Regular training may erase some molecular signs of muscle aging

Muscles of regularly trained older adults retain some molecular features seen in younger people, particularly those linked to energy production.

Regular training may erase some molecular signs of muscle aging

Table of contents

    Muscle aging is more than losing mass and strength

    As people age, muscles change in ways that go far beyond what can be seen from the outside. Changes also occur in gene expression, metabolism, and mitochondrial function — the cellular machinery involved in energy production.

    One of the key questions is therefore: how much of muscle aging is an unavoidable consequence of age, and how much may be influenced by lifestyle and regular exercise?

    This is difficult to separate because older adults are, on average, less physically active than younger people. When researchers compare the muscles of a 20-year-old and a 70-year-old, some of the observed differences may therefore reflect age itself, while others may reflect lower activity levels.

    A study published in Nature Aging attempted to separate these factors. Researchers compared younger adults with older adults who had similar levels of everyday physical activity, and then examined how their muscles differed from those of older adults who trained regularly and consistently.

    Study details

    The study examined muscle aging at a much deeper level than simply measuring muscle mass or strength. The researchers analyzed several biological layers at once and looked at muscles both at rest and after a single exercise session.

    • Publication title: Delayed molecular aging, preservation of energy metabolism and enhanced exercise response in exercise-trained human muscle
    • Authors: Georges E. Janssens, Maria M. Trętowicz, Lotte Grevendonk, Marit Kotte, Angelique Scantlebery, Bauke V. Schomakers, Michel van Weeghel and colleagues.
    • Affiliations: the research team included scientists affiliated with the University of Amsterdam / Amsterdam UMC and Maastricht University in the Netherlands.
    • Publication date: July 3, 2026.
    • Journal: Nature Aging, volume 6, pages 1482–1500; peer-reviewed publication.
    • DOI: 10.1038/s43587-026-01150-x.
    • PMID: 42399371.
    • Full text: Nature Aging
    • PubMed: PMID 42399371
    • Study type: observational comparison of groups differing in age and training status, combined with an analysis of the response to a single bout of exercise.
    • Sample: 47 participants — 11 young adults, 15 normally active older adults, 16 exercise-trained older adults, and 5 older adults with impaired physical function.
    • Exposure: long-term regular exercise training was compared with typical daily physical activity and lower physical function.
    • Measurements: muscle biopsies were analyzed using transcriptomics, metabolomics and lipidomics.
    • Exercise test: participants were assessed before and after approximately one hour of submaximal cycling.
    • Main outcome: around half of the age-related molecular differences seen when comparing young adults with normally active older adults were not observed in exercise-trained older adults.
    • Funding: the project received support including a Longevity Impetus Grant from the Norn Group, Horizon Europe MSCA-Doctoral Network NADIS funding, Velux Stiftung, the Netherlands Organization for Scientific Research, and the TIFN Mitochondrial Health program. The authors reported that funders were not involved in data collection, analysis, or the decision to publish.
    • Conflicts of interest: the authors declared no competing interests.

    This context matters: the study compared people who had already been training or not training over the long term. It was not a randomized trial in which inactive participants were assigned to months or years of exercise.

    One of the most striking findings came from the analysis of gene expression in muscle.

    When researchers compared young adults with normally active older adults, they found numerous age-related differences. They then examined whether the same pattern appeared in older adults who trained regularly.

    The answer was only partly.

    Among genes whose expression increased with age, 56% did not show the same age-related pattern in trained older adults. Among genes whose expression decreased with age, the corresponding figure was 57%.

    In other words, for a substantial share of the molecular changes measured in the study, the muscles of trained older adults looked more similar to those of younger participants.

    That does not mean exercise made their muscles “50% younger.” The result refers to specific molecular differences detected in this population with these methods.

    A large proportion of age-related changes remained present despite high levels of fitness. Exercise did not stop muscle aging, but it was associated with a meaningfully different molecular profile.

    The strongest differences involved energy metabolism and mitochondria

    A particularly clear signal appeared in biological processes related to energy production.

    Normally active older adults showed lower expression of genes involved in processes such as cellular respiration and mitochondrial energy production. Metabolomic analyses pointed in a similar direction.

    In trained older adults, many of these differences were smaller or absent.

    This is important because mitochondria are central to the energy infrastructure of muscle. Their function influences the ability to produce energy, use metabolic fuels, perform physical work, and adapt to exercise.

    The researchers also observed links between physical fitness and NAD+ metabolism, which plays an important role in cellular energy reactions and multiple regulatory processes.

    However, the study does not show that increasing NAD+ on its own would reproduce the effects seen in trained muscle. The findings concern the broader biological profile associated with fitness and long-term exercise, not the isolated effect of a single metabolite or supplement.

    Trained muscles also responded differently to a single exercise bout

    The researchers did not only examine muscle at rest. They also wanted to understand how aging muscles respond to a physical challenge.

    Participants therefore completed approximately one hour of submaximal cycling, after which the researchers analyzed molecular changes in muscle.

    Exercise activated gene programs linked to cellular stress and immune signaling across the groups. In older adults, the magnitude of this response was positively associated with physical fitness.

    The most highly trained older adults showed a response that was more similar to that of younger participants than to less fit older adults.

    Genes involved in pathways related to IL-6, IL-1β and TNF were among those affected.

    This should not be interpreted as evidence that exercise causes harmful chronic inflammation. A short-lived inflammatory and stress response after exercise is part of normal physiological adaptation and is fundamentally different from persistent systemic inflammation.

    Daily activity is not the same as structured training

    One of the most interesting elements of the study was the comparison between younger and older participants with broadly similar amounts of daily movement.

    Younger participants averaged around 10,200 steps per day, while normally active older adults averaged around 9,600 steps. Despite this relatively similar amount of movement, their muscle molecular profiles differed substantially.

    The trained older adults formed a distinct group. In this study, regular training meant at least three planned exercise sessions of roughly one hour per week for more than a year.

    The results therefore highlight an important distinction: being active during the day is valuable, but it may not produce the same adaptations as structured exercise that provides a sufficiently strong physiological stimulus.

    This does not make daily walking unimportant. The study addresses a different question: whether older adults with similar everyday activity levels show additional molecular differences when some of them also train systematically.

    They did.

    The study does not prove that exercise reverses aging

    The most appealing interpretation would be that exercise “reverses” biological aging in muscle. The data do not justify such a strong conclusion.

    Several limitations are important:

    • The study was observational, meaning it identifies associations between long-term training and muscle biology but cannot establish causality with certainty. People who remain capable of sustained training into older age may differ from other participants in additional ways.

    • The sample was small, with 47 participants in total, and the individual groups were smaller still. The group of older adults with impaired physical function included only five people.

    • Not all age-related molecular changes were associated with training status. Roughly half of the measured differences remained present even in trained older adults.

    • The acute exercise bout was prescribed relative to each participant’s own capacity. This means the absolute workload differed between groups, which may have influenced the molecular response.

    A more accurate interpretation is therefore that regular training is associated with preservation of a more youthful profile in some molecular pathways in muscle, rather than that exercise literally reverses muscle aging.

    What does this mean in practice?

    The study reinforces the idea that muscle aging is not a single, uniform process.

    Some molecular changes remained visible even in highly fit older adults. Others — particularly those related to energy metabolism and mitochondrial function — were strongly associated with training status.

    The practical implications are therefore more nuanced than a simple claim that exercise “turns back the clock”:

    • Regular exercise may affect muscle far beyond strength or muscle size. Differences were also visible in gene expression, metabolites, and lipid profiles.

    • A high daily step count is not equivalent to structured training. Everyday movement remains important, but planned exercise may provide additional biological stimuli and adaptations.

    • Mitochondrial function and energy metabolism appear to be among the areas most strongly associated with training status. This may help explain why fitter people tend to preserve better muscle function with age.

    • Exercise does not appear to erase every molecular feature of muscle aging. The study also highlights clear limits to what even high levels of fitness may change.

    The broader message is that exercise should not be viewed only as a way to preserve appearance, muscle mass, or aerobic capacity. It is also a long-term biological stimulus that influences how muscle tissue functions at the molecular level.

    At the same time, these results should not be turned into a promise that training can stop or reverse aging. A more precise conclusion is that regular exercise may help preserve selected aspects of muscle biology in a state that more closely resembles that of younger people.

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