NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health

May combine two claims.

NMN was not detected in plasma in that trial, most likely because sample freezing before extraction caused NMN degradation.

“However, NMN was not detected in plasma, most likely because the sample freezing before extraction may have caused NMN degradation [40].”

• cites [40] Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J. 2020;67(2):153–60. sourceSupported
• cites [83] Liu L, Su X, Quinn WJ, Hui S, Krukenberg K, Frederick DW, et al. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab. 2018;27(5):1067–1080.e5. sourceDisputed

  In Results, ‘Tracing the fate of NR and NMN’ (page unavailable), the paper says NMN was barely detectable even after IV administration—not undetected. It reports rapid degradation in whole blood and says the researchers accordingly flash-froze specimens before extraction; it does not attribute the low measured level to freezing. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

NAD+ synthesis can occur from tryptophan and vitamin B3, and NR and NMN also promote NAD+ synthesis.

“NAD+ synthesis can occur from tryptophan and vitamin B3 (niacin and nicotinamide). Later, the intermediates NR and NMN have also been identified to promote NAD+ synthesis [13, 55].”

• cites [13] Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528–36. sourcePartly supported

  The Results section (page not supplied) shows that administered NMN was converted to NAD+ and enhanced NAD+ biosynthesis. It reports an increase in NR after NMN administration, but does not establish that NR itself promotes NAD+ synthesis. The citation is attached to the sentence about NR and NMN, not the preceding sentence about tryptophan and vitamin B3. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [55] Bieganowski P, Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a preiss-handler independent route to NAD+ in fungi and humans. Cell. 2004;117(4):495–502. sourceNot checked — no full text of the source

May combine two claims.

In rats, orally administered isotope-labeled NMN was partly deamidated to NAMN by intestinal microbiota before absorption, and liver NAAD levels increased.

“The isotope-labeled NMN orally administered in rats was partially deamidated into NAMN by the intestinal microbiota before its absorption. Despite to a noticeably lesser extent than the amidated metabolites NMN and NAD+, nicotinic acid adenine dinucleotide (NAAD) levels in the liver increased [43]”

• cites [43] Kim L-J, Chalmers TJ, Smith GC, Das A, Poon EWK, Wang J, et al. Nicotinamide mononucleotide (NMN) deamidation by host-microbiome interactions. bioRxiv [Internet]. 2020;2020.09.10.289561. Available from: http://biorxiv.org/content/early/2020/09/11/2020.09.10.289561.abstract. sourcePartly supported

  The Animal experiments section (page unavailable) says the isotope-labeled NMN was given orally to mice, not rats. The Discussion and ‘NMN treatment alters the de novo arm of NAD+ synthesis’ sections support microbiome-associated deamidation and an increase in liver NaAD, but the paper describes deamidation before incorporation rather than establishing that it occurred before absorption. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

NR can raise NAD+ either by direct absorption through the salvage pathway or by hydrolysis to NAM by BST1 and further microbial conversion to nicotinic acid via the Preiss-Handler pathway.

“In addition, NR can increase NAD+ levels in two different ways. Through direct absorption following the salvage pathway, or be hydrolyzed to nicotinamide (NAM) by the glycohydrolase bone marrow stromal cell antigen 1 (BST1), and further metabolized by the gut microbiota to nicotinic acid, following through the Preiss–Handler pathway.”

• cites [64] Yaku K, Palikhe S, Izumi H, Yoshida T, Hikosaka K, Hayat F, et al. BST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities. Nat Commun. 2021;12(1):6767. sourceSupported

May combine two claims.

NMN and NR protect against diabetes, Alzheimer disease, endothelial dysfunction, and inflammation.

“NMN and NR demonstrated protect against diabetes, Alzheimer disease, endothelial dysfunction, and inflammation.”

