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

Abstract

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle aging and sarcopenia1-3, but it remains unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we reporta functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ 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-occuring and isotopically-labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool, and increases NAD+ levels in C. elegans, mice and primary myotubes from healthy and sarcopenic humans. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the NAPRT/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during aging. Collectively, we identify nutritional supplementation of trigonelline as a novel NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

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Identifiers

ORCID for Emma S. Garratt: orcid.org/0000-0001-5268-4203

ORCID for Karen A. Lillycrop: orcid.org/0000-0001-7350-5489

ORCID for Keith M. Godfrey: orcid.org/0000-0002-4643-0618

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