Skeletal muscle from older adults who train consistently appears to age more slowly at the molecular level, and a new multiomic study now shows just how far that rejuvenation extends. In an analysis of thousands of transcripts, lipids and metabolites measured in human muscle before and after a single session of exercise, researchers report that roughly half of the molecular differences normally associated with aging are absent in the muscles of trained older adults, leaving their tissue profiles strikingly similar to those of young adults. The findings, published in Nature Aging, also reveal that the intensity of the immediate molecular response to exercise scales with a person’s physical fitness, offering one of the most detailed pictures to date of how sustained training reshapes the biology of aging muscle.
The research team, led by George Janssens and colleagues, set out to address two persistent questions in the biology of exercise and aging. First, how exactly does regular physical activity mitigate the molecular changes that accumulate in skeletal muscle as people grow older? Second, why do individuals of the same chronological age respond so differently to an acute bout of exercise? Both questions matter because exercise is widely regarded as one of the most effective interventions for healthy aging, yet the molecular mechanisms linking fitness level to exercise responsiveness have remained largely opaque.
To interrogate these questions, the investigators performed transcriptomics, lipidomics and metabolomics on skeletal muscle biopsies taken from young and older adults with differing levels of physical function. Crucially, each participant provided samples at rest and again after an acute bout of submaximal exercise, allowing the researchers to capture both the baseline molecular landscape of aging muscle and the dynamic response it mounts when challenged. This dual design made it possible to distinguish age-related changes that are fixed features of older muscle from those that are modified by long-term training.
At baseline, the comparisons between sedentary or normally active young and older participants told a familiar but important story. Older adults exhibited reduced expression of genes associated with cellular respiration and energy metabolism compared with young adults who maintained comparable levels of everyday physical activity. This transcriptional signature suggests a decline in the muscle’s intrinsic capacity for oxidative energy production, a change long suspected to underlie the reduced endurance and metabolic resilience that accompany aging. Because the young and older comparison groups had similar activity levels, the differences pointed to aging itself, rather than lifestyle alone, as the driver of the energy-metabolism decline.
The most striking result emerged when the researchers examined older adults who had undertaken sustained physical training. In these trained older participants, approximately 50 percent of the age-related molecular differences observed at baseline were simply absent. Their muscle profiles resembled those of young adults across a substantial portion of the transcriptome and metabolome, indicating that long-term training does not merely slow functional decline but measurably rewrites the molecular age of the tissue. The authors describe this phenomenon as delayed molecular aging, and the preservation of energy-metabolism gene expression appears to be a central component of it.
Exercise training, in other words, seems to buffer the aging muscle against some of its most consequential losses. The genes that code for components of the respiratory chain, mitochondrial function and associated metabolic pathways—those most diminished in untrained older muscle—were maintained at levels much closer to those seen in young tissue. This suggests that the well-documented benefits of lifelong physical activity, from preserved strength to improved metabolic health, are rooted in a durable molecular reprogramming of the muscle itself rather than in compensatory mechanisms elsewhere in the body.
The study also captured what happens in muscle in the hours immediately following an acute bout of exercise. All participants, young and old, trained and untrained, displayed a clear transcriptional immune and stress response after the submaximal exercise challenge. This reaction, which involves the activation of stress-response pathways and immune-related signaling, is thought to be part of the adaptive process through which muscle remodels itself in response to exertion. What differed between individuals was the magnitude of that response: in older adults, the strength of the transcriptional reaction was positively correlated with their physical fitness. Fitter older individuals mounted a more vigorous molecular response to the same relative workload than their less fit peers.
This finding carries significant implications for understanding how exercise acts as a biological stimulus. Each bout of exercise is, in essence, a controlled perturbation that triggers repair and remodeling programs in muscle. If a fit older adult’s muscle responds more robustly to each bout, then over months and years of training the cumulative effect could compound, creating a feedback loop in which fitness begets stronger molecular responses, which in turn drive further adaptation. The results provide a molecular explanation for why maintaining training status into older age appears to preserve not just muscle function but the muscle’s very capacity to keep adapting.
Beyond the transcriptome, the integrated multiomic analyses uncovered a web of relationships connecting mitochondrial respiration, lipid metabolism, cellular stress responses and NAD+ biology. NAD+, a central coenzyme in cellular redox reactions and energy transfer, has become a major focus of aging research because its tissue concentrations decline with age, and the new data tie these NAD+-dependent processes directly to the exercise-responsive molecular programs in human muscle. The lipidomic and metabolomic layers of the dataset similarly linked shifts in fat metabolism to both mitochondrial performance and the stress response, reinforcing the idea that aging muscle is shaped by tightly coupled metabolic networks rather than isolated pathways.
