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Cited by 148Sirtuins and Resveratrol in MedicineNutrition and Health in AgingMuscle Physiology and Disorders

Trigonelline Is an NAD+ Precursor That Improves Muscle Function during Ageing and Is Reduced in Human Sarcopenia

Open access
Membrez, Mathieu, Migliavacca, Eugenia, Christen, Stefan, Yaku, Keisuke, Trieu, Jennifer, Lee, Alaina K., Morandini, Francesco, Giner, Maria Pilar +27 more·2024·Nature Metabolism
DOI 10.1038/s42255-024-00997-xPMC PMC10963276
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Abstract

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD + ) levels are hallmarks of skeletal muscle ageing and sarcopenia 1–3 , 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 acid 4 , 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.

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Written from the paper’s full text.

TL;DR

Trigonelline, a natural alkaloid related to nicotinic acid, is identified as an NAD+ precursor that boosts NAD+ via the NAPRT/Preiss–Handler pathway and improves mitochondrial and muscle function during ageing across human, mouse and C. elegans models. Serum trigonelline is reduced in human sarcopenia and correlates with muscle strength, mitochondrial oxidative phosphorylation and muscle NAD+.

Key findings

  • In the MEMOSA Singapore Sarcopenia Study, serum trigonelline was lower in individuals with sarcopenia than in healthy controls (n = 20 per group) and correlated positively with ALMI, grip strength and gait speed; it was also associated with skeletal muscle NAD+ and mitochondrial oxidative phosphorylation, with replication in the Bushehr elderly health cohort.
  • Trigonelline increased NAD+ in human skeletal muscle myotubes (EC50 = 315 µM in control cells; EC50 = 110 µM in FK866-treated cells), in primary myotubes from healthy donors and donors with sarcopenia, in aged mouse myotubes, in C. elegans and in mouse tissues; isotopically labelled trigonelline was directly incorporated into NAD+ as M + 1 NAD+.
  • Trigonelline required NAPRT/Preiss–Handler pathway activity: NAPRT knockdown or 2-OHNA blocked trigonelline-driven NAD+ increases and mitochondrial rescue, whereas NR still worked; trigonelline did not activate GPR109A up to 1 mM, while nicotinic acid had an EC50 = 2.5 µM.
  • In C. elegans, trigonelline extended lifespan, improved mobility, reduced paralysis and improved myofibre integrity through nprt-1 and sir-2.1; in aged mice, 12-week dietary trigonelline increased grip strength and prevented approximately 50% of age-related fatigue decline without changing muscle mass or maximal tetanic force.

Methods

  • Human studies included the MEMOSA Singapore Sarcopenia Study (20 Chinese men aged 65–79 years with sarcopenia and 20 age-matched healthy controls), the Bushehr elderly health cohort (186 older men aged ≥60 years) and the Hertfordshire Sarcopenia Study Extension for primary myotubes; serum metabolites were measured by LC–MS/MS, muscle RNA-seq was used for pathway enrichment, and muscle mass/function were assessed by DXA, grip strength and gait speed.
  • Cell and animal experiments used human skeletal muscle myotubes, primary human and mouse myotubes, HepG2, C2C12 and PTEC cells; NAPRT shRNA, FK866 and 2-OHNA treatments; isotopically labelled trigonelline; C. elegans N2 and RNAi strains; and aged C57BL/6JRj mice given acute or chronic trigonelline at 300 mg kg−1 per day, with Seahorse respirometry, LC–HRMS metabolomics, qPCR, immunoblot, histology and in situ muscle contractility.
  • Statistical analyses used two-tailed unpaired Student’s t-tests, one-way or two-way ANOVA with post hoc tests, log-rank tests for lifespan, and Spearman correlations, with data expressed as mean ± s.e.m.

Limitations

  • The paper states that no trigonelline demethylase is known, that the SHMT2 correlation requires further exploration, that trigonelline cannot reverse all causes of sarcopenia and should be combined with other nutrients such as protein, vitamin D or omega-3 fatty acids, and that preclinical muscle function tests do not always translate to human performance.
  • The paper also notes heterogeneity and complexity in systemic NAD+ metabolism and calls for future comparative studies with different precursors in specific models and in humans.
  • Evident from the text: the human sarcopenia association is cross-sectional and cannot establish causality; the main MEMOSA serum analysis is small (n = 20 per group) and restricted to Chinese male participants; the mouse supplementation studies used male mice; and chronic trigonelline exposure flattened muscle NAD+ and oxidative phosphorylation protein effects compared with acute exposure, suggesting long-term physiological compensation.

Model-written summary. Check it against the paper before relying on it.

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Registry

Crossref · 10.1038/s42255-024-00997-x

Cites

88 of 88 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 42 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Serum trigonelline levels are independent of dietary caffeine and vitamin B3 intake in the Bushehr cohort.

