doi: 10.1038/s42255-024-00997-x.
Epub 2024 Mar 19.
Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia
Affiliations
- PMID: 38504132
- PMCID: PMC10963276
- DOI: 10.1038/s42255-024-00997-x
Item in Clipboard
Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia
Nat Metab.
2024 Mar.
Abstract
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.
© 2024. The Author(s).
Conflict of interest statement
M.M., E.M., S.C., F.M., M.P.G., J.S., M.V., L.C., J.L.S.-G., C.C., L.G.K., M.J.S., S.M., V.S. and J.N.F. are or were employees of Nestlé Research, which is part of the Société des Produits Nestlé S.A. L.G.K. was an employee of Nestlé Health Sciences. K.M.G. has received reimbursement for speaking at conferences sponsored by companies selling nutritional products and is part of an academic consortium that has received research funding from BenevolentAI, Nestlé Research and Danone. The other authors declare no competing interests.
Figures
a, Serum levels of trigonelline in healthy controls (n = 20) and individuals with sarcopenia (n = 20) from the MEMOSA SSS (unpaired, two-tailed Student’s t-test). b, Association of serum trigonelline levels with ALMI, grip strength and gait speed; the Pearson correlation coefficient and its P value were calculated on n = 40 serum samples from the SSS. c, SSS muscle RNA-seq association with serum trigonelline levels. Gene set enrichment ordered according to the significance of enrichment with only the top ten gene sets being reported. A false discovery rate (FDR) < 10−20 was trimmed at FDR = 10−20 (n = 39 muscle samples). d, Enrichment plot for the hallmark oxidative phosphorylation gene set from c. e,f, Relative NAD+ levels in HSMMs after treatment with increasing concentrations of trigonelline, in the absence (e) or presence (f) of FK866 (one-way analysis of variance (ANOVA), mean ± s.e.m, n = 6 biological replicates per group). g, Relative NAD+ levels in human primary myotubes from healthy controls and patients with sarcopenia from the Hertfordshire Sarcopenia Study Extension (HSSe) cohort treated ex vivo with or without trigonelline (unpaired, two-tailed Student’s t-test, mean ± s.e.m, n = 3 biological replicates per group). h, Relative NAD+ levels in primary myotubes from aged mice (22 months) treated ex vivo with trigonelline (unpaired, two-tailed Student’s t-test, mean ± s.e.m, n = 8 and n = 9 biological replicates per group). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. For the individual P values, see Fig. 1 in the Source data. Source data
a, Experimental design of isotope-labelled trigonelline incorporation into NAD+. b, NAD+ levels measured using LC–HRMS in the liver, gastrocnemius muscle and whole blood 2 h or 16 h (overnight) after labelled trigonelline gavage in young mice (one-way ANOVA, n = 4–5 mice per group). c, NAD+ levels measured using LC–HRMS in HSMM (left) and relative isotopic enrichment of NAD+ (right) after 24-h incubation with 1 mM labelled trigonelline (unpaired, two-tailed Student’s t-test, n = 3 biological replicates per group). d, Representation of the Preiss–Handler and salvage pathways of NAD+ production. e, Relative NAD+ levels in HSMMs 48 h after adenoviral infection with a scrambled or NAPRT shRNA (unpaired, two-tailed Student’s t-test, n = 6 biological replicates per group). f, Relative NAD+ levels in HSMMs after 24-h trigonelline or NR treatment, with or without 2-OHNA co-treatment (one-way ANOVA, n = 12 biological replicates per group). g–j, NAD+ metabolites measured using LC–HRMS in HSMMs (NAD+, g; NAAD, h; NAMN, i; NA, j) after 24-h incubation with trigonelline in co-treatment with FK866, 2-OHNA or their combination (one-way ANOVA, n = 3 biological replicates per group). k, Quantitative PCR (qPCR) mRNA expression of Naprt in the liver of wild-type (WT) and Naprt knockout (KO) mice (one-way ANOVA, n = 4–6 animals per group). l–n, LC–HRMS measurement of NA (l) and NAMN (m) levels in the blood and liver, and of NAAD (n) in liver 2 h after trigonelline gavage in WT or Naprt KO mice (one-way ANOVA, n = 4–6 animals per group). o, Relative NAD+ levels in HSMMs after 72 h trigonelline or NR treatment, with or without co-treatment with FK866, 2-OHNA or their combination (one-way ANOVA, n = 10 biological replicates per group). p, Mitochondrial membrane potential (ΔΨm) measured using JC-1 staining in HSMMs treated as in o (one-way ANOVA, n = 16 biological replicates per group). q, Maximum oxygen consumption rate (OCR) in HSMMs treated as in o after stimulation with 3 μM carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (one-way ANOVA, n = 9–10 biological replicates per group). All data are expressed as the mean ± s.e.m with *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. NS, not significant. Individual P values are reported in Fig. 2 of the Source data. a.u., arbitrary units. Source data
