As people age, many of them experience memory decline, slower cognitive processing, and a higher risk of cerebrovascular disease and cognitive impairment. In aging research, a major question is where brain aging begins and how early vascular dysfunction contributes to neurological decline.

In a study published in Neuron, a team of researchers led by FANG Cheng and MA Yinzhong from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences uncovered a key mechanism by which aging weakens the brain's vascular protection system.

Blood-brain barrier (BBB) is a highly selective interface between the bloodstream and the brain. Its breakdown has been increasingly recognized as an important contributor to age-related cognitive decline, cerebral small vessel disease, vascular cognitive impairment, and neurodegenerative disorders.

How BBB begins to fail during aging remains unclear. It has been assumed that BBB leakage is mainly caused by the disruption of tight junctions between endothelial cells. In this study, researchers found that early BBB leakage during aging is driven by abnormal activation of endothelial transcytosis, a process in which molecules are transported across brain endothelial cells through intracellular vesicles.

Using mouse models, researchers found that BBB leakage began in midlife and gradually worsened with age. The leakage first appeared in the hippocampus. At this early stage, tight junctions between brain endothelial cells remained largely intact, while caveolae-mediated transcytosis, a vesicle-based transport pathway within endothelial cells, was already markedly increased.

This finding suggests that the brain's protective barrier may become vulnerable earlier than previously thought. Rather than first leaking through gaps between cells, the aging BBB appears to lose control over transport pathways inside endothelial cells.

Moreover, Mfsd2a was identified as a key protective molecule in brain endothelial cells, which helps maintain BBB integrity by suppressing nonspecific caveolae-mediated transcytosis. During aging, endothelial Mfsd2a expression declined, while Caveolin-1 (Cav-1) increased. When Mfsd2a expression or reduced Cav-1 in aged mice was restored, endothelial vesicle formation and BBB leakage were significantly reduced.

To determine why Mfsd2a decreases during aging, researchers screened several secreted factors known to affect BBB function. They found that transforming growth factor-β1 (TGF-β1) suppressed Mfsd2a expression in brain endothelial cells. TGF-β1 activated Tgfbr2–Smad2/4 signaling pathway in brain endothelial cells, repressing Mfsd2a transcription. This led to increased caveolae-mediated transcytosis and allowed blood-derived proteins to leak into brain tissue.

Researchers also found that TGF-β1 levels increased in both brain and bloodstream during aging. Elevating TGF-β1 in young mice reproduced key features of aged BBB, including reduced Mfsd2a expression, enhanced endothelial transcytosis, and increased barrier leakage. Conversely, endothelial-specific deletion of Tgfbr2 or pharmacological inhibition of TGF-β signaling in aged mice restored Mfsd2a expression, reduced abnormal transcytosis, improved BBB integrity, and alleviated neurological dysfunction.

These findings indicate that age-related BBB breakdown is not merely a passive consequence of structural deterioration; instead, it is actively driven by systemic aging signals and dysregulated endothelial transport within the neurovascular unit. This study provides insights into how brain vascular dysfunction contributes to cognitive aging and suggests potential strategies for preserving BBB integrity in age-related neurovascular disorders.