• cites [13] Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528–36. sourcePartly supported

  The Results and Discussion (page unavailable) report that NMN improved glucose tolerance in diet- and age-induced diabetic mice and reversed inflammatory-response gene-expression changes. They do not show that NR protects against these conditions; NR was measured after NMN administration, not tested as a treatment. The paper also does not establish protection against Alzheimer disease or endothelial dysfunction, or demonstrate prevention of inflammation as a clinical condition. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [18] Trammell SAJ, Weidemann BJ, Chadda A, Yorek MS, Holmes A, Coppey LJ, et al. Nicotinamide riboside opposes type 2 diabetes and neuropathy in mice. Sci Rep. 2016;6(1). sourcePartly supported

  The Abstract and Results and Discussion (page unavailable) report that NR improved glucose measures in prediabetic and type 2 diabetic mice; the Abstract also reports prior evidence that NMN improves insulin sensitivity and glycemic control. The paper does not support the attributed protection against Alzheimer disease, endothelial dysfunction, or inflammation, and its diabetes evidence is limited to mice. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [19] Hu L, Guo Y, Song L, Wen H, Sun N, Wang Y, et al. Nicotinamide riboside promotes Mfn2-mediated mitochondrial fusion in diabetic hearts through the SIRT1-PGC1α-PPARα pathway. Free Radic Biol Med. 2022;1(183):75–88. sourcePartly supported

  The Results (p. 9) show that NR improved cardiac function in diabetic mice, and the Conclusion (p. 14) proposes it as a strategy for cardiac complications of diabetes—not for preventing diabetes itself. The Background (p. 4) mentions NMN as a product of NR metabolism, but the paper does not establish that both compounds protect against Alzheimer disease, endothelial dysfunction, or inflammation. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [20] Caton PW, Kieswich J, Yaqoob MM, Holness MJ, Sugden MC. Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function. Diabetologia [Internet]. 2011;54(12):3083–92. Available from: https://doi.org/10.1007/s00125-011-2288-0. sourcePartly supported

  The Results and Discussion (page unavailable) report that NMN reduced an inflammatory marker and restored impaired insulin secretion in fructose-fed mice and cytokine-exposed islets. This supports a limited claim about NMN, islet inflammation, and diabetes-related dysfunction—not protection against diabetes itself. The paper does not establish protective effects of NR or address Alzheimer disease or endothelial dysfunction. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [22] Wang X, Hu X, Yang Y, Takata T, Sakurai T. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 2016;1643:1–9. sourceNot checked — no full text of the source
• cites [23] Yao Z, Yang W, Gao Z, Jia P. Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci Lett. 2017;647:133–40. sourceNot checked — no full text of the source
• cites [24] Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, et al. NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci [Internet]. 2018;115(8):E1876 LP–E1885. Available from: http://www.pnas.org/content/115/8/E1876.abstract. sourcePartly supported

  The Discussion (p. 7) reports that NR improved several Alzheimer-like features, including neuroinflammation, in mouse models; it also cites animal-model findings for NMN and Alzheimer-related outcomes. The paper does not establish protection against diabetes or endothelial dysfunction, and its inflammation finding is specific to neuroinflammation in the Alzheimer mouse models. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [32] de Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, et al. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell [Internet]. 2016;15(3):522–30. Available from: https://doi.org/10.1111/acel.12461. sourcePartly supported

  The Discussion (page unavailable) reports that NMN restored age-related endothelial function in old mice. It does not show that NR protects against endothelial dysfunction, or that either supplement protects against diabetes, Alzheimer’s disease, or inflammation. Alzheimer’s disease is mentioned as a condition linked to endothelial dysfunction, not as an outcome of supplementation. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [93] Mateuszuk Ł, Campagna R, Kutryb-Zając B, Kuś K, Słominska EM, Smolenski RT, et al. Reversal of endothelial dysfunction by nicotinamide mononucleotide via extracellular conversion to nicotinamide riboside. Biochem Pharmacol. 2020;1(178):114019. sourcePartly supported

  The Abstract (p. 1) reports that both NMN and NR reduced endothelial inflammation and prevented endothelial dysfunction in the models tested. The Abstract (p. 2) describes benefits in mouse models of type 2 diabetes and a rat model of Alzheimer’s disease for NMN only; it does not establish those effects for NR. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

Under stress conditions, NAD+ biosynthesis and NAD+ levels decrease while the activity of NAD-consuming enzymes increases.