    “Dietary records indicate that serum trigonelline levels are independent of dietary caffeine and vitamin B3 intake in this cohort, but possibly linked to other dietary factors, such as folate and fibre intake (Extended Data Fig. 1c and Extended Data Table 3).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Trigonelline increased NAD+ levels in primary myotubes derived from aged mice.

    “Similarly, trigonelline also increased NAD+ levels in primary myotubes derived from aged mice (Fig. 1h).”
    Quote in the paperSubstantial claim
  • Findingown data

    Dietary trigonelline supplementation in male mice prevents fatigue during ageing.

    “Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing.”
    Quote in the paperSubstantial claim
  • Findingown data

    SHMT2 had the strongest association with serum trigonelline among genes with demethylating or methyltransferase activity in human sarcopenic muscle.

    “SHMT2, which is involved in mitochondrial one-carbon metabolism, had the strongest association with serum trigonelline (Extended Data Fig. 1k)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Serum trigonelline levels correlate positively with gait speed in humans.

    “Trigonelline levels were positively correlated with muscle mass assessed via Appendicular Lean Mass Index (ALMI) measured using dual-energy X-ray absorptiometry (DXA), grip strength and gait speed, all parameters used in the clinical definition of sarcopenia3,9 (Fig. 1b).”
    Quote in the paperSubstantial claim
  • May combine two claims. 54
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data

    In C. elegans, trigonelline improves mitochondrial respiration and biogenesis.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Trigonelline fully rescued NAD+ deficiency in FK866-treated HSMMs with an EC50 of 110 μM.

    “fully rescued NAD+ deficiency in FK866-treated cells (EC50 = 110 µM) (Fig. 1f)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treating primary myotubes from donors with sarcopenia and aged-matched healthy controls with trigonelline raised cellular NAD+ with comparable efficiency between groups.

    “Treating primary myotubes from different donors with sarcopenia and aged-matched healthy controls35 raised cellular NAD+ (Fig. 1g) with comparable efficiency between groups (Extended Data Fig. 1j).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Patel, H. P. et al. Hertfordshire sarcopenia study: design and methods. BMC Geriatr. 10, 43 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In primary human muscle cells, trigonelline and NAM induced NAD+ by approximately 50%, while NR and NMN increased NAD+ levels approximately twofold.

    “When compared to other NAD+ precursors in primary human muscle cells, trigonelline and the salvage precursor NAM induced NAD+ by approximately 50% while the NRK pathway precursors NR and NMN33 increased NAD+ levels approximately twofold (Extended Data Fig. 1f).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Bogan, K. L. & Brenner, C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr. 28, 115–130 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    All NAD+ precursors had similar efficacy in renal proximal tubular epithelial cells (PTECs).

    “while all precursors had similar efficacy in renal proximal tubular epithelial cells (PTECs) (Extended Data Fig. 1h).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Labelled trigonelline was largely cleared after an overnight wash-out in mice.

    “and were largely cleared after an overnight wash-out (Extended Data Fig. 2a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After trigonelline gavage, Nampt and Nrk1 expression was downregulated in the liver, while Nrk1 and Nrk2 were upregulated in muscle in both treatment groups.

    “After trigonelline gavage, Nampt and Nrk1 expression was downregulated in the liver, while Nrk1 and Nrk2 were upregulated in muscle in both treatment groups (Extended Data Fig. 2o).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Acute dosing of trigonelline in WT and Naprt KO mice equally increased trigonelline in tissues, distal NAD+ metabolite fluxes in liver and blood, and tissue NAD+ levels.

    “Acute dosing of trigonelline in wild-type (WT) and Naprt KO mice40 (Fig. 2k and Extended Data Fig. 2j) equally increased trigonelline in tissues (Extended Data Fig. 2k), distal NAD+ metabolite fluxes in the liver and blood (Extended Data Fig. 2l,m) and tissue NAD+ levels (Extended Data Fig. 2l–n).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Yaku, K. et al. BST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities. Nat. Commun. 12, 6767 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In Naprt KO mice treated with trigonelline, NA accumulated in the blood and liver, while NAMN was strongly downregulated.

    “However, in Naprt KO mice treated with trigonelline, NA accumulated in the blood and liver (Fig. 2l), while NAMN was strongly downregulated (Fig. 2m)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    2-OHNA blocks increased NAD+ after trigonelline treatment without affecting cellular trigonelline levels.

    “LC–HRMS analysis also confirmed that 2-OHNA blocks increased NAD+ after trigonelline treatment (Fig. 2g), without affecting cellular trigonelline levels in the treated groups (Extended Data Fig. 2h).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Administration of isotopically labelled trigonelline in mice was highly bioavailable with high levels of parent trigonelline detected in liver, gastrocnemius muscle, kidney, blood and urine 2 h after oral intake.

