Age-Related Metabolic Vulnerability of Glia in Intracerebral Hemorrhage: Mechanisms and Therapeutic Opportunities.

Intracerebral hemorrhage (ICH), caused by the rupture of blood vessels within the brain parenchyma, represents the most severe form of stroke, characterized by the highest mortality rate and predominantly affecting the elderly population. Glial cells, including microglia, astrocytes, and oligodendrocytes, serve as the resident immune cells of the central nervous system and undergo significant metabolic reprogramming following ICH. Microglia exhibit dual roles in post-ICH tissue damage by altering their polarization states: they contribute to secondary brain injury through pro-inflammatory responses while also promoting hematoma clearance via anti-inflammatory mechanisms. Astrocytes primarily provide neuroprotective effects by extending branched processes to maintain neuronal architecture and preserve the integrity of the blood-brain barrier. Oligodendrocytes are susceptible to metabolic dysregulation following ICH, leading to myelin sheath damage and subsequent axonal dysfunction. Metabolically, the acute phase of ICH is marked by suppressed glucose metabolism, which gradually normalizes in later stages. Concurrently, oxidative stress and lipid peroxidation disrupt glial cell homeostasis. The extravasation of blood components leads to iron overload, exacerbating metabolic disturbances through impaired iron regulation. These metabolic disruptions propagate through intracellular signaling pathways, thereby influencing glial pathophysiology. Unlike previous reviews that primarily describe these changes, this review offers a conceptual framework that explicitly integrates aging, metabolic reprogramming, and intercellular communication across different phases of injury. We critically assess the robustness of current evidence, differentiate between correlative observations and causal mechanisms, and identify significant knowledge gaps. We conclude that the age-related metabolic vulnerability of glial cells constitutes a promising therapeutic target, and we propose testable hypotheses to guide future mechanistic and translational research. By synthesizing recent literature within this integrative framework, this review seeks to enhance understanding of metabolic regulation in glial cells following ICH, thereby laying the groundwork for the development of targeted metabolic interventions.