Therapeutic hypothermia represents a highly promising approach for alleviating ischemic brain injury. However, the majority of preclinical studies predominantly rely on reperfusion-based models using young animals, which poorly reflect the clinical situation of elderly stroke patients with limited recanalization. This study sought to bridge these gaps and accelerate the clinical translation of therapeutic hypothermia while elucidating its neuroprotective mechanisms. In aged (18–20 months old) mice with permanent distal middle cerebral artery occlusion, brain-selective mild hypothermia mitigated acute F-actin stress fiber formation and junctional protein degradation in microvascular endothelial cells, thereby effectively reducing blood-brain barrier leakage and infiltration of peripheral inflammatory cells into the brain parenchyma. Hypothermia treatment induced anti-inflammatory polarization of microglia/macrophages acutely, attenuating white matter loss at both early (7 days) and chronic (35 days) stages of ischemic injury. Moreover, hypothermia treatment significantly promoted cognitive and sensorimotor recovery for at least 35 days after ischemic injury, as reflected in the electrophysiological preservation of compound action potentials in white matter tracts. Long-term behavioral recovery was strongly associated with angiogenesis and oligodendrogenesis, supporting that hypothermia-induced cell regeneration and neural tissue repair foster positive neurological outcomes. These findings underscore the potential of mild, brain-selective hypothermia for treating elderly stroke patients.
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