    “Administration of isotopically labelled trigonelline in mice was highly bioavailable with high levels of the parent trigonelline molecule detected in the liver, gastrocnemius muscle, kidney, blood and urine 2 h after oral intake”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After trigonelline treatment, Preiss-Handler pathway metabolites NAAD and NAMN downstream of NAPRT were increased and blocked by NAPRT inhibition with 2-OHNA.

    “After trigonelline treatment, the Preiss–Handler pathway-related metabolites nicotinic acid adenine dinucleotide (NAAD) and NAMN downstream of NAPRT6,33 were increased and blocked by NAPRT inhibition with 2-OHNA (Fig. 2h,i)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Ruggieri, S., Orsomando, G., Sorci, L. & Raffaelli, N. Regulation of NAD biosynthetic enzymes modulates NAD-sensing processes to shape mammalian cell physiology under varying biological cues. Biochim. Biophys. Acta 1854, 1138–1149 (2015). source

      Not checked in the free run.

    • cites [33] Bogan, K. L. & Brenner, C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr. 28, 115–130 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Trigonelline boosted NAD+ in HSMMs where low NAD+ was modelled with FK866 for 72 h, and this effect was blocked by NAPRT inhibition with 2-OHNA.

    “Like the 24-h treatment (Extended Data Fig. 2g), trigonelline boosted NAD+ and this effect was blocked by NAPRT inhibition with 2-OHNA (Fig. 2o)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    2-OHNA abolished the effects of trigonelline but not NR on mitochondrial membrane potential in HSMMs.

    “while 2-OHNA abolished the effects of trigonelline but not NR (Fig. 2p).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Various levels of cellular NAD+ depletion by blocking NAD+ salvage with FK866 for 24 h were rescued by trigonelline, but not when co-treating with 2-OHNA.

    “Conversely, various levels of cellular NAD+ depletion by blocking NAD+ salvage with FK866 for 24 h were rescued by trigonelline (Fig. 1f and Extended Data Fig. 2f), but not when co-treating with 2-OHNA (Extended Data Fig. 2g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Trigonelline activated the expression of genes linked to mitochondrial respiration and proteostasis in C. elegans, similar to NR.

    “activated the expression of genes linked to mitochondrial respiration and proteostasis (Fig. 3e), similar to NR (Extended Data Fig. 3c and14,43)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Trigonelline raised NAD+ levels in aged nematodes; its NAD+-boosting effects were comparable to NA and NAM, and partially lower than NR and NMN.

    “trigonelline raised NAD+ levels in aged nematodes (Fig. 3c); its NAD+-boosting effects were comparable to NA and NAM, and partially lower than NR and NMN (Extended Data Fig. 3b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Trigonelline significantly extended lifespan in C. elegans, with comparable effects to equimolar NR.

    “Trigonelline significantly extended the lifespan, with comparable effects to equimolar levels of NR (Fig. 3b and Extended Data Fig. 3a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Knockdown of nprt-1 or sir-2.1 both blunted the lifespan-extending effects and mobility benefits of trigonelline in C. elegans.

    “Knockdown of nprt-1 or sir-2.1 (Extended Data Fig. 3j), the predominant sirtuin in N2 worms (Extended Data Fig. 3k), both blunted the lifespan-extending effects and mobility benefits of trigonelline (Fig. 3l–n)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    NR was still able to bypass NAPRT inhibition and increase respiration in HSMMs.

    “In contrast, NR was still able to bypass NAPRT inhibition and increase respiration (Fig. 2q).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Trigonelline rescued the decrease in maximal mitochondrial respiration caused by FK866, but this rescue was blocked when trigonelline was co-treated with 2-OHNA.

    “which was also rescued by trigonelline but blocked when trigonelline was co-treated with 2-OHNA (Fig. 2q).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Respirometry with mitochondrial complex inhibitors revealed higher levels of complex II-driven and complex IV-driven respiration in trigonelline-treated cells, dependent on NAPRT.

    “Finally, respirometry performed with mitochondrial complex inhibitors revealed higher levels of complex II-driven and complex IV-driven respiration in trigonelline-treated cells, again dependent on NAPRT (Extended Data Fig. 2q).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Body composition was not impacted by trigonelline treatment, with no changes in lean and fat mass distribution in trigonelline-treated mice.

    “Body composition was not impacted by the treatment, with no changes in lean and fat mass distribution in trigonelline-treated mice (Fig. 4g and Extended Data Fig. 4e)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Trigonelline treatment in aged mice increased different domains of muscle performance that mobilize both leg and arm muscles by improving both muscle fatigue and grip strength.

    “Trigonelline treatment in aged mice increased different domains of muscle performance that mobilize both leg and arm muscles by improving both muscle fatigue and grip strength”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Trigonelline is metabolized via the Preiss-Handler pathway and requires NAPRT to boost NAD+, stimulate mitochondrial metabolism and increase mobility and lifespan during ageing.

    “we showed that trigonelline is metabolized via the Preiss–Handler pathway and requires NAPRT to boost NAD+, stimulate mitochondrial metabolism and increase mobility and lifespan during ageing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In a Middle Eastern population, circulating trigonelline was not associated with dietary caffeine intake, possibly because coffee consumption is low in this population.

