Tissue-specific lipidomic alterations in aging rats

Abstract Aging drives tissue-specific lipidome remodeling, but comprehensive multi-tissue lipidomic profiles in rodents remain scarce. Here, we conducted untargeted LC–MS lipidomics on frontal cortex (FC), cerebellum (CB), liver (LV), muscle (MS), and plasma (PL) from young and old male Wistar rats, quantifying 884 lipids across 36 classes. Muscle showed the largest number of lipidomic changes, with PG and PE O- enrichment indicating mitochondrial dysfunction. Plasma showed alterations in phosphocholine LPC and PC O-, while liver displayed an unexpected decline in triglycerides, particularly shorter- and odd-chain species, consistent with reduced gut microbiota–derived fatty acids. Brain regions showed myelin-related changes: decreased MGDG O- in cerebellum and mixed SHexCer alterations in the frontal cortex. Our cross-tissue analyses revealed that aging trajectories clustered by tissue function rather than baseline composition, with muscle more closely resembling brain, and liver mirroring plasma alterations. While no individual lipid showed ubiquitous age-related changes across all tissues, we found consistent patterns at the lipid class level, particularly among solid tissues. Notably, PG showed the strongest coordinated age-related changes, highlighting mitochondrial lipid remodeling as a common aging feature. Our data supports tissue-specific lipid aging processes, as well as mitochondrial dysfunction patterns shared across multiple tissues.