“In stress conditions, NAD+ biosynthesis and levels decrease as well as the activity of consuming enzymes rises.”

• cites [11] Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One [Internet]. 2012;7(7):e42357 Available from: https://doi.org/10.1371/journal.pone.0042357. sourcePartly supported

  The Results (Correlation between related biochemical entities) report that higher PARP activity, an NAD+-consuming process, correlated with lower NAD+ levels in the male cohort; the Conclusion links this pattern to oxidative stress and aging in males. The paper does not establish that NAD+ biosynthesis decreases under stress, and it does not establish the same PARP–NAD+ pattern in females. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [12] Seyedsadjadi N, Berg J, Bilgin AA, Braidy N, Salonikas C, Grant R. High protein intake is associated with low plasma NAD+ levels in a healthy human cohort. PLoS One. 2018;13(8). sourcePartly supported

  The Discussion (page unavailable) reports that urea-induced oxidative stress can increase activity of the NAD-consuming enzyme PARP-1 and proposes that this could lower NAD+ levels. It also proposes a possible reduction in NAD+ biosynthesis through SIRT5-mediated inhibition of glutaminase. These are context-specific mechanisms requiring further investigation, not an established pattern under stress conditions generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [13] Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528–36. sourcePartly supported

  The Results report that inflammatory and oxidative-stress treatments reduced NAMPT and NAD+ levels in primary hepatocytes, and the Discussion links reduced NAD+ biosynthesis to inflammation or oxidative stress. The paper does not report a rise in NAD-consuming enzyme activity under those conditions; its Results instead suggest that SIRT1 activity is suppressed by a high-fat diet. No page numbers are available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

NR and NMN have beneficial pharmacological activities in acute renal failure, inflammation, cardio- and vasoprotection, telomere lengthening, and lifespan extension.

“In addition, they have demonstrated beneficial pharmacological activities in acute renal failure [28], anti-inflammatory [29–31], cardio and vasoprotective actions [32–35], telomere lengthening [36, 37•], extend lifespan and promote health in various organisms, from yeasts to mammals [10, 14, 15, 38].”

• cites [28] Guan Y, Wang S-R, Huang X-Z, Xie Q, Xu Y-Y, Shang D, et al. Nicotinamide mononucleotide, an NAD+ precursor, rescues age-associated susceptibility to AKI in a sirtuin 1–dependent manner. J Am Soc Nephrol [Internet]. 2017;28(8):2337 LP – 2352. Available from: http://jasn.asnjournals.org/content/28/8/2337.abstract. sourceNot checked — no full text of the source
• cites [29] Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 2019;28(7):1717–1728.e6. sourceSupported
• cites [30] Traba J, Kwarteng-Siaw M, Okoli TC, Li J, Huffstutler RD, Bray A, et al. Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects. J Clin Invest. 2015;125(12):4592–600. sourcePartly supported

  The Discussion reports that NR reduced cytokine release and blunted NLRP3 inflammasome activation in cells from healthy volunteers, supporting the anti-inflammatory portion of the citing sentence. This paper does not establish the same effect for NMN, and its cell experiments do not demonstrate a clinical anti-inflammatory benefit. The other claimed activities have separate citations in the citing sentence and are not attributed to this source. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [31] Liu J, Zong Z, Zhang W, Chen Y, Wang X, Shen J, et al. Nicotinamide mononucleotide alleviates lps-induced inflammation and oxidative stress via decreasing COX-2 expression in macrophages. Front Mol Biosci. 2021;6:8. sourceSupported
• cites [32] de Picciotto NE, Gano LB, Johnson LC, Martens CR, Sindler AL, Mills KF, et al. Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice. Aging Cell [Internet]. 2016;15(3):522–30. Available from: https://doi.org/10.1111/acel.12461. sourceSupported
• cites [33] Yamamoto T, Byun J, Zhai P, Ikeda Y, Oka S, Sadoshima J. Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. PLoS One. 2014;9(6). sourcePartly supported

  The Results section, “NMN administration reduces the infarct area after I/R” (page unavailable), reports that NMN reduced infarct size in mice under specific dosing schedules, supporting a cardioprotective action. The cited paper does not establish vasoprotection or a corresponding effect of NR. The renal, anti-inflammatory, telomere, and lifespan claims have separate citations in the citing sentence and are not judged here. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [34] Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun [Internet]. 2018;9(1):1286. Available from: https://doi.org/10.1038/s41467-018-03421-7. sourcePartly supported

  The relevant attribution is the cardio- and vasoprotective claim, rather than the separately cited renal, inflammatory, telomere, and lifespan claims. In the Results (Effect of NR on indicators of cardiovascular health; page unavailable), NR showed a trend toward reduced aortic stiffness, but the reduction was not significant after correction for multiple comparisons, and no effect was observed on vascular endothelial function. The Discussion reports vascular improvement with NMN in old mice, but describes the human NR findings as preliminary rather than demonstrated protection. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [35] Diguet N, Trammell SAJ, Tannous C, Deloux R, Piquereau J, Mougenot N, et al. Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation [Internet]. 2018;137(21):2256–73. Available from: https://doi.org/10.1161/CIRCULATIONAHA.116.026099. sourcePartly supported

  The Results section reports that NR preserved cardiac function in mice with dilated cardiomyopathy. It also reports no difference in vascular reactivity between NR-fed and control mice, so this paper does not support a vasoprotective effect. The other listed activities are attached to different citations in the citing sentence. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

The rat study found increased kidney, liver, and adrenal gland weights relative to control, correlating with histopathology findings in kidney and liver.

“There was an increase in the kidney, liver, and adrenal gland weights relative to control, correlating with histopathology findings in the kidney and liver.”

• cites [82] Cros C, Cannelle H, Laganier L, Grozio A, Canault M. Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C®) in Sprague-Dawley rats. Food Chem Toxicol. 2021;1(150):112060. sourceSupported

May combine two claims.

Lowering the cellular methyl pool could reduce DNA and protein methylation, altering gene expression and protein activity, because promoter DNA methylation is typically associated with transcriptional repression.

“This could lead to a reduction in DNA and protein methylation, and as consequence, alter gene expression patterns and protein activity, once that DNA methylation in gene promoter regions is typically associated with transcriptional repression.”

• cites [89] Hwang ES, Song SB. Possible adverse effects of high-dose nicotinamide: mechanisms and safety assessment. Biomolecules. 2020;10(5). sourcePartly supported

  Section 3.5 explains that nicotinamide methylation affects the methyl groups available for DNA and protein methylation, which can influence gene expression and protein function. Section 3.6 reports one example in which reduced promoter methylation accompanied increased gene expression, but the paper does not establish the broader claim that promoter methylation is typically associated with transcriptional repression. No page numbers are available in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

NAAD is a product of NR utilization in humans and a biomarker of increased NAD+ metabolism, consistent with findings in mice that the deamidated Preiss-Handler pathway for NR is predominant.

“Thus, confirming that NAAD is a product of NR utilization in humans and a biomarker of increased NAD+ metabolism, which corroborates with findings in mice that the metabolic NR deamidated Preiss–Handler pathway is predominant [64].”

• cites [64] Yaku K, Palikhe S, Izumi H, Yoshida T, Hikosaka K, Hayat F, et al. BST1 regulates nicotinamide riboside metabolism via its glycohydrolase and base-exchange activities. Nat Commun. 2021;12(1):6767. sourcePartly supported

  The Introduction (page unavailable) reports that oral NR increased NAAD in mice and humans, and the Results (‘Role of the base-exchange reaction against NR and NAR in vivo’; page unavailable) conclude that NR-derived nicotinic acid is mainly converted to NAD+ through the Preiss–Handler pathway in mice. The paper does not establish NAAD as a biomarker of increased NAD+ metabolism in humans; that part goes beyond its evidence. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Repeated oral administration of synthetic NMN up to 1500 mg/kg/day over a 90-day sub-chronic period in rats appears safe and did not promote toxic effects based on body weight, food and water consumption, feed conversion efficiency, biochemical, and blood parameters.

“A toxicity study in rats demonstrated that repeated oral administration of synthetic NMN (NMN-C®) at doses up to 1500 mg/kg/day over a sub-chronic (90-day) treatment period appears to be safe and did not promote toxic effects as seen from body weight change, food and water consumption, feed conversion efficiency, biochemical, and blood parameters [82]”

• cites [82] Cros C, Cannelle H, Laganier L, Grozio A, Canault M. Safety evaluation after acute and sub-chronic oral administration of high purity nicotinamide mononucleotide (NMN-C®) in Sprague-Dawley rats. Food Chem Toxicol. 2021;1(150):112060. sourceSupported

May combine two claims.

After NR, NAM removal pathways were highly active, with excess MeNAM, Me-2py, and Me-4py, and about a 20-fold increase of NAR in urine.

“NAM removal pathways were highly active after NR, with an excess of MeNAM, Me-2py, and Me-4py, and about a 20-fold increase of NAR in urine [29].”

• cites [29] Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 2019;28(7):1717–1728.e6. sourceSupported

May combine two claims.

NAM increases tissue NAD+ but also inhibits sirtuin and PARP activity.

“Although NAM has been shown to be effective to increase NAD+ in tissues, it also exerts an inhibitory effect on sirtuin [88] and PARPs activity [89].”

• cites [88] Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. J Biol Chem. 2002;277(47):45099–107. sourceNot checked — no full text of the source
• cites [89] Hwang ES, Song SB. Possible adverse effects of high-dose nicotinamide: mechanisms and safety assessment. Biomolecules. 2020;10(5). sourceSupported

May combine two claims.

NMN and NR are metabolites of the plant NAD+ pool, and vegetal foodstuffs are sources of these compounds.

“These findings characterizes NMN and NR as metabolites of the plant NAD+ pool [67, 69], and vegetal foodstuffs as sources of these compounds.”

• cites [67] Hashida S, Takahashi H, Uchimiya H. The role of NAD biosynthesis in plant development and stress responses. Ann Bot [Internet]. 2009;103(6):819–24. Available from: https://doi.org/10.1093/aob/mcp019. sourceNot checked — no full text of the source
• cites [69] Decros G, Beauvoit B, Colombié S, Cabasson C, Bernillon S, Arrivault S, et al. Regulation of pyridine nucleotide metabolism during tomato fruit development through transcript and protein profiling. Front Plant Sci [Internet]. 2019;10:1201. Available from: https://www.frontiersin.org/article/10.3389/fpls.2019.01201. sourceCould not verify

  The Introduction (page unavailable) describes NAD+ metabolism in plant cells, but identifies NaMN as nicotinic acid mononucleotide, not NMN. Searches for NMN, nicotinamide riboside, and food sources found no passage establishing that NMN and NR occur in the plant NAD+ pool or that vegetal foodstuffs supply them. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

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

Microbial species such as fructophilic lactic acid bacteria could be used biotechnologically to produce NMN and NR for functional probiotic products and supplements.

“This would bring new possibilities alongside the potential biotechnological use of microbial species (e.g., fructophilic lactic acid bacteria) to produce NMN and NR [78] for functional probiotic products and supplements.”

• cites [78] Sugiyama K, Iijima K, Yoshino M, Dohra H, Tokimoto Y, Nishikawa K, et al. Nicotinamide mononucleotide production by fructophilic lactic acid bacteria. Sci Rep [Internet]. 2021