    “our correlation analyses did not detect an association between circulating trigonelline and dietary caffeine intake levels in a population from the Middle East, possibly because coffee consumption is low in this population.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Dietary intake of folate and fibre was linked to circulating trigonelline levels.

    “the dietary intake of folate and fibre was linked to circulating trigonelline levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Trigonelline has similar cellular and physiological benefits to NA and NR in cells or nematodes, most probably because of its higher stability than ribosylated precursors.

    “our comparative studies demonstrate that trigonelline has similar cellular and physiological benefits to NA and NR in cells or nematodes, most probably because of its higher stability than ribosylated precursors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Trigonelline is a natural alkaloid found in plants and animals, including humans.

    “However, patients with sarcopenia had lower circulating concentrations of trigonelline, a natural alkaloid found in plants4 and animals, including in humans29,30 (Fig. 1a).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Ashihara, H. et al. Trigonelline and related nicotinic acid metabolites: occurrence, biosynthesis, taxonomic considerations, and their roles in planta and in human health. Phytochem. Rev. 14, 765–798 (2015). source

      Not checked in the free run.

    • cites [29] Barton, W. et al. The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. Gut 67, 625–633 (2018).

      Not checked in the free run.

    • cites [30] Calvani, R. et al. Gut microbiome-derived metabolites characterize a peculiar obese urinary metabotype. Int. J. Obes. 34, 1095–1098 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Nutritional supplementation of trigonelline is an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

    “Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The effects of trigonelline on muscle ageing observed in C. elegans and mice are predictive of therapeutic benefit in humans.

  • May combine two claims.

    Premisecitation

    Mitochondrial dysfunction and low NAD+ levels are hallmarks of skeletal muscle ageing and sarcopenia.

    “Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1–3”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Gomes, A. P. et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013). source

      Not checked in the free run.

    • cites [2] Janssens, G. E. et al. Healthy aging and muscle function are positively associated with NAD+ abundance in humans. Nat. Aging 2, 254–263 (2022). source

      Not checked in the free run.

    • cites [3] Migliavacca, E. et al. Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities. Nat. Commun. 10, 5808 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Trigonelline is metabolized through the Preiss-Handler pathway via NAPRT and promotes NAD+ biosynthesis via both direct and indirect mechanisms.

    “Altogether, our in vitro and in vivo results indicate that trigonelline is metabolized through the Preiss–Handler pathway via NAPRT and promotes NAD+ biosynthesis via both direct and indirect mechanisms.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Trigonelline is a bona fide NAD+ precursor that is directly incorporated in NAD+ in cells and multiple tissues.

    “Altogether, these results demonstrate that trigonelline is a bona fide NAD+ precursor that is directly incorporated in NAD+ in cells and multiple tissues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Trigonelline engages the Preiss-Handler pathway during first-pass metabolism and secondary compensations through the NR-NMN-NRK pathway also contribute to NAD+ in Naprt KOs.

    “This suggests that trigonelline engages the Preiss–Handler pathway during first-pass metabolism and that secondary compensations through the NR–NMN–NRK pathway also contribute to NAD+ in Naprt KOs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationown data

    Hepatic incorporation of labelled trigonelline was faster, probably because of a first-pass effect.

    “with hepatic incorporation being faster probably because of a first-pass effect (Extended Data Fig. 2c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    SHMT2 is unlikely to directly demethylate trigonelline because it is not a N-methyltransferase and is known to cross-talk with NAD+ metabolism indirectly.

    “SHMT2 is unlikely to directly demethylate trigonelline because it is not a N-methyltransferase and is known to cross-talk with NAD+ metabolism indirectly37,38.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Ye, J. et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 4, 1406–1417 (2014). source

      Not checked in the free run.

    • cites [38] Zhang, Y. et al. SHMT2 promotes cell viability and inhibits ROS-dependent, mitochondrial-mediated apoptosis via the intrinsic signaling pathway in bladder cancer cells. Cancer Gene Ther. 29, 1514–1527 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Trigonelline increased NAD+ levels after sir-2.1 knockdown because sirtuins act as NAD+ sensors downstream of NAD+ biosynthesis and sir-2.1 knockdown did not change baseline NAD+ levels.

    “As expected, trigonelline increased NAD+ levels after sir-2.1 knockdown because sirtuins act as NAD+ sensors downstream of NAD+ biosynthesis and sir-2.1 knockdown did not change baseline NAD+ levels (Extended Data Fig. 3l).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    In chronic versus acute exposure, proteins (Fig. 4b,d and Extended Data Fig. 4p) were flattened, probably because of long-term physiological compensation as observed in clinical studies in muscle with dietary administration of other NAD+ precursors.

