The Lipidome of the Lateral Ventricle Choroid Plexus Exhibits Sex‐Specific Changes Across Aging

During aging, the brain's lipid composition and the cerebrospinal fluid (CSF) secreted by the choroid plexus (ChP) undergo significant modifications. The ChP, an epithelial tissue located in each brain ventricle, experiences a decline in key functions, including protein secretion and CSF production. A critical gap in our understanding of the ChP lies in its lipid composition and the potential impact of age-related changes on its physiology. This study hypothesized that the lipidome of the lateral ventricle choroid plexus (LVCP) is modulated during aging, potentially generating pro-inflammatory mediators. To address this, we performed quantitative lipidomics on LVCP from male and female mice across aging and investigated whether pro-inflammatory lipid mediators increase with age. LVCP and cortex tissues from C57BL/6 mice aged 6, 12, 18, and 24 months (n = 5/age/sex) were analyzed using liquid chromatography-tandem mass spectrometry, and data were processed using Lipidr and univariate statistical methods. Given the pronounced sex differences, analyses were stratified by sex. During aging, 9 lipids in males and 19 in females were significantly modulated. In males, most changes occurred at 24 months and involved higher levels of arachidonic acid (ARA) in alkyl ether and plasmalogen phosphatidylcholine species. In females, most changes occurred at 18 months and were characterized by lower levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), whereas at 24 months, females exhibited higher levels of EPA, DHA, and ARA in alkyl ether and plasmalogens compared to other ages. Additionally, younger females showed higher levels of oxygenated derivatives of linoleic acid compared to older females. These findings reveal dynamic, sex-specific remodeling of the LVCP lipidome during aging, suggesting that lipid homeostasis in this structure is tightly regulated and may influence inflammatory signaling and barrier function in an age-dependent manner.