PROJECT SUMMARY/ABSTRACT Lipids make up half of the brain’s weight and are required for the proper development, structure, and function of healthy brains. As we age, the risk of cognitive decline and neurodegenerative diseases increases. This proposal seeks to understand whether aging changes the lipid composition of the brain and whether these changes contribute to aging and/or predispose us to disease. Unfortunately, the field currently lacks a deep understanding of lipid composition and dynamics in the aging brain, preventing progress toward this larger goal. Using a unique approach to lipidomics that integrates chemistry to examine the brain lipidome of aging mice led to the discovery of the unannotated 3-sulfo galactosyl diacylglycerol (SGDG) lipids as the most significantly decreased lipids in the aging brain. Furthermore, SGDGs are a novel class of anti-inflammatory lipids, suggesting that decreased SGDG levels with aging may promote brain inflammation. The discovery of SGDGs as age-regulated lipids represent a new frontier at the interface of aging research and lipid biology. This proposal seeks to answer the most pressing questions about SGDGs and their role in aging and disease. Specifically, this proposal asks how SGDG levels are controlled during aging and neurodegenerative disease (Aim 1); determine whether SGDGs are bioactive in vivo and whether they reverse inflammation or any other age- or disease-associated phenotypes (Aim 2); and measure SGDG distribution in the brain and myelin of mouse models of aging and neurogenerative disease (Aim 3). To accomplish these goals, the approach relies heavily on chemistry to synthesize of SGDGs and SGDG analogs and use these unique reagents for cell biology, in vivo pharmacology and biology, proteomics, genomics, and imaging methods to elucidate SGDG’s role in aging and neurodegenerative disease. These studies will explain how age-related differences in lipids and lipid metabolism can contribute to aging and neurodegenerative disease. Furthermore, since SGDGs are also found in human and primate brains, this information may contribute to the longer-term goal of knowing which age-regulated changes in lipids and lipid metabolism predispose humans to cognitive decline and neurodegeneration.