    “proteins (Fig. 4b,d and Extended Data Fig. 4p) were flattened in chronic versus acute exposure, probably because of long-term physiological compensation as observed in clinical studies in muscle with dietary administration of other NAD+ precursors46,47.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Elhassan, Y. S. et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 28, 1717–1728 (2019). source

      Not checked in the free run.

    • cites [47] Yoshino, M. et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372, 1224–1229 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Mitochondrial dysfunction and reduced NAD+ are prominent features of pathological progression and sarcopenia, as revealed by previous profiling of muscle biopsies from patients with sarcopenia versus age-matched healthy controls.

    “Our previous profiling of muscle biopsies from patients with sarcopenia versus age-matched healthy controls revealed that mitochondrial dysfunction and reduced NAD+, two well-established molecular hallmarks of organismal ageing11, are prominent features of pathological progression and sarcopenia3.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Migliavacca, E. et al. Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities. Nat. Commun. 10, 5808 (2019). source

      Not checked in the free run.

    • cites [11] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Its synthesis from NA via methylation confers protective and adaptive functions, without an established reutilization as a Preiss-Handler substrate.

    “Its synthesis from NA via methylation confers protective and adaptive functions4,48, without an established reutilization as a Preiss–Handler substrate49,50.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [4] Ashihara, H. et al. Trigonelline and related nicotinic acid metabolites: occurrence, biosynthesis, taxonomic considerations, and their roles in planta and in human health. Phytochem. Rev. 14, 765–798 (2015). source

      Not checked in the free run.

    • cites [48] Ashihara, H., Ludwig, I.A. and Crozier, A. Physiological aspect and biotechnology of trigonelline. In Plant Nucleotide Metabolism: Biosynthesis, Degradation, and Alkaloid Formation (eds Ashihara, H., Ludwig, I. A. and Crozier, A.) 351–365 (John Wiley & Sons, 2020). source

      Not checked in the free run.

    • cites [49] Li, W. et al. A Novel N-methyltransferase in Arabidopsis appears to feed a conserved pathway for nicotinate detoxification among land plants and is associated with lignin biosynthesis. Plant Physiol. 174, 1492–1504 (2017). source

      Not checked in the free run.

    • cites [50] Wu, R. et al. MeNA, controlled by reversible methylation of nicotinate, is an NAD precursor that undergoes long-distance transport in Arabidopsis. Mol. Plant 11, 1264–1277 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Chronic trigonelline administration mitigates muscle decline during ageing by stimulating mitochondria and increasing muscle performance and resistance to fatigue during high-intensity contraction.

    “chronic trigonelline administration mitigates muscle decline during ageing by stimulating mitochondria and increasing muscle performance and resistance to fatigue during high-intensity contraction.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The lack of effect of trigonelline on maximum tetanic force is probably because tetanic force relies on muscle mass and neuromuscular coupling, both of which were not affected by trigonelline.

    “probably because tetanic force relies on muscle mass and neuromuscular coupling, both of which were not affected by trigonelline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Trigonelline functionally rescues NAD+ deficiency and requires NAPRT and a functional Preiss-Handler pathway for physiological activity on mitochondrial bioenergetics.

    “Collectively, these results demonstrate that trigonelline functionally rescues NAD+ deficiency and confirm that trigonelline requires NAPRT and a functional Preiss–Handler pathway for physiological activity on mitochondrial bioenergetics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The physiological requirement of the Preiss-Handler pathway for longevity, mitochondrial and functional benefits of trigonelline in vivo is validated, and the observed benefits on ageing and health span require the NAD+-dependent sirtuin deacetylase.

    “Together, these results validate the physiological requirement of the Preiss–Handler pathway for longevity, mitochondrial and functional benefits of trigonelline in an in vivo model, and demonstrate that the observed benefits on ageing and health span require the NAD+-dependent sirtuin deacetylase.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Trigonelline is particularly abundant in plant-derived food products, such as coffee beans and fenugreek seeds, which have been reported to modulate endogenous trigonelline levels in humans.

    “trigonelline is particularly abundant in plant-derived food products, such as coffee beans and fenugreek seeds, which have been reported to modulate endogenous trigonelline levels in humans4,51,52.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] Ashihara, H. et al. Trigonelline and related nicotinic acid metabolites: occurrence, biosynthesis, taxonomic considerations, and their roles in planta and in human health. Phytochem. Rev. 14, 765–798 (2015). source

      Not checked in the free run.

    • cites [51] Midttun, Ø., Ulvik, A., Nygård, O. & Ueland, P. M. Performance of plasma trigonelline as a marker of coffee consumption in an epidemiologic setting. Am. J. Clin. Nutr. 107, 941–947 (2018). source

      Not checked in the free run.

    • cites [52] Gadgil, M. D. et al. Diet patterns are associated with circulating metabolites and lipid profiles of South Asians in the United States. J. Nutr. 152, 2358–2366 (2022). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The benefits of trigonelline on muscle performance did not arise from structural adaptations in skeletal muscle architecture, such as myofibre cross-sectional area, vascularization and fibrosis, but were linked to functional improvements of the mitochondrial respiratory activity of complexes I and II.