Taken together, these findings demonstrate that sustained physical training transforms the age-related molecular profile of human skeletal muscle, and they establish what the authors describe as a molecular atlas for the study of fitness-dependent aging mechanisms. Such a resource gives researchers a reference map against which future interventions—new exercise regimens, nutritional strategies or pharmacological agents aimed at mimicking the benefits of training—can be benchmarked. If the molecular signature of the trained older muscle can be defined, it becomes a measurable target, not merely an abstraction.
The work also sharpens a message that has been emerging from epidemiology and physiology alike: chronological age and biological age are not the same thing, and lifestyle exerts a powerful influence over the gap between them. Half of the molecular hallmarks of aging measured in this study were erased by training, which is a remarkably large fraction given the multi-tissue, multi-decade nature of the aging process. While the study was observational in the sense that trained participants were compared across groups rather than randomly assigned to exercise interventions, the scale and depth of the molecular data make the association between long-term training and delayed muscle aging difficult to dismiss.
For clinicians and public health researchers, the correlation between fitness and exercise responsiveness adds a practical dimension. Physical fitness is not only an outcome of training but also, apparently, a determinant of how the body reads and responds to each new exercise stimulus. This supports the idea that preserving fitness through middle and older age has value that goes beyond current capacity—it maintains the machinery that allows future activity to keep delivering molecular benefit.
Future studies built on this atlas will likely explore how quickly these molecular changes reverse when training stops, which specific components of the response are driven by NAD+ availability, and whether the same patterns hold in other metabolically active tissues. For now, the study stands as one of the clearest demonstrations to date that the aging muscle is not on a fixed molecular timetable. With enough sustained training, a substantial share of the molecular decay of aging can be postponed, and the muscle of a 70-year-old can, in measurable ways, look and behave more like that of someone decades younger.
Subject of Research: Molecular effects of long-term exercise training on aging human skeletal muscle, assessed through transcriptomics, lipidomics and metabolomics before and after acute exercise.
Subject of Research: Medicine
Article Title: Delayed molecular aging, preservation of energy metabolism and enhanced exercise response in exercise-trained human muscle
Article References: Janssens, G. E., Trętowicz, M. M., Grevendonk, L., Kotte, M., Scantlebery, A., Schomakers, B. V., van Weeghel, M., Hermans, J., Vervaart, M. A. T., Wever, E. J. M., Denis, S. W., Jongejan, A., Salomons, G. S., Vaz, F. M., Schrauwen, P., Hoeks, J., & Houtkooper, R. H. (2026). Delayed molecular aging, preservation of energy metabolism and enhanced exercise response in exercise-trained human muscle. Nature Aging, 6(7), 1482-1500. https://doi.org/10.1038/s43587-026-01150-x
Image Credits: AI Generated
DOI: 10.1038/s43587-026-01150-x
Keywords: skeletal muscle aging, exercise training, transcriptomics, lipidomics, metabolomics, mitochondrial respiration, energy metabolism, NAD+ biology, physical fitness, molecular atlas, immune stress response, healthy aging
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Beatrice Stafford. (September 6, 2026). Exercise-trained muscle resists aging and boosts energy metabolism. Scienmag. https://scienmag.com/exercise-trained-muscle-resists-aging-and-boosts-energy-metabolism/
Beatrice Stafford. “Exercise-trained muscle resists aging and boosts energy metabolism.” Scienmag, 6 September 2026, https://scienmag.com/exercise-trained-muscle-resists-aging-and-boosts-energy-metabolism/. Accessed 6 September 2026.
Beatrice Stafford. “Exercise-trained muscle resists aging and boosts energy metabolism.” Scienmag. September 6, 2026. https://scienmag.com/exercise-trained-muscle-resists-aging-and-boosts-energy-metabolism/
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Tags: age-associated lipid and metabolite profiles in muscleage-related molecular changes in skeletal muscleaging biomarkersaging mitigation strategiesaging muscle resistance to declinebenefits of regular exercise on energy metabolismbiological rejuvenation through muscle trainingdifferences in exercise response among older adultsenergy metabolismExerciseexercise response variabilityexercise-induced muscle rejuvenationimpact of exercise intensity on muscle biologymolecular biology of agingmolecular effects of physical activity on agingmolecular markers of muscle agingmolecular rejuvenationmultiomic analysismultiomic analysis of trained musclemuscle agingmuscle tissue profilespersonalized exercise effects on aging musclesphysical fitness impactskeletal muscle
