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

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, 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 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 ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

NAD+ Metabolism and Interventions in Premature Renal Aging and Chronic Kidney Disease.

Premature aging causes morphological and functional changes in the kidney, leading to chronic kidney disease (CKD). CKD is a global public health issue with far-reaching consequences, including cardio-vascular complications, increased frailty, shortened lifespan and a heightened risk of kidney failure. Dialysis or transplantation are lifesaving therapies, but they can also be debilitating. Currently, no cure is available for CKD, despite ongoing efforts to identify clinical biomarkers of premature renal aging and molecular pathways of disease progression. Kidney proximal tubular epithelial cells (PTECs) have high energy demand, and disruption of their energy homeostasis has been linked to the progression of kidney disease. Consequently, metabolic reprogramming of PTECs is gaining interest as a therapeutic tool. Preclinical and clinical evidence is emerging that NAD+ homeostasis, crucial for PTECs' oxidative metabolism, is impaired in CKD, and administration of dietary NAD+ precursors could have a prophylactic role against age-related kidney disease. This review describes the biology of NAD+ in the kidney, including its precursors and cellular roles, and discusses the importance of NAD+ homeostasis for renal health. Furthermore, we provide a comprehensive summary of preclinical and clinical studies aimed at increasing NAD+ levels in premature renal aging and CKD.