    “the benefits of trigonelline on muscle performance did not arise from structural adaptations in the skeletal muscle architecture, such as myofibre cross-sectional area, vascularization and fibrosis, but were linked to functional improvements of the mitochondrial respiratory activity of complexes I and II.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Fatigue and grip strength are well-established measures of sarcopenia and physical frailty and are commonly used to assess pathological impairment of quality of life in older people in clinical practice.

    “fatigue and grip strength are also well-established measures of sarcopenia and physical frailty54,55 and are commonly used to assess the pathological impairment of quality of life in older people in clinical practice.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54] Cruz-Jentoft, A. J. et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 48, 16–31 (2019). source

      Not checked in the free run.

    • cites [55] Fried, L. P. et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 56, M146–M156 (2001). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Trigonelline was proposed as a biomarker of metabolic health or physical fitness because urinary trigonelline levels decrease during obesity and increase in professional athletes.

    “Trigonelline was proposed as a biomarker of metabolic health or physical fitness because urinary trigonelline levels decrease during obesity and increase in professional athletes29,30.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Barton, W. et al. The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level. Gut 67, 625–633 (2018).

      Not checked in the free run.

    • cites [30] Calvani, R. et al. Gut microbiome-derived metabolites characterize a peculiar obese urinary metabotype. Int. J. Obes. 34, 1095–1098 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Trigonelline cannot reverse all causes of sarcopenia and will have to be combined with other nutrients that support muscle mass, such as protein, vitamin D or omega 3 fatty acids, for the nutritional management of sarcopenia.

    “we conclude that trigonelline cannot reverse all causes of sarcopenia and will have to be combined with other nutrients that support muscle mass, such as protein, vitamin D or omega 3 fatty acids, or for the nutritional management of sarcopenia7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Cruz-Jentoft, A. J. & Sayer, A. A. Sarcopenia. Lancet 393, 2636–2646 (2019). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Sarcopenia is a multifactorial disease where both muscle mass and function decline beyond pathological thresholds.

    “sarcopenia is a multifactorial disease where both muscle mass and function decline beyond pathological thresholds7,8.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Cruz-Jentoft, A. J. & Sayer, A. A. Sarcopenia. Lancet 393, 2636–2646 (2019). source

      Not checked in the free run.

    • cites [8] Cruz-Jentoft, A. J. et al. Sarcopenia: European consensus on definition and diagnosis: report of the European Working Group on Sarcopenia in Older People. Age Ageing 39, 412–423 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    Trigonelline could cross-talk with the S-adenosyl-L-methionine-dependent methyltransferase activity of SHMT2 and folate/one-carbon metabolism.

    “suggests that trigonelline could cross-talk with the S-adenosyl-L-methionine-dependent methyltransferase activity of SHMT2 and folate/one-carbon metabolism”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Therapeutic dietary supplementation of trigonelline benefits mitochondrial function, muscle health and mobility during ageing.

    “demonstrates the benefits of its therapeutic dietary supplementation for mitochondrial function, muscle health and mobility during ageing.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    High coffee consumption has been associated with a lower prevalence of sarcopenia in some populations.

    “Although high coffee consumption has been associated with a lower prevalence of sarcopenia in some populations53”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Chung, H. et al. Association of coffee consumption with sarcopenia in Korean elderly men: analysis using the Korea National Health and Nutrition Examination Survey, 2008–2011. Korean J. Fam. Med. 38, 141–147 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Equal protein load (20 μg per well) and consistent gel transfer were verified by Revert Total Protein Stain in immunoblot analyses.

    “Equal protein load (20 µg per well) and consistent gel transfer was verified by Revert Total Protein Stain (LI-COR).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Respiration rates were normalized to the number of worms in each well and averaged over five measurements.

    “Respiration rates were normalized to the number of worms in each well and averaged over five measurements.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    NAD+ levels in worms were normalized on protein content.

    “NAD+ levels were normalized on the protein content.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Trigonelline can protect from metabolic dysfunction and improve glucose tolerance both in mice and humans.

    “trigonelline can protect from metabolic dysfunction and improve glucose tolerance both in mice and humans62,63.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [62] van Dijk, A. E. et al. Acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance. Diabetes Care 32, 1023–1025 (2009). source

      Not checked in the free run.

    • cites [63] Yoshinari, O. & Igarashi, K. Anti-diabetic effect of trigonelline and nicotinic acid, on KK-Ay mice. Curr. Med. Chem. 17, 2196–2202 (2010). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Isotopically labelled internal standards were included for data normalization in metabolomics analyses.