a, Experimental design of compound treatments at 1 mM started from day 1 of adulthood (D1) in N2 WT worms. Illustration created with BioRender.com . b, Lifespan in trigonelline-treated worms (log-rank test, n = 90 worms per group). c, Relative NAD+ levels in aged worms on day 8 (D8). Unpaired, two-tailed Student’s t-test, n = 6 biological replicates per group). d, mitochondrial and nuclear DNA in aged worms (D8). Unpaired, two-tailed Student’s t-test, n = 12 worms per group). e, mRNA expression of mitochondrial genes in worms treated with trigonelline (unpaired, two-tailed Student’s t-test, n = 6 biological replicates per group). f, Basal and maximal OCR in L4 worms treated from the embryo stage (unpaired, two-tailed Student’s t-test, n = 36 animals per group). g, Confocal images (left) and quantitative integrity scoring (right) of green fluorescent protein (GFP)-labelled muscle fibres in adult (D1) and aged (D11) RAW1596 (myo-3p::GFP) worms (one-way ANOVA, n = 6 worms and 9–31 sarcomeres per group). Scale bar, 10 µm. h, Percentage of paralyzed aged worms (D11) (n = 3 independent experiments, unpaired two-tailed Student’s t-test). i, Spontaneous mobility of worms at different ages (unpaired, two-tailed Student’s t-test, n = 33–49 worms per group). j, Relative NAD+ levels in D1 adult worms treated from the embryo stage and fed with control (empty vector (e.v.)) or nrpt-1 RNA interference (RNAi) (one-way ANOVA, n = 6–14 biological replicates per group). k, Mitochondrial and nuclear DNA in worms treated as in j (one-way ANOVA, n = 10–12 animals per group). l,m, Lifespan of control (e.v.), nrpt-1 RNAi (l) and sir-2.1 RNAi (m) worms (log-rank test, n = 100 animals per group). n, Spontaneous mobility of control (e.v.), nrpt-1 RNAi and sir-2.1 RNAi worms at D6 (unpaired, two-tailed Student’s t-test, n = 63–123 individual worms per group). All data are expressed as the mean ± s.e.m. with *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Individual P values of the worms per group are reported in Fig. 3 of the Source data. Source data
a, Mitochondrial complex I activity normalized to citrate synthase activity (UCI × UCS−1) in gastrocnemius muscle of aged mice (20 months) after a 5-day dietary supplementation of trigonelline (unpaired, two-tailed Student’s t-test, n = 7–8 biological replicates per group). b, Mitochondrial complex I (NDUFB8) protein levels in the same samples as in a (unpaired, two-tailed Student’s t-test, n = 6 biological replicates per group). c, Succinate dehydrogenase (SDH) activity in the quadriceps muscle of the same groups as in a (unpaired, two-tailed Student’s t-test, n = 7 biological replicates per group). d, Mitochondrial complex II (succinate dehydrogenase [ubiquinone] iron-sulphur subunit, mitochondrial (SDHE)) protein levels in the same samples as in a (unpaired, two-tailed Student’s t-test, n = 6 biological replicates per group). e, Plasma trigonelline levels measured in aged mice (22–24 months) after 12 weeks of trigonelline supplementation (unpaired, two-tailed Student’s t-test, n = 13 and 15 biological replicates per group). f, LC–HRMS measurement of trigonelline levels in gastrocnemius muscle and liver of the same mice groups as in e (unpaired, two-tailed Student’s t-test; gastrocnemius: n = 5 and 6, liver: n = 13 and 16 biological replicates per group); <LOQ, below the level of quantification. g, Lean mass normalized to body weight of aged mice after 12 weeks of treatment as in e (unpaired, two-tailed Student’s t-test, n = 13 and 15 biological replicates per group). h, Tibialis anterior muscle mass of aged mice after 12 weeks of treatment as in e (unpaired, two-tailed Student’s t-test, n = 13 and 15 biological replicates per group). i, Grip strength of aged mice after 12 weeks of treatment as in e (unpaired, two-tailed Student’s t-test, n = 13 and 15 biological replicates per group). j, In situ muscle contractility normalized to initial force after supramaximal stimulation of the tibialis anterior muscle in young controls and aged mice after 12 weeks of treatment as in e (two-way ANOVA followed by uncorrected Fisher’s least significant difference tests; n = 11–14 biological replicates per group). All data are expressed as the mean ± s.e.m. with *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Individual P values are reported in Fig. 4 of the Source data. Source data
