# Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood–brain barrier dysfunction, metabolic reprogramming, and increased inflammation in the aging brain

## TL;DR

Aging causes lipid buildup in brain endothelial cells, leading to blood-brain barrier issues, inflammation, and metabolic changes that may contribute to cognitive decline.

## Contribution

This study identifies a novel transcriptomic signature in lipid-laden endothelial cells linked to aging and cerebrovascular dysfunction.

## Key findings

- Aging promotes lipid droplet accumulation in brain endothelial cells.
- Lipid accumulation is associated with impaired blood-brain barrier function and increased inflammation.
- Altered metabolism in aged endothelial cells includes increased fatty acid oxidation and reduced glycolysis.

## Abstract

Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial aging remains poorly understood. In this study, we conducted a secondary analysis of single-cell transcriptomic data from young and aged mouse brains, with a specific focus on endothelial cells (ECs). Our analyses revealed that aging promotes lipid droplet accumulation in brain ECs. These lipid-laden brain ECs exhibit a transcriptomic signature indicative of impaired blood–brain barrier function, increased cellular senescence, and inflammation in aging. Furthermore, lipid accumulation is associated with an altered metabolic phenotype characterized by increased fatty acid oxidation and decreased glycolysis and impaired mitochondrial electron transport chain activity in the ECs of the aging brain. We have also validated lipid accumulation in aged ECs in vivo. Collectively, our findings indicate that lipid accumulation may drive structural, functional, and metabolic impairments in the brain ECs, likely contributing to cerebrovascular aging. Understanding the mechanisms underlying lipid accumulation-induced endothelial dysfunction may offer novel therapeutic strategies for mitigating microvascular dysfunction and cognitive decline in aging.

The online version contains supplementary material available at 10.1007/s11357-025-01986-y.