    “Isotopically labelled internal standards, including fully labelled 13C yeast extract and nicotinamide-d4, were included for data normalization.”
    • Also stated in: § Metabolomics analyses in cells and rodent tissues · plain
      “Additionally, isotopically labelled acyl-carnitines (NSK-B, Cambridge Isotope Laboratories) were added for normalization in cell metabolomics.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Trigonelline concentrations were determined using calibration curves ranging from 10 μM to 1,000 μM.

    “Trigonelline concentrations were determined using calibration curves ranging from 10 µM to 1,000 µM.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The trigonelline monohydrate used for in vivo treatments had more than 99.9% purity as shown by internal quality control using mass spectrometry.

    “In vivo treatments were performed with trigonelline monohydrate (Laurus Labs) after internal quality control using MS, showing more than 99.9% purity”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Protein layers from cells, liver and muscle samples were quantified using a bicinchoninic acid assay for normalization.

    “Protein layers from cells, liver and muscle samples were quantified using a bicinchoninic acid assay (Thermo Fisher Scientific) for normalization.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Trigonelline is an NAD+ precursor that optimizes mitochondrial function to improve muscle strength and prevent fatigue during ageing.

    “Our preclinical experiments demonstrated that trigonelline is an NAD+ precursor that optimizes mitochondrial function to improve muscle strength and prevent fatigue during ageing.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Some physiological specificity may exist between different precursors across organs.

    “The heterogeneity of NAD+ biosynthesis and metabolism also suggests that some physiological specificity may exist between different precursors across organs”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    For C. elegans gene expression analyses, two housekeeping genes (act-1 and pmp-3) were used to normalize the expression data.

    “For worms, two housekeeping genes were used to normalize the expression data, that is, actin (act-1) and peroxisomal membrane protein 3 (pmp-3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The normality of each readout was assessed based on historical values of the laboratory for that readout.

    “The normality of each readout was assessed based on historical values of the laboratory for this readout.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Because of its high bioavailability and serum stability, trigonelline can reach the brain and impact cognitive performance in mice with Alzheimer's disease.

    “Because of its high bioavailability and serum stability, trigonelline can reach the brain and impact cognitive performance in mice with Alzheimer’s disease61”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Farid, M. M., Yang, X., Kuboyama, T. & Tohda, C. Trigonelline recovers memory function in Alzheimer’s disease model mice: evidence of brain penetration and target molecule. Sci. Rep. 10, 16424 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Results from C. elegans mobility assays are representative of data obtained from at least two independent experiments.

    “Results are representative of data obtained from at least two independent experiments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Trigonelline is a nutritional geroprotector with therapeutic potential to manage sarcopenia and other age-related pathologies.

    “Therefore, trigonelline is a nutritional geroprotector with therapeutic potential to manage sarcopenia and other age-related pathologies.”
    Quote in the paperSubstantial claim
68 of 68

  • The paper relies on this without support.

    The effects of trigonelline on muscle ageing observed in C. elegans and mice are predictive of therapeutic benefit in humans.

    “Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.”

  • The paper relies on this without support.

    Serum trigonelline levels reflect the availability of trigonelline to skeletal muscle in humans.

    “Serum levels of trigonelline are also associated with NAD+ levels in skeletal muscle (Extended Data Fig. 1a), which we previously found to be linked with clinical measures of sarcopenia and muscle health3.”

  • The paper relies on this without support.

    Trigonelline can be produced by the microbiome.

    “In addition, trigonelline can be produced by the microbiome.”

  • The paper relies on this without support.

    The prominent factors that drive inter-individual susceptibility to sarcopenia and disability versus healthy ageing are poorly understood for therapeutic intervention.

    “the prominent factors that drive the inter-individual susceptibility to sarcopenia and disability versus healthy ageing are poorly understood for therapeutic intervention.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • SIRT1 activators like resveratrol and NAD+ precursors have been shown to enhance mitochondrial biogenesis and oxidative metabolism, leading to improved muscle function and recovery.

    “Similarly, SIRT1 activators like resveratrol and NAD+ precursors have been shown to enhance mitochondrial biogenesis and oxidative metabolism, leading to improved muscle function and recovery”

    From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [126]

    The Main section reports that the NAD+ precursor trigonelline improved mitochondrial function and muscle strength and reduced fatigue in aged mice; it also reports mitochondrial and mobility benefits requiring a sirtuin in worms. The paper does not establish the claim about SIRT1 activators such as resveratrol or show improved muscle recovery. The Methods describe measuring force recovery, but do not report an improvement in the passages found. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Tracer sampling time differs between figure and Methods

    Minor

    Fig. 2 describes the overnight measurement as 16 hours after gavage; the Methods specify sampling at 24 hours for the in vivo tracer experiment.

  • Different correlation methods specified for the same serum associations

    Minor

    The Fig. 1 legend says the associations between serum trigonelline and muscle measures used Pearson correlations, whereas the Statistics section says associations between two continuous variables were determined using Spearman rank correlations.

  • Different ages given for mice supplying primary myotubes

    Minor

    The Fig. 1 legend describes the mice used for the primary-myotube experiment as 22 months old, but the cell-culture Methods say those myotubes came from 24-month-old mice.

3 of 3

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Related

Authors
Membrez, M., Migliavacca, E., Christen, S., Yaku, K., Trieu, J., Lee, A. K., Morandini, F., Giner, M. P., Stiner, J., Makarov, M. V., Garratt, E. S., Vasiloglou, M. F., Chanvillard, L., Dalbram, E., Ehrlich, A. M., Sanchez-Garcia, J. L., Canto, C., Karagounis, L. G., Treebak, J. T., Migaud, M. E., Heshmat, R., Razi, F., Karnani, N., Ostovar, A., Farzadfar, F., Tay, S. K. H., Sanders, M. J., Lillycrop, K. A., Godfrey, K. M., Nakagawa, T., Moco, S., Koopman, R., Lynch, G. S., Sorrentino, V., & Feige, J. N.
Affiliations
  • Nestlé (Switzerland) (CH)
  • University of Toyama (JP)
  • The University of Melbourne (AU)
  • USA Mitchell Cancer Institute (US)
  • University Hospital Southampton NHS Foundation Trust (GB)
  • University of Copenhagen (DK)
  • University of Bern (CH)
  • Endocrinology and Metabolism Population Sciences Institute (IR)
  • Metabolomics and Genomics Research Center (IR)
  • Agency for Science, Technology and Research (SG)
  • Endocrinology and Metabolism Clinical Sciences Institute (IR)
  • National University Hospital (SG)
  • National University of Singapore (SG)
Corresponding author
Sorrentino, Vincenzo
ORCID
Venue
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Published
2024-03-19
Volume
6
Issue
3
Pages
433-447
ISSN
2522-5812 (ISSN-L)
DOI
10.1038/s42255-024-00997-x
PMC
PMC10963276
OpenAlex
W4392956639
Semantic Scholar
50a16e3631e2d843ea2846a55e7d62f9c10be710
Cited by
148
References
88
Citations by year
2026: 55 · 2025: 59 · 2024: 34
FWCI
40.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Metabolism (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • National University of Singapore (submittedVersion)
  • BORIS (University Library Bern) (submittedVersion, cc-by)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • VU Research Portal (submittedVersion, other-oa)
  • Open Access CRIS of the University of Bern
Funders
  • Japan Agency for Medical Research and Development (23gm6710007h0002)
  • National Institute for Health and Care Research (MC_UU_12011/4, NF-SI-0515-10042, 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP, SP/F/21/150013, U24AG047867, RG/15/17/3174, NIHR203319)
  • British Heart Foundation (598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP, SP/F/21/150013, MC_UU_12011/4, NF-SI-0515-10042, RG/15/17/3174)
  • European Commission (RG/15/17/3174, NF-SI-0515-10042, SP/F/21/150013, ImpENSA 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP, 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP, MC_UU_12011/4, 598488-EPP-1-2018-1)
  • Agency for Science, Technology and Research (NF-SI-0515-10042, RG/15/17/3174, 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP, MC_UU_12011/4)
  • National University of Singapore (NUHSRO/2022/047/Startup/11)
  • Singapore Institute for Clinical Sciences (RG/15/17/3174, MC_UU_12011/4, NF-SI-0515-10042, 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP)
  • University of Melbourne
  • Novo Nordisk (NNF18CC0034900)
  • Novo Nordisk Fonden (NNF 18 CC0034900)
  • National University Health System (NUHSRO/2022/047/Startup/11,)
  • Centro de Investigação em Biomedicina
  • National Institute for Health Research Southampton Biomedical Research Centre (NIHR203319, NF-SI- 0515-10042, SP/F/21/150013, MC_UU_12011/4, 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP, RG/15/17/3174)
  • National Institutes of Health
  • Directorate for Biological Sciences
  • HORIZON EUROPE Framework Programme (101073251)
  • Medical Research Council (RG/15/17/3174, 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP, MC_UU_12011/4, NF-SI-0515-10042, SP/F/21/150013, NIHR203319)
  • Economic and Social Research Council (ES/M00919X/1)
  • Japan Society for the Promotion of Science (10042, 21K11593, 22H03505)
  • Erasmus+ (ImpENSA 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP, 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP)
  • National Institute on Aging (U24AG047867)
  • National Center for Complementary and Integrative Health (R21AT009908)
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords
trigonelline, NAD+ precursors, sarcopenia, skeletal muscle aging, mitochondrial dysfunction, oxidative phosphorylation, NAPRT, Preiss-Handler pathway, GPR109A, sirtuins, mitochondrial biogenesis, muscle strength, muscle fatigue, dietary supplementation, lifespan, Caenorhabditis elegans, myotubes
MeSH terms
Aging, Alkaloids, Animals, Humans, Male, NAD, Caenorhabditis elegans, Muscle, Skeletal, Mice, Sarcopenia

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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