The Metabolome Atlas of 22 Tissues in Aging Mice Reveals a Switch in Thermogenesis from Brown Fat to Skeletal Muscle

Aging impairs thermoregulatory capacity, yet the metabolic mechanisms remain unclear. We report an organ-resolved metabolome atlas of 2,875 structurally annotated metabolites of old (90-96 weeks) versus young mice (16 weeks) across 22 tissues and four biological matrices. For thermoregulation, aging induces widespread remodeling of mitochondrial cardiolipins, with severe depletion of nascent species in brown adipose tissue (BAT) and a compensatory shift in thermogenic workload from BAT to muscle, evidenced by higher levels of long-chain fatty acids, acylcarnitines, and ω-oxidation markers in quadriceps. BAT showed reduced lipolysis and lower levels of the thermogenic lipokine 12,13-DiHOME, whereas muscle exhibited increased 12,13-DiHOME, lipid uptake, β-oxidation, and stress-associated metabolites including oxidized/reduced glutathione ratio. Hence, thermogenic adaptation comes at a cost: aged muscles exhibited signs of proteostatic stress, energetic strain, and oxidative damage, suggesting compensation contributes to sarcopenia. The atlas is publicly available at GitHub https://github.com/minliuUCDavis/AgingMiceAtlas and serves as a cornerstone resource for aging biology.