Aging erodes microglial chromatin, unleashing retroelements to fuel inflammation and senescence

Aging reduces chromatin compaction and downregulates the histone chaperone DAXX in microglia, enabling derepression of endogenous retroelements and shifting microglia from a homeostatic to a reactive, inflammatory state. Loss of DAXX drives chromatin decompaction at LTR-RTEs, loss of homeostatic markers, cell-cycle re-entry and DNA damage, followed by microglial depletion and replacement by DAXX-deficient, ApoE-high microglia exhibiting senescence features. Sustained senescence relies on PML and interferon targets, underscoring chromatin maintenance as key to microglial identity, brain homeostasis and aging-related behavioral changes.