Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD⁺) levels are hallmarks of skeletal muscle ageing and sarcopenia^1,2,3, 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 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 occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD⁺ pool and increases NAD⁺ levels in Caenorhabditis elegans, 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^5,6 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 ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD⁺-boosting strategy with therapeutic potential for age-associated muscle decline.

线粒体功能障碍和低烟酰胺腺嘌呤二核苷酸 (NAD ⁺ ) 水平是骨骼肌衰老和肌肉减少症的标志^1,2,3，但尚不清楚这些缺陷是由局部变化引起还是由全身或饮食因素介导。在这里，我们报告了天然生物碱葫芦巴碱循环水平之间的功能联系，其在结构上与多个物种的烟酸⁴、NAD ^{+水平和肌肉健康有关。}在人类中，血清葫芦巴碱水平随肌肉减少症而降低，并与骨骼肌中的肌肉力量和线粒体氧化磷酸化呈正相关。使用天然存在的同位素标记的葫芦巴碱，我们证明葫芦巴碱融入 NAD ⁺池中，并增加秀丽隐杆线虫、小鼠和来自健康个体和肌少症个体的原代肌管的NAD ⁺水平。从机制上讲，葫芦巴碱不会激活 GPR109A，而是通过烟酸磷酸核糖基转移酶/Preiss–Handler 通路^5,6在模型中进行代谢。在秀丽隐杆线虫中，葫芦巴碱通过需要 Sirtuin 的 NAD ⁺依赖性机制改善线粒体呼吸和生物合成，减少与年龄相关的肌肉消耗并延长寿命和活动能力。雄性小鼠的膳食补充剂可以增强肌肉力量并防止衰老过程中的疲劳。总的来说，我们将葫芦巴碱的营养补充确定为一种 NAD ⁺增强策略，具有治疗与年龄相关的肌肉衰退的潜力。