Trigonelline: A Coffee Compound Linked to Stronger Muscles and Healthy Aging
Skeletal muscle aging and sarcopenia are marked by significant functional decline, impairing mobility and independence due to myofibre wasting, and a confluence of molecular and cellular hallmarks of aging. Among these, mitochondrial dysfunction and reduced nicotinamide adenine dinucleotide (NAD +) levels are prominent features. The precise source of these defects, whether localized or systemically driven, is still unknown. However, recent studies highlight a crucial link between circulating levels of the natural alkaloid trigonelline, NAD+ homeostasis, and muscle health across diverse species (Membrez et al, 2024). This advancing understanding highlights trigonelline as a potential dietary approach with therapeutic value in addressing muscle loss linked to aging.
Trigonelline is readily found in various dietary sources, with coffee beans being one of the richest, comprising about 1% of the dry weight of green coffee beans. Fenugreek seeds are another significant source. Other foods like yellow bell peppers, oranges, chickpeas, bananas, and Brussels sprouts also contain trigonelline. Its presence in human plasma increases with coffee consumption, indicating its bioavailability.
Trigonelline as a Biomarker for Sarcopenia and Mitochondrial Health
The Multi-Ethnic Molecular determinants of the Sarcopenia (MEMOSA) study, which has extensively profiled human sarcopenia, identified a significant reduction in serum trigonelline levels in sarcopenic individuals compared to healthy controls (Membrez et al, 2024). This observation is particularly salient given the positive correlation between trigonelline levels and key clinical indicators of sarcopenia, such as Appendicular Lean Mass Index (ALMI), grip strength, and gait speed. Furthermore, serum trigonelline levels exhibit a strong positive association with NAD+ levels in skeletal muscle and with mitochondrial oxidative phosphorylation, a critical metabolic pathway, as revealed by gene set enrichment analysis. An independent replication study within the Bushehr elderly health cohort further substantiated this association between serum trigonelline and muscle function. Interestingly, dietary records suggest that these circulating trigonelline levels are independent of caffeine and vitamin B3 (aka Niacin) intake, potentially linking to other dietary factors like folate and fiber. This comprehensive profiling underscores trigonelline's emergence as a novel circulating metabolite directly linked to muscle function, mitochondrial metabolism, and NAD+ status, offering a potential biomarker for sarcopenia. Its reduced levels in sarcopenia and positive correlation with muscle strength and mitochondrial oxidative phosphorylation further solidify its role in muscle function (Membrez et al, 2024).
Mechanistic Insights into Trigonelline's NAD+-Boosting Activity
Trigonelline, structurally akin to nicotinic acid (NA), is an N-methylated derivative synthesized by various plants. It is produced through endogenous metabolism and the gut microbiome in humans. Its capacity to function as an NAD+ precursor and its direct impact on NAD+, mitochondrial homeostasis, and muscle homeostasis have been rigorously examined. In primary human skeletal muscle myotubes (HSMMs), trigonelline treatment effectively increased NAD+ levels, even rescuing NAD+ deficiency induced by the NAMPT inhibitor FK866, which mimics the low NAD+ environment found in sarcopenic muscle. While other NAD+ precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) demonstrated a roughly twofold increase in NAD+ levels, trigonelline, alongside nicotinamide (NAM), achieved approximately a 50% increase (Perchat et al, 2018).
A critical mechanistic insight is that trigonelline is metabolized via the nicotinate phosphoribosyl transferase (NAPRT)-dependent Preiss-Handler pathway. This is evidenced by its inability to raise NAD+ levels in HepG2 and C2C12 cells, which have low NAPRT expression, and by the blocking effect of NAPRT knockdown or inhibition on trigonelline-mediated NAD+ generation. Furthermore, isotopically labeled trigonelline studies confirmed its direct incorporation into the NAD+ molecule in cells and multiple tissues, necessitating the loss of its deuterated methyl group. In fact, administration of labeled trigonelline in mice led to high bioavailability and increased NAD+ content in the liver, gastrocnemius muscle, kidney, and whole blood.
Trigonelline does not activate GPR109A, a receptor associated with the skin flushing side effect of NA, suggesting a potentially more favorable therapeutic profile (Perchat et al, 2018).
The degradation pathway of trigonelline has been further elucidated in bacteria like Acinetobacter baylyi ADP1. This organism can utilize trigonelline as its sole source of carbon, nitrogen, and energy, relying on a specific gene cluster (tgn). This catabolic pathway involves a series of enzymatic steps, where trigonelline is first oxygenized to (Z)-2-((N-methyl formamido) methylene)-5-hydroxy-butyrolactone (MFMB) by the two-component, flavin-dependent oxygenase TgnAB. MFMB is then oxidized into (E)-2-((N-methylformamido) methylene) succinate (MFMS) by the MFMB dehydrogenase TgnC, and subsequently hydrolyzed into carbon dioxide, formate, methylamine, and succinate semialdehyde (SSA) by the MFMS hydrolase TgnD. Finally, SSA is oxidized to succinate by TgnE, an SSA dehydrogenase, whose activity is stimulated by TgnF. This bacterial pathway provides insight into the diverse metabolic transformations trigonelline can undergo in different biological contexts, though the mammalian NAD+ boosting mechanism is distinct (Perchat et al, 2018).
