Abstract
Cerebromicrovascular dysfunction is a key driver of age-related cognitive decline, yet interventions targeting microvascular aging remain limited. Here, we show that time-restricted feeding (TRF) preserves cognitive function and rejuvenates cerebrovascular physiology in aged mice. TRF improves resting cerebral blood flow and neurovascular coupling while attenuating blood–brain barrier disruption, neuroinflammation, and endothelial senescence. Mechanistically, TRF enhances metabolic flexibility and restores mitochondrial bioenergetic capacity in cerebromicrovascular endothelial cells. Ketone bodies elevated by TRF recapitulate key mitochondrial and vascular effects, improving endothelial respiration, membrane potential, and redox balance in aged mice and primary human brain endothelial cells, but do not fully reproduce neurovascular unit protection. These findings identify endothelial mitochondrial reprogramming as a central mechanism linking dietary timing to cerebrovascular resilience and cognitive preservation, and suggest that metabolic interventions can partially reverse key features of vascular brain aging.
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