Fasting as Medicine: Mitochondrial and Endothelial Rejuvenation in Vascular Aging

Aging drives a progressive decline in vascular health, undermining endothelial function, neurovascular coupling (NVC), and blood-brain barrier (BBB) integrity, three processes essential for maintaining cerebral perfusion and cognitive resilience. Central to these age-related deficits is mitochondrial dysfunction, which disrupts redox balance, bioenergetics, and nutrient-sensing pathways within vascular cells, thereby promoting oxidative stress, impaired mitophagy, mitochondrial fragmentation, and endothelial senescence. These molecular derangements are especially consequential in the brain's microvasculature, where the exquisite metabolic demands of neural tissue depend on intact endothelial signaling. As a result, cerebrovascular aging becomes a major driver of cognitive decline and vascular contributions to dementia. This review synthesizes current mechanistic insights into mitochondrial and endothelial pathways that shape vascular aging, with particular focus on the neurovascular unit. We further highlight emerging evidence that time-restricted feeding/eating (TRF/TRE), a circadian-aligned dietary intervention that limits food intake to a daily feeding window without reducing calories, can restore mitochondrial function, activate adaptive nutrient-sensing networks including AMPK and SIRT1, suppress mTOR signaling, and promote metabolic switching toward ketone synthesis and utilization. Through these mechanisms, TRF enhances endothelial resilience, preserves NVC and BBB integrity, and may counteract the cerebrovascular processes that accelerate cognitive aging. Understanding how TRF/TRE re-engages mitochondrial and vascular repair programs offers a translational framework for developing accessible, non-pharmacological strategies to extend healthspan and mitigate age-related cognitive impairment.