Notably, trigonelline exhibits remarkable stability in serum, lasting over 72 hours, a significant advantage over NR and NMN, which are rapidly converted to NAM. This stability contributes to its sustained effect on NAD+ levels. Endogenous trigonelline levels also appear to increase in cells treated with NAPRT inhibitor 2-OHNA in the absence of exogenous trigonelline, suggesting an inherent flux of trigonelline through NAPRT in muscle cells (Perchat et al, 2018).
Methylation Considerations with NAD⁺ Precursors
While compounds such as NMN and NR are effective at raising NAD⁺ levels, their metabolism can place a burden on the cellular methylation cycle. When NR or NMN are catabolized to nicotinamide (NAM), excess NAM is cleared through methylation by nicotinamide N-methyltransferase (NNMT), which consumes methyl groups derived from S-adenosylmethionine (SAM). This increased demand may deplete methyl donors and reduce the availability of homocysteine-remethylating cofactors. Supplementing with trimethyl glycine (TMG, betaine) provides an efficient methyl donor that helps maintain methylation balance, supports homocysteine metabolism, and offsets potential depletion caused by chronic NAD⁺ precursor use (Ulanovskaya et. al., 2013; Trammell et al., 2016).
Additionally, trigonelline appears to bypass this methylation burden, as it engages the NAPRT-dependent Preiss-Handler pathway rather than relying on NAM clearance. This distinction may give trigonelline a metabolic advantage over NMN and NR by supporting NAD⁺ homeostasis without taxing the methylation cycle, further highlighting its therapeutic promise in aging muscle health.
Functional Benefits of Trigonelline on Muscle Health and Longevity
The physiological relevance of trigonelline's NAD+-boosting and mitochondrial-enhancing effects has been demonstrated across multiple models. In Caenorhabditis elegans, trigonelline supplementation significantly extended lifespan, improved mitochondrial respiration and biogenesis, and reduced age-related muscle wasting, thereby increasing mobility (Perchat et al, 2018). These benefits were contingent on an NAD+-dependent mechanism requiring sirtuin, as knockdown of the worm orthologues nprt-1 or sir-2.1 abolished these effects (Membrez et al, 2024). Even with later-life supplementation, worms maintained better mobility than controls, indicating benefits on health span.
Translating these findings to mammals, dietary trigonelline supplementation in aged male mice enhanced muscle strength and prevented fatigue during aging. A 5-day treatment regimen in aged mice increased the expression and activity of mitochondrial oxidative phosphorylation complexes I and II in skeletal muscle, indicating improved mitochondrial function without altering mitochondrial abundance. Chronic 12-week supplementation also increased grip strength and normalized age-related declines in spontaneous activity, highlighting its impact on both forelimb and hindlimb muscles. While trigonelline did not influence muscle mass or maximal tetanic force in all contexts, it notably attenuated the age-related decline in muscle force during high-intensity contractions, thereby improving resistance to fatigue. These functional improvements were not linked to structural adaptations such as myofibre cross-sectional area or fibrosis, but rather to enhanced mitochondrial respiratory activity.
Conclusion
The collective evidence strongly supports trigonelline as a potent nutritional geroprotector with significant therapeutic potential for managing sarcopenia and other age-related pathologies. Its role as an NAD+ precursor that specifically optimizes mitochondrial function to enhance muscle strength and prevent fatigue during aging is now well-established. The decline of circulating trigonelline in human sarcopenia, coupled with its ability to boost NAD+ levels and rescue mitochondrial dysfunction in both healthy and sarcopenic muscle cells, positions it as a promising intervention. While trigonelline primarily engages the Preiss–Handler pathway, its high bioavailability, serum stability, and lack of GPR109A activation provide a favorable therapeutic profile compared to other NAD+ precursors. These findings expand the understanding of NAD+ metabolism and increase the potential for interventions with NAD+-producing vitamins for both healthy longevity and age-associated diseases (3). As sarcopenia is a multifactorial condition, future strategies may involve combining trigonelline with other nutrients that support muscle mass, such as protein, vitamin D, or omega-3 fatty acids, to provide a holistic approach to nutritional management. Further research is warranted to fully elucidate the mechanisms of trigonelline demethylation and to explore its broader translational applications, including its potential neurocognitive benefits and its role in protecting against metabolic dysfunction.
About The Author
Dr. Tien Bui is the founder and pioneering biohacker behind a cutting-edge approach to mental wellness, cognitive enhancement, and human peak performance. His work blends scientific rigor with personal optimization strategies to extend healthspan, enhance cognition, and defy biological limits.
References:
1. Membrez M, Migliavacca E, Christen S, et al. Trigonelline is an NAD+ precursor that improves muscle function during aging and is reduced in human sarcopenia. Nat Metab. 2024;6(3):433-447.
2. Perchat N, Saaidi PL, Darii E, et al. Elucidation of the trigonelline degradation pathway reveals previously undescribed enzymes and metabolites. Proc Natl Acad Sci U S A. 2018;115(19): E4358-E4367.
3. National University of Singapore, Yong Loo Lin School of Medicine Mar 22 2024. (2024). Natural molecule trigonelline can help to improve muscle health and ... https://www.news-medical.net/news/20240322/Natural-molecule-trigonelline-can-help-to-improve-muscle-health-and-function.aspx
4. Ulanovskaya OA, Zuhl AM, Cravatt BF. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat Chem Biol. 2013; 9(5):300-306.
5. Trammell SAJ, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, Migaud ME, Brenner C. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016; 7:12948.