Microglia-astrocyte crosstalk-driven metabolic-inflammatory imbalance and cerebrovascular frailty in exacerbating stroke injury during aging

The severity of ischemic stroke damage increases markedly with age, which is closely tied to the physical and functional deterioration of the neurovascular unit. In this review, we discuss how the bidirectional microglia-astrocyte interactions essentially dictate this age-associated vascular frailty. Distinct from previous reviews that separately summarize post-ischemic microglia-astrocyte crosstalk or senescent microglia biology, this review focuses on the aging ischemic brain and integrates these two fields within the framework of neurovascular unit frailty. With sustained metabolic pressure, microglia undergo an irreversible immunometabolic shift toward senescence, pivoting into active drivers of inflammation. These dysfunctional microglia induce neighboring astrocytes into a neurotoxic state by releasing senescence-associated secretory phenotype factors. Pathological microglia-astrocyte crosstalk drives the brain into a vicious cycle of chronic neuroinflammation, directly leading to enzymatic disruption of the blood-brain barrier, pericyte degeneration, and neurovascular decoupling. Ultimately, these cellular abnormalities manifest as clinical outcomes such as impaired microvascular recanalization and progressive white matter damage. Therefore, targeted intervention strategies centered on clearing senescent cells and intervening in metabolic reprogramming hold promise as a new therapeutic pathway to alleviate neuroinflammation and salvage cerebral vascular function.