a, Correlation of serum trigonelline levels with muscle NAD+, (n = 10 validation muscle samples remaining from the MEMOSA SSS cohort). b, Heatmap showing the top 50 oxidative phosphorylation genes associated with serum trigonelline levels. c, Correlation analysis of serum trigonelline levels with appendicular lean mass (ALM) index, grip strength, dietary caffeine and vitamin B3 intake in a replication cohort; Pearson correlation coefficient and its p-value were calculated on n = 186 serum samples from the Bushehr elderly health cohort. d, Molecular structures of nicotinic acid or niacin (NA), trigonelline which differs from NA only for the methyl group, and the ribosylated (rib) molecules nicotinamide riboside (NR) and NAD+. e, NAD+ levels relative to untreated cells measured in HSMM with or without trigonelline for 6 hours or 24 hours (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 10 biological replicates per group). f, NAD+ levels relative to untreated control measured in HSMM myotubes following 24 h NAD+ precursors treatment at 1 mM (One-way ANOVA; mean ± s.e.m, n = 6 biological replicates per group). g, Naprt mRNA expression in the indicated cell lines (n = 4–12 biological replicates per group). h, NAD+ levels relative to untreated control measured in HepG2, C2C12 and IM-PTECs cells following 24 h NAD+ precursors treatment (One-way ANOVA; mean ± s.e.m, n = 8–12 biological replicates per group). i, Stability assessment of trigonelline, NR and NMN added at 1 mM in human serum and incubated at 37 °C for the indicated durations (Two-way ANOVA; mean ± s.e.m, n = 3 biological replicates per group). j, Percentage increase in NAD+ levels in trigonelline treated primary myotubes from healthy control and sarcopenic HSSe subjects relative to untreated cells (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 3 biological replicates per group). k, Correlation analysis of serum trigonelline levels with SHMT2 mRNA levels in muscle biopsies from the SSS cohort; Pearson correlation coefficient and its p-value were calculated on n = 39 serum samples. l, Correlation analysis of SHMT2 gene expression in muscle biopsies with grip strength and appendicular lean mass index in the SSS cohort; Pearson correlation coefficient and its p-value were calculated on n = 40 serum samples. P: <0.05 (*); < 0.01 (**); < 0.001 (***); < 0.0001 (****); n.s., non-significant. For all the individual p values, see the Extended Data Fig. 1 Source file. Source data
a, LC-HRMS measurements of trigonelline levels in liver, gastrocnemius muscles, kidney, whole blood and urine of C57BL/6J mice, collected at 2 hours (2 h) or overnight (o/n) after labelled trigonelline gavage (unpaired two-tailed Student’s t-test compared to control group, mean ± s.e.m, n = 5 biological replicates per group, except in urine samples where only 2 samples were collected in controls and 4 in treated group); LOQ, level of quantification. b, NAD+ levels relative to untreated control mice measured in liver, gastrocnemius and kidney tissues from the same groups as in (a) (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 5 biological replicates per group). c, LC-HRMS-based relative trigonelline incorporation into NAD+ in the same tissues as in (a), related to the NAD+ measured in Fig. 2b (unpaired two-tailed Student’s t-test compared to control group, mean ± s.e.m, n = 5 biological replicates per group). d, Naprt mRNA levels by qPCR in HSMM cells following 48 h incubation with an adenovirus carrying either a scrambled or NAPRT shRNA construct (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 3 biological replicates per group). e, NAD+ levels relative to untreated control measured in HSMM myotubes following 24 h incubation with NA in presence or absence of the NAPRT shRNA construct (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 6 biological replicates per group). f, NAD+ levels relative to untreated control measured in HSMM myotubes following 24 h trigonelline or NR treatment, in the presence or absence of FK866 (one-way ANOVA; mean ± s.e.m, n = 6 biological replicates per group). g, NAD+ levels relative to untreated control measured in HSMM myotubes following 24 h trigonelline or NR treatment, in the presence of FK866 and with or without co-treatment with 2-OHNA (one-way ANOVA; mean ± s.e.m, n = 10 biological replicates per group). h-i, LC-HRMS based measurements of trigonelline and NAM in HSMM myotubes treasted as in Fig. 2g–j (One-way ANOVA, mean ± s.e.m, n = 3 biological replicates per group; in red ****, unpaired two-tailed Student’s t-test for comparisons in conditions without trigonelline); AU, abitrary units. j, Naprt mRNA expression by qPCR in gastrocnemius muscle of wildtype (WT) and Naprt knockout (KO) C57BL/6N mice (One-way ANOVA, mean ± s.e.m, n = 4–6 animals per group). k, LC-MS measurements of trigonelline levels in liver, plasma and gastrocnemius muscles harvested 2 hours post trigonelline gavage in WT or Naprt KO mice (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 4–6 animals per group); AU, abitrary units. l-n, LC-MS measurements of NAD+ metabolites in (l) liver, (m) blood, (n) gastrocnemius of the same groups as in (k) (One-way ANOVA, mean ± s.e.m, n = 4–6 animals per group); AU, abitrary units. o, Nampt and Nrk mRNA levels by qPCR in liver and muscle of the same groups as in (j) (One-way ANOVA, mean ± s.e.m, n = 4–6 animals per group). p, Apoptosis detection via annexing staining time course in HSMM myotubes following treatments of trigonelline, FK866 or 2-OHNA and their combinations. Staurosporin (2.5 µM) is used as a positive control for apoptosis induction (two-way ANOVA; mean ± s.e.m, n = 6 biological replicates per group). q, Seahorse-based substrate-driven OCR measurement in permeabilized HSMM myotubes following 24 h trigonelline treatment, in the presence or absence of 2-OHNA, and with a sequence of substrate/inhibitors to extract contribution of different complexes (one-way ANOVA; mean ± s.e.m, n = 11 biological replicates per group). r, GPR109A agonist assay in cells incubated with increasing doses of NA or trigonelline (mean ± S.D., n = 4). P: <0.05 (*); < 0.01 (**); < 0.001 (***); < 0.0001 (****); n.s., non-significant. For all the individual p values, see the Extended Data Fig. 2 Source file. Source data
a, Lifespan assessment in N2 worms treated with or without NR as designed in Fig. 2a (log-rank test, n = 90 animals per group). b, NAD+ levels (% control) in D1 adult N2 worms treated with NAD+ precursors from embryo stage (One-way ANOVA, mean ± s.e.m, n = 6–8 biological replicates per group). c, mRNA levels by qPCR of genes regulating mitochondrial function in N2 worms treated with NR from Day 1 to Day 2 of adulthood (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 6 biological replicates per group). d, Seahorse-based oxygen consumption of L4 stage N2 worms from the Fig. 3f. e, Additional integrity scoring parameters of GFP-labeled muscle fibers in the worms from the Fig. 3g (One-way ANOVA, mean ± s.e.m, n = 6 animals, 9–31 sarcomeres per group). f, Lifespan of N2 worms treated with vehicle or trigonelline starting from Day 4 of adulthood (log-rank test, n = 90 animals per group). g, Percentage of paralyzed aged N2 worms (D11=Day 11) after vehicle or trigonelline treatment started at Day 4 of adulthood (n = 3 independent experiments, unpaired two-tailed Student’s t-test, mean ± s.e.m). h, Lifespan in N2 worms treated with or without NA or trigonelline and fed with control (empty vector; e.v.) or nrpt-1 RNAi constructs from Day 1 of adulthood (comparing NA-treated worms to e.v., log-rank test, n = 100 animals per group). i, Lifespan in N2 worms treated with or without NA or trigonelline and fed with control (e.v.) or sir-2.1 RNAi from Day 1 of adulthood (comparing NA-treated worms to e.v., log-rank test, n = 100 animals per group). j, sir-2.1 mRNA levels by qPCR in D1 adult N2 worms fed with control (e.v.) or sir-2.1 RNAi from embryo stage (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 8 biological replicates per group). k, sirtuin mRNA levels in N2 worms from publicly available RNA seq data (n = 9 replicates per group). l, NAD+ levels (% control) in D1 adult N2 worms treated with trigonelline from embryo stage and fed with control (e.v.) or sir-2.1 RNAi constructs (One-way ANOVA, mean ± s.e.m, n = 6 biological replicates per group). P: <0.05 (*); < 0.01 (**); < 0.001 (***); < 0.0001 (****); n.s., non-significant. For all the individual p values, see the Extended Data Fig. 3 Source file. Source data
a, mt/nDNA of gastrocnemius muscle of aged C57BL/6J mice (20 months) following a 5 day diet supplementation of trigonelline (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 8 animals per group), related to Fig. 4a–d. b, Citrate synthase activity and additional enzymatic activity of Oxphos subunits from gastrocnemius muscles of the same groups as in (a) (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 8 animals per group, 3 samples in control group for complex V analyses could not be measured). c, Western blot of SDHB and NDFUB8 Oxphos subunits, and Licor staining for total proteins, quantified in Fig. 4b, d. d,e Plasma aspartate aminotransferase (AST) and creatine kinase levels measured in aged C57BL/6J mice (22–24 months) after a 12 week trigonelline supplementation (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 13 and 15 animals per group), related to Fig. 4e–j. f, Fat mass composition at the end of the intervention study normalized to body weight in the same groups as in (d) (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 13 and 15 animals per group). g, Liver mass at the end of the study normalized to body weight (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 13 and 15 animals per group). h-i, Muscle mass of additional muscles at the end of the study normalized to body weight (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 13 and 15 animals per group). j, Quantification of vascularization via CD31 immunostaining in TA muscle of the control and trigonelline-treated old mice (One-way ANOVA; mean ± s.e.m, n = 12 and 14 animals per group). k, Fiber size distribution in TA muscle of the same groups, with an average of 1543 ± 13 µm2 for trigonelline treated group and 1575 ± 13 µm2 for control group (Kolmogorov-Smirnov test, n = 13 and 16 animals per group). l, Average fiber area of TA muscle quantified in the same groups (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 13 and 16 animals per group). m, Quantification of PAS glycogen staining of TA muscles of the same groups (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 12 and 15 animals per group). n, Quantification of Van Gieson (VG) fibrosis staining of TA and diaphgram muscles of the same groups (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 12 and 15 animals per group). o, NAD+ levels relative to untreated old mice measured in liver, gastrocnemius and kidney tissues after chronic trigonelline administration (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 13 and 15 biological replicates per group for liver and muscle, n = 9 and 10 biological replicates per group for kidney). p, Western blot and related quantification of Oxphos protein levels in gastrocnemius muscle of the aged control and trigonelline-treated mice (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 5 biological replicates per group). q, Spontaneous fine activity of the aged control and trigonelline-treated mice, and of the young reference group (One-way ANOVA; mean ± s.e.m, n = 13 aged animals, and 16 animals for young and trigonelline groups). r, Peak force normalized to body weight of the same groups (unpaired two-tailed Student’s t-test, mean ± s.e.m, n = 13 and 15 biological replicates per group). P: <0.05 (*); < 0.01 (**); < 0.001 (***); < 0.0001 (****); n.s., non-significant. For all the individual p values, see the Extended Data Fig. 4 Source file. Source data
Similar articles
-
A study protocol to investigate if acipimox improves muscle function and sarcopenia: an open-label, uncontrolled, before-and-after experimental medicine feasibility study in community-dwelling older adults.BMJ Open. 2024 Feb 27;14(2):e076518. doi: 10.1136/bmjopen-2023-076518. BMJ Open. 2024. PMID: 38417968 Free PMC article.
-
NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging.Mol Cell Biochem. 2022 Jun;477(6):1829-1848. doi: 10.1007/s11010-022-04408-1. Epub 2022 Mar 25. Mol Cell Biochem. 2022. PMID: 35334034 Free PMC article. Review.
-
NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle.Cell Rep. 2021 Jan 19;34(3):108660. doi: 10.1016/j.celrep.2020.108660. Cell Rep. 2021. PMID: 33472069 Free PMC article.
-
Sarcopenia and Muscle Aging: A Brief Overview.Endocrinol Metab (Seoul). 2020 Dec;35(4):716-732. doi: 10.3803/EnM.2020.405. Epub 2020 Dec 23. Endocrinol Metab (Seoul). 2020. PMID: 33397034 Free PMC article. Review.
-
Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin-resistant men.J Physiol. 2020 Feb;598(4):731-754. doi: 10.1113/JP278752. Epub 2019 Dec 26. J Physiol. 2020. PMID: 31710095 Clinical Trial.
References
-
- Janssens GE, et al. Healthy aging and muscle function are positively associated with NAD+ abundance in humans. Nat. Aging. 2022;2:254–263. - PubMed
-
- 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. 2015;14:765–798.
