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

Exercise is fundamental to healthy aging, yet the degree to which it mitigates age-related molecular changes and how varying physical fitness levels influence the molecular response to exercise with age 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. Remarkably, in trained older adults, 50% of these age-related differences were absent, resulting in transcriptomic profiles for cellular respiration that closely aligned with those of young adults. Following acute exercise, trained older adults demonstrated molecular responses that more closely resembled those of younger individuals. 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. These findings underscore the capacity of sustained physical training to transform age-related molecular profiles, highlight a positive link between physical fitness level and exercise-induced inflammation in older adults, and provide a multi-omic molecular atlas for examining aging and fitness regulatory networks.