Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia

• DOI: 10.1038/s42255-024-00997-x
• Publication Date: 2024-03-19T11:02:05Z
• Authors: Mathieu Membrez; Eugenia Migliavacca; Stefan Christen; Keisuke Yaku; Jennifer Trieu; Alaina K. Lee; Francesco Morandini; Maria Pilar Giner; Jade Stiner; Mikhail V. Makarov; Emma S. Garratt; Maria F. Vasiloglou; Lucie Chanvillard; Emilie Dalbram; Amy M. Ehrlich; José Luis Sanchez...; Carles Canto; Leonidas G. Karag...; Jonas T. Treebak; Marie E. Migaud; Ramin Heshmat; Farideh Razi; Neerja Karnani; Afshin Ostovar; Farshad Farzadfar; Stacey K. H. Tay; Matthew J. Sanders; Karen A. Lillycrop; Keith M. Godfrey; Takashi Nakagawa; Sofia Moco; René Koopman; Gordon S. Lynch; Vincenzo Sorrentino; Jerome N. Feige
• Keywords: Trigonelline; Nicotinamide phosphoribosyltransferase; Sirtuin 1; SIRT3

Abstract Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD + ) levels are hallmarks of skeletal muscle ageing sarcopenia 1–3 , but it is unclear whether these defects result from local changes or can be mediated by systemic dietary cues. Here we report a functional link between circulating the natural alkaloid trigonelline, which structurally related to nicotinic acid 4 NAD health in multiple species. In humans, serum trigonelline reduced with correlate positively strength mitochondrial oxidative phosphorylation muscle. Using naturally occurring isotopically labelled demonstrate that incorporates into pool increases Caenorhabditis elegans mice primary myotubes healthy individuals sarcopenia. Mechanistically, does not activate GPR109A metabolized via nicotinate phosphoribosyltransferase/Preiss–Handler pathway 5,6 across models. C. improves respiration biogenesis, reduces age-related wasting lifespan mobility through an -dependent mechanism requiring sirtuin. Dietary supplementation male enhances prevents fatigue during ageing. Collectively, identify nutritional as -boosting strategy therapeutic potential for age-associated decline.