Delayed molecular aging, preservation of energy metabolism and enhanced exercise response in exercise-trained human muscle

Exercise is fundamental to healthy aging, yet how it mitigates age-related molecular changes and how fitness level shapes exercise responses remain unclear. To address this, we performed transcriptomics, lipidomics, and metabolomics on skeletal muscle of young and older adults with differing physical function, both before and after an acute bout of sub-maximal exercise. At baseline, older adults exhibited reduced expression of genes associated with cellular respiration and energy metabolism compared to young adults with comparable activity levels. Here we show that in trained older adults, 50% of these age-related differences were absent, resulting in profiles resembling those of young adults. While all participants displayed transcriptional immune and stress responses upon acute exercise, the magnitude of these responses in older adults correlated positively with their physical fitness. Integrated multi-omic analyses further revealed links between mitochondrial respiration, lipid metabolism, stress responses and NAD⁺ biology. These findings demonstrate that sustained physical training transforms age-related molecular profiles and provides a molecular atlas for studying fitness-dependent aging mechanisms.