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

Abstract

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