However, genome-wide methylation profiling using DNA methylation arrays revealed that microglial repopulation also reversed a large fraction of age-associated DNA methylation changes, particularly within pathways related to immune activation and inflammatory responses. These findings suggest that microglial D/R, though linked to epigenetic age acceleration, leads to the widespread reversal of aging-associated DNA methylation changes, which may help explain the beneficial outcomes observed after microglial replacement. Overall, our results highlight the complexity of interpreting epigenetic age measures and underscore the potential of microglial replacement strategies for brain rejuvenation.

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