A lipidome landscape of aging in mice

Understanding the molecular mechanisms associated with aging is important to improve the longevity of healthy individuals. Herein, we performed untargeted lipidomics to elucidate the relationship between aging and lipid metabolism in 13 mouse tissues at various life stages (2, 12, 19, and 24 months), in which sex and microbiome dependencies (specific pathogen free/germ free) were investigated. By analyzing 2,817 unique molecular profile data of 121 lipid subclasses, we characterized the common and tissue-specific lipidome changes associated with aging. For example, bis(monoacylglycerol)phosphate containing polyunsaturated fatty acids was enriched in various organs during aging, while other phospholipids containing saturated and monounsaturated fatty acids were decreased. In addition, we discovered an age-dependent increase of sulfonolipid (SL), which is biosynthesized in Alistipes and Odoribacter genera. SL molecules were absent in germ-free mice. Furthermore, the molecules appeared to be translocated from the intestinal lumen to various tissues such as the liver, kidney, and spleen. In the kidney, the associations of glycolipids such as galactosyl ceramides (GalCer), galabinosyl ceramides (Gal2Cer), trihexosyl ceramides (Hex3Cer), and mono and digalactosyl diacylglycerols were found in male mice, in which two lipid classes Gal2Cer and Hex3Cer were significantly enriched in aged mice. Integrated analysis of the kidney transcriptome revealed uridine diphosphate galactosyltransferase UGT8a, alkylglycerone phosphate synthase, and fatty acyl-CoA reductase 1 as potential enzymes responsible for male-specific glycolipid biosynthesis in vivo, which would be relevant to sex dependency in kidney diseases. Our lipidome results will become an important resource, led to the understanding of the molecular mechanisms underlying cellular senescence and age-related diseases.