Age-related muscle decline reduces mobility and increases the risk of fractures, diabetes, and other chronic diseases. Nobiletin (Nob), a citrus-derived polymethoxylated flavonoid, is known for its antioxidant and anti-inflammatory properties, but its effects on aerobic metabolism and muscle function have been unclear. A study published in Food Science & Nutrition (Jan 9, 2026) using D-galactose-induced aging mice found that nobiletin enhanced antioxidant capacity and mitochondrial function, leading to improved aerobic metabolism and skeletal muscle performance. These findings suggest nobiletin may have potential in strategies targeting age-related muscle decline.
Introduction
With advancing age, loss of muscle mass and strength contributes to impaired movement, increased risk of chronic diseases such as diabetes, osteoporosis, and fractures, and a decline in life quality in older adults. Skeletal muscle accounts for a large proportion of total body mass and plays a central role in resting and exercise-regulated metabolism.
Nobiletin (Nob) is a naturally occurring flavonoid abundant in citrus fruit peels, known for anti-oxidative, anti-inflammatory, and metabolic regulatory activities. Researchers have hypothesized that Nob may improve muscle performance and counteract age-associated declines in muscle function by enhancing aerobic metabolic capacity at the cellular level.
To test this hypothesis, the study established a sarcopenia model in mice by subcutaneous injection of D-galactose for 10 weeks. Alongside D-gal treatment, mice received daily oral gavage of either saline or nobiletin.
Nobiletin Improves Muscle Mass and Functional Performance
The D-gal treatment accelerated muscle loss in the gastrocnemius and soleus muscles. In contrast, nobiletin administration significantly improved muscle mass metrics. Functional tests showed that nobiletin enhanced grip strength and running endurance in aging mice, indicating an overall improvement in skeletal muscle performance.
Skeletal muscle is a major contributor to glucose disposal and overall metabolic regulation. Enhancement of muscle performance by nobiletin was accompanied by partial restoration of glucose homeostasis, suggesting improved metabolic flexibility in aging mice.
Furthermore, nobiletin increased adaptive thermogenesis capacity, as shown by cold-challenge infrared imaging and body temperature measurements. Compared to control aging mice, the nobiletin-treated group displayed higher surface temperatures and more robust thermogenic responses.
Enhanced Aerobic Metabolism and Gene Expression Regulation
Skeletal muscle mitochondria are critical for aerobic metabolism, and aging impairs mitochondrial function. Compared with control mice, aging mice exhibited reduced expression of key genes involved in oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and β-oxidation pathways. Nobiletin intervention upregulated the expression of these genes toward control levels, indicating enhanced aerobic metabolic capacity at the molecular level.
This enhancement was evident in genes regulating oxidative phosphorylation (OXPHOS), citrate cycle activity, and fatty acid oxidation, which collectively support efficient ATP generation in muscle fibers. These molecular changes reflect improved energy provision capacity within aging muscle tissue.
Mitochondrial Morphology and Function Improvements
Ultrastructural analysis revealed that mitochondria in D-gal mice had abnormal morphology, including vacuolization, loss of cristae, and reduced number and size. Nobiletin markedly restored mitochondrial structure, with clearer cristae architecture and decreased signs of degradation.
Biochemical measures further showed that nobiletin rescued declines in mitochondrial respiratory complex activity and total ATP production, indicating functional improvement of the energy-generating machinery in skeletal muscle. Additionally, expression levels of mitochondrial dynamics proteins — including fusion-promoting proteins (Mfn1, Mfn2, Opa1) and fission regulator Drp1 — were favorably modulated by nobiletin to support mitochondrial health.
Antioxidant Protection and Signaling Pathway Activation
Oxidative stress plays a pivotal role in muscle aging. Aging mice exhibited elevated reactive oxygen species (ROS) and malondialdehyde (MDA), markers of oxidative damage, along with reduced activity of antioxidant enzymes such as superoxide dismutase (SOD). Nobiletin treatment reduced ROS and MDA levels and restored SOD activity toward normal ranges.
At the molecular level, nobiletin activated the SIRT1/PGC-1α/Nrf2 signaling axis in skeletal muscle — a central regulator of antioxidant responses and mitochondrial biogenesis. This activation likely contributed to enhanced oxidative stress resistance and increased expression of cytoprotective genes involved in energy homeostasis and mitochondrial function.
Mechanistic Considerations and Broader Context
Nobiletin’s multifaceted mechanisms align with broader research demonstrating its influence on metabolic regulation, inflammatory pathways, and mitochondrial quality control. Previous in vitro studies have shown that nobiletin improves mitochondrial function, enhances ATP production, and reduces inflammation and apoptosis in aged muscle cell models.
While the present animal model provides strong mechanistic evidence, further research in naturally aged models and controlled clinical studies will be essential to evaluate translational potential in humans.
Conclusion
Nobiletin demonstrated the capacity to improve skeletal muscle performance in D-galactose-induced aging mice by enhancing aerobic metabolic pathways, restoring mitochondrial morphology and function, and boosting antioxidant capacity through regulatory signaling networks. These actions helped improve muscle endurance, metabolic health, and resilience against age-associated decline. Such findings support ongoing exploration of nobiletin for the prevention and management of sarcopenia and related metabolic dysfunctions.