Trigonelline supplementation has therapeutic potential for age-associated muscle decline in sarcopenia: Study

"Dietary trigonelline supplementation in male mice prevents fatigue and enhances strength during aging," the researchers reported in Nature Metabolism. "We identified nutritional supplementation of trigonelline as a nicotinamide adenine dinucleotide (NAD+)-boosting strategy with therapeutic potential for age-associated muscle decline."

Sarcopenia is the progressive loss of muscle strength and mass and affects many adults when they get older. The disease is thought to affect approximately 10%-16% of people over the age of 65, and prevalence is higher in people with other conditions, for example, diabetes and cancer.

The muscle mass loss can contribute to frailty, mobility problems, and subsequent reduction in independence for many older people. As such, it represents a significant disease burden in an aging population.

Mitochondrial dysfunction and low NAD+ levels are hallmarks of skeletal muscle aging and sarcopenia, however, there is no clarity on whether these defects result from local changes or can be mediated by dietary or systemic cues. Considering this, Jerome N. Feige, Nestlé Institute of Health Sciences, Nestlé Research, Lausanne, Switzerland, and colleagues report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid, NAD+ levels, and muscle health in multiple species.

In humans, there is a reduction in serum trigonelline levels with sarcopenia and correlates positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. The researchers using, naturally occurring and isotopically labeled trigonelline, demonstrated that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in mice, Caenorhabditis elegant, and primary myotubes from healthy individuals, and individuals with sarcopenia.

Mechanistically, trigonelline did not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss–Handler pathway across models. In C. elegans, trigonelline, through an NAD+-dependent mechanism requiring sirtuin, improves biogenesis and mitochondrial respiration, reduces age-related muscle wasting, and increases mobility and lifespan.

Correcting for dietary caffeine and vitamin B3 intake did not impact the association between trigonelline and muscle strength. The targeted metabolomic profiling of human sarcopenia revealed trigonelline as a new metabolite associated with mitochondrial metabolism, muscle function, and NAD+.

In conclusion, clinical profiling revealed an association between trigonelline and human muscle health. The preclinical experiments showed that trigonelline is an NAD+ precursor that optimizes mitochondrial function to improve muscle strength and prevent fatigue during aging.

"Therefore, trigonelline is a nutritional geroprotector with therapeutic potential to manage sarcopenia and other age-related pathologies," the researchers wrote.

Reference:

Membrez, M., Migliavacca, E., Christen, S., Yaku, K., Trieu, J., Lee, A. K., Morandini, F., Giner, M. P., Stiner, J., Makarov, M. V., Garratt, E. S., Vasiloglou, M. F., Chanvillard, L., Dalbram, E., Ehrlich, A. M., Luis, J., Canto, C., Karagounis, L. G., Treebak, J. T., . . . Feige, J. N. (2024). Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature Metabolism, 6(3), 433-447. https://doi.org/10.1038/s42255-024-00997-x