Lipids contribute to the structure, development, and function of healthy brains. Dysregulated lipid metabolism is linked to aging and diseased brains. However, our understanding of lipid metabolism in aging brains remains limited. Here we examined the brain lipidome of mice across their lifespan using untargeted lipidomics. Co-expression network analysis highlighted a progressive decrease in 3-sulfogalactosyl diacylglycerols (SGDGs) and SGDG pathway members, including the potential degradation products lyso-SGDGs. SGDGs show an age-related decline specifically in the central nervous system and are associated with myelination. We also found that an SGDG dramatically suppresses LPS-induced gene expression and release of pro-inflammatory cytokines from macrophages and microglia by acting on the NF-κB pathway. The detection of SGDGs in human and macaque brains establishes their evolutionary conservation. This work enhances interest in SGDGs regarding their roles in aging and inflammatory diseases and highlights the complexity of the brain lipidome and potential biological functions in aging.

脂质有助于健康大脑的结构、发育和功能。脂质代谢失调与大脑衰老和患病有关。然而，我们对衰老大脑中脂质代谢的了解仍然有限。在这里，我们使用非靶向脂质组学检查了小鼠整个生命周期的脑脂质组。共表达网络分析强调了 3-磺基半乳糖二酰基甘油 (SGDG) 和 SGDG 途径成员（包括潜在降解产物 lyso-SGDG）的逐渐减少。SGDG 显示出与年龄相关的衰退，特别是在中枢神经系统中，并且与髓鞘形成有关。我们还发现，SGDG 通过作用于 NF-κB 通路，显着抑制 LPS 诱导的基因表达以及巨噬细胞和小胶质细胞促炎细胞因子的释放。在人类和猕猴大脑中检测到 SGDG 确立了它们的进化保守性。这项工作增强了人们对 SGDG 在衰老和炎症性疾病中的作用的兴趣，并强调了大脑脂质组的复杂性和衰老中潜在的生物学功能。