Failure of Neuroinflammatory Resolution in Brain Aging: Molecular Mechanisms and an Integrative Framework of...

Persistent neuroinflammation is a central feature of brain aging and a common pathological context across neurodegenerative diseases. Although microglial activation has been extensively studied, why inflammatory responses in aging brains become increasingly difficult to resolve remains insufficiently understood. In this review, we propose inflammometabolic locking as an evidence-informed working framework describing impaired recovery and declining reversibility of microglial states. Rather than viewing persistent neuroinflammation simply as prolonged activation, the framework emphasizes failure of inflammatory exit and homeostatic re-entry. We integrate current evidence across four interrelated domains: metabolic remodeling, defective lipid handling and post-phagocytic processing, disrupted organelle homeostasis, and persistent transcriptional and epigenetic remodeling. Abnormalities across these domains may become functionally coupled and mutually reinforcing, progressively limiting microglial plasticity and recovery. Their pathological significance therefore depends not only on their presence, but also on whether they resolve as pathological burden declines and whether clearance, repair, and homeostatic functions recover. By distinguishing transient adaptation from locking-like states, this recovery-oriented framework suggests that therapeutic strategies should aim not only to suppress inflammatory output but also to restore microglial recovery capacity. Inflammometabolic locking remains a working hypothesis requiring longitudinal and intervention-based validation.