From mice to muscle: does MitoQ translate to human strength in ageing?

Preclinical animal models are used to test a pharmaceutical's safety, efficacy and mechanism of action, before being translated to human research (Mitchell et al., 2025). Optimal preclinical models mirror the human population of interest in terms of age, sex and genetics to enhance translational outcomes and should be aligned with factors important to humans, including independence and quality of life (Mitchell et al., 2025). It has been well documented that advancing age is associated with a progressive loss of skeletal muscle (SKM) mass and physical function, known as sarcopenia (Grevendonk et al., 2021). This condition often results in impaired physical capacity (including reduced SKM strength, endurance and co-ordination), limiting independence and performance of activities of daily living, with an increased risk of disability (Grevendonk et al., 2021). Declines in mitochondrial function are seen in typical ageing and have been linked to sarcopenia development in both rodent and human studies (Grevendonk et al., 2021). This work therefore underscores the need for strategies to mitigate mitochondria-related declines in SKM health and function with ageing. One such strategy may lie in supplement use. Mitoquinone mesylate (MitoQ) is a mitochondrial-targeted antioxidant composed of ubiquinol linked to a lipophilic triphenylphosphonium cation (Murray et al., 2026). This chemical modification allows the compound to cross cell membranes and accumulate within the negatively charged inner mitochondrial membrane, where it reduces mitochondrial reactive oxygen species (mitoROS)-related oxidative stress. By targeting the primary site of ROS production, MitoQ differs from conventional antioxidants aimed at improving physical function with ageing that lack mitochondrial specificity. Previous translational work by Rossman et al. (2018) supports supplementation with MitoQ to improve age-related vascular dysfunction, therefore making it plausible that the antioxidant may improve multiple domains of SKM health known to decline with age. In a recent issue of The Journal of Physiology, Murray et al. (2026) examined chronic supplementation of MitoQ to test the hypothesis that targeting excess mitoROS improves age-related physical dysfunction. This two-phase translational investigation consisted of preclinical murine study followed by a pilot randomized, double-blind, placebo-controlled, cross-over clinical trial in older adults. Murray et al. (2026) first conducted a 4 week preclinical intervention on mice treated with MitoQ (250 µm in drinking water). Groups of young (∼6 months) and old (∼27 months) mice were assigned to either MitoQ-treated or control conditions, resulting in four groups: young control (YC, n = 20), young MitoQ (YMQ, n = 18), old control (OC, n = 26) and old MitoQ (OMQ, n = 22) (Murray et al., 2026). This intervention was followed by mechanistic assessment of skeletal muscle mitochondrial oxidative stress and assessment of physical function to capture multiple domains of neuromuscular function relevant to ageing. Murine results demonstrated that chronic MitoQ supplementation improved grip strength, co-ordination and endurance in OMQ mice, alongside reduced mitochondria-specific superoxide (mediator of oxidative stress) production, and less activation of p66 SHC – a marker and regulator of oxidative stress from mitoROS (Murray et al., 2026). Several proinflammatory cytokines (interleukin-6, tumour necrosis factor-α, interferon-γ) were also significantly lower in OMQ mice. These encouraging results prompted Murray et al. (2026) to conduct a human cross-over trial in high functioning adults (n = 18, aged 60–79 years), where participants received 20 mg day−1 oral MitoQ or identical placebo tablets over two 6 week phases. Primary analysis revealed no significant effects on physical function, however, a secondary subgroup analysis of younger (60–69 years old; n = 13) vs. older (70–79 years old; n = 5) participants taking MitoQ found differences in peak leg extension power and grip strength, with increases in strength in the older MitoQ group compared to age-matched controls. This suggests that MitoQ might be an effective therapy for adults aged 70–79 years to improve upper and lower body strength. The significance of this study is twofold. First, advancing age is associated with progressive declines in skeletal muscle mitochondrial capacity and physical function, with significant consequences for independence and quality of life (Grevendonk et al., 2021). Research evaluating mitoROS modulation as a therapeutic target therefore addresses a genuine and pressing clinical need. Second, the two-phase translational design employed here is more rigorous than many single-species investigations in ageing research. Assessing multiple functional end-points, rather than relying on a single performance outcome, alongside mechanistic markers of mitochondrial oxidative stress strengthens the biological rationale for the functional effects of MitoQ prior to human testing. The randomized, double-blind, cross-over design of the human trial appropriately limits inter-individual variability in a small sample, and the authors’ decision to classify the ≥70 years old subgroup analysis as explicitly exploratory strengthens the study integrity at the same time as reducing concerns of outcome-driven data dredging. Despite these strengths, several limitations warrant consideration. Most notably, there is a mismatch in functional status between the preclinical and clinical populations. The 27-month-old mice used in the preclinical phase are considered the murine corollary of ∼75 human years of age, representing a population with considerably more severe age-related physical dysfunction than the largely high functioning 60–79 years old cohort recruited for the clinical trial. This disconnect probably contributed to the null findings in the broader human cohort. Additionally, the sex composition of the human cohort merits attention. With 11 postmenopausal women and only seven older men, the sample was underpowered for meaningful sex-based comparisons – a source of unexamined variability, given preclinical evidence that age-related decline in 17β-oestradiol differentially impairs skeletal muscle mitochondrial function and increases susceptibility to oxidative stress in females (Moreira-Pais et al., 2024). Furthermore, the absence of confirmed SKM target engagement in humans remains the most consequential unanswered question. Without evidence that the 20 mg day−1 dose meaningfully reduced mitoROS in human skeletal muscle, it is difficult to determine whether participant phenotype (i.e. ceiling effects in high-functioning individuals), intervention duration or incomplete confirmation of skeletal muscle target engagement in humans contributed to the limited translation of the murine effects. We argued at the outset of this article that understanding whether mitoROS modulation can improve age-related physical dysfunction requires rigorous translational evaluation. The findings presented here suggest that, although MitoQ robustly improves SKM function, oxidative stress and inflammation in aged mice, these effects do not directly translate to healthy older adults, at least not within a short intervention window or in high-functioning individuals. This is important for the field of ageing research because it highlights a critical and underappreciated gap between preclinical efficacy and human translation. To date, MitoQ has been positioned primarily as a standalone supplement, yet this study raises important questions about whether participant phenotype, intervention duration and incomplete target engagement in human SKM have limited its functional impact. We propose that future trials should prioritize lower-functioning or pre-frail older adults, longer intervention durations, employ sex-stratified analyses to clarify whether hormonal status moderates the efficacy of MitoQ in skeletal muscle, and examine synergistic effects with exercise to fully evaluate the therapeutic potential of MitoQ. Exercise is among the most effective interventions for improving mitochondrial function and redox balance in ageing skeletal muscle (Grevendonk et al., 2021) and pre-frail or frail older adults exhibit diminished mitochondrial adaptability that may amplify the therapeutic effects of mitoROS modulation. Only through more targeted trial design can the field determine whether MitoQ represents a viable therapeutic strategy for preserving physical function in ageing. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare no competing interests. E.Y.D., K.D. and T.Y.C. each contributed to project conception, and the writing and editing of the manuscript. No funding was received for this work. We warmly thank Dr Robert Bentley (Faculty of Kinesiology and Physical Education, University of Toronto) for his insightful feedback and guidance on this article. No generative AI was used in the drafting of this manuscript.