Lipid accumulating aged brain endothelial cells exhibit increased senescence and impaired blood-brain barrier function – Implications for vascular cognitive impairment

Microvascular endothelial dysfunction, characterized by impaired neurovascular coupling, reduced glucose uptake, blood-brain barrier (BBB) disruption, and microvascular rarefaction, plays a critical role in the pathogenesis of age-related vascular cognitive impairment (VCI). However, the mechanisms that contribute to endothelial dysfunction in aging are not clear. Lipid droplets (LDs) are lipid-storing organelles that play an important role in cellular lipid metabolism. Dysregulated lipid homeostasis and subsequent LD accumulation in brain cells, specifically glial cells, has been implicated in neuroinflammation linked to aging and neurodegenerative diseases. However, the impact of age-related lipid dysregulation in brain endothelial cells on cognitive impairment with aging is unknown. We hypothesize that age-related changes in lipid metabolism contribute to lipid droplet accumulation in brain endothelial cells which in turn impairs endothelial structure and function, ultimately driving cognitive decline in aging. To assess this, we analyzed publicly available single-cell RNA sequencing (sc-seq) datasets to determine if and how lipid accumulation affects endothelial phenotype in the aging brain. Our results showed that, like glial cells, endothelial cells also accumulate LDs in the aging brain. In addition, LD-accumulating endothelial cells exhibit a transcriptomic profile indicative of decreased lipid turnover, increased inflammation, and impaired BBB function. Furthermore, LD-containing endothelial cells displayed elevated scores for senescence and senescence-associated secretory phenotype (SASP)-related genes, suggesting a link between altered lipid metabolism and senescence. We have also validated our results from sc-seq studies in vivo in naturally aged C57BL/6J mice and confirmed that endothelial cells accumulate LDs in the aging brain using immunohistochemistry (IHC) and real-time PCR analysis. These studies provide evidence that pathological LD accumulation in aged brain endothelial cells leads to structural and functional impairments and could potentially contribute to cognitive decline in aging. Ongoing in vitro and in vivo studies using models that promote or reduce LD accumulation in endothelial cells will elucidate the mechanistic role of endothelial lipid dysregulation in age-related cognitive impairment. Funding was provided by NIH K01AG073613, AFAR Junior Faculty Award, American Heart Association Career Development Award, and Stephenson Cancer Center, OUHSC. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.