Translational studies of chronic supplementation with a mitochondria-targeted antioxidant to improve physical function with ageing.

Declines in physical function with advancing age increase the risk of functional limitations and chronic disease. Excess mitochondrial reactive oxygen species (mitoROS)-related oxidative stress is linked to physical dysfunction with ageing, but the effects of therapies targeting excess mitoROS on age-associated physical dysfunction are unclear. Here, we determined the efficacy of the mitochondria-targeted antioxidant MitoQ for improving multiple domains of physical function, first in old mice and then in high-functioning older adults in a randomized, placebo-controlled, cross-over design clinical trial. In old male C57BL6/N mice (N = 22-26; 27 months), we found that 4 weeks of treatment with MitoQ (250 µm in the drinking water) attenuated the age-related decline in grip strength, co-ordination, and endurance without effects in young mice (N = 18-20; 6 months). The effects of MitoQ in old mice were accompanied by lower levels of skeletal muscle mitochondria-specific superoxide production and markers of mitoROS-related oxidative stress (i.e. phosphorylated SHC adaptor protein 1, isoform p66) and inflammation (i.e. interleukin-6, tumour necrosis factor-alpha, interferon-gamma). In the clinical trial, we did not observe convincing effects of 6 weeks of MitoQ (20 mg day-1) treatment on physical function in healthy older adults (N = 18; aged 60-79 years). However, exploratory subgroup analyses suggest possible effects of MitoQ on peak leg extension power and grip strength in participants ≥70 years of age. Our findings provide preclinical, proof-of-concept evidence for targeting excess mitoROS with MitoQ to reverse physical dysfunction with ageing. Although the effects of MitoQ did not directly translate to high functioning older adults, our initial observations suggest MitoQ may have greater efficacy in older, more physically frail individuals. KEY POINTS: Excess mitochondrial reactive oxygen species (mitoROS)-related oxidative stress is linked to physical dysfunction with ageing, but the effects of therapies targeting excess mitoROS on age-associated physical dysfunction are unclear. In old mice, chronic supplementation with the mitochondria-targeted antioxidant MitoQ improves measures of physical function, which was accompanied by reductions in mitochondria-specific superoxide production in skeletal muscle. The effects of MitoQ in old mice did not directly translate to humans as there were no convincing effects on measures of motor function in a randomized, placebo-controlled, cross-over design clinical trial of 6 weeks of 20 mg day-1 MitoQ. However, in participants ≥70 years of age, we observed possible evidence of efficacy of MitoQ supplementation for improving select measures of strength. Future clinical trials with MitoQ and possibly other mitochondria-targeted antioxidant approaches for enhancing physical function with ageing should focus on older adults of more advanced age or more frail clinical populations.