Senolytic treatment guided by carotid stenosis confers protection against acute ischemic stroke in aged rodents
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Background
Advanced age is associated with larger infarct volumes and poorer functional recovery after acute ischemic stroke (AIS). Carotid stenosis is also a common comorbidity in older individuals and often predicts subsequent AIS. However, no age-specific therapy is currently available to protect the aging brain from aggravated ischemic injury. Here, we investigated whether a senolytic approach could improve cerebrovascular status and reduce ischemic brain injury in a comorbid aging model of AIS.
Methods
Unilateral common carotid artery occlusion was induced in young and aged rats and served as a diagnostic trigger for chronic senolytic therapy with dasatinib plus quercetin (D+Q). Two weeks later, the distal middle cerebral artery was occluded for 60 min. Compared with untreated animals, infarct size was measured, spreading depolarizations (SDs) were recorded electrophysiologically, cerebral blood flow (CBF) dynamics were monitored by laser speckle contrast imaging, and cerebrovascular senescent cell burden was assessed by immunocytochemistry. Cerebral angiogenesis, central and systemic inflammatory markers, and metabolic status were evaluated using protein arrays and blood glucose measurements.
Results
Aged rats developed larger infarcts than young controls, and this age-related increase was attenuated by D+Q treatment. D+Q reduced the higher frequency of SDs observed in the aged ischemic brain. Increased cerebrovascular senescence in aged animals was diminished by D+Q, accompanied by enhanced angiogenesis, although CBF responses to SDs and reperfusion were unchanged. In addition, D+Q modulated central and systemic inflammatory profiles and counteracted age-related metabolic impairment.
Conclusions
Senolytic D+Q therapy administered after carotid artery occlusion confers multifaceted protection against subsequent AIS in the aged brain. By targeting fundamental aging mechanisms that exacerbate brain vulnerability to AIS, D+Q enhances the resilience of the aging neurovascular niche. These results identify senolytic therapy as a promising preventive personalized approach to mitigate the disproportionate impact of AIS in older individuals and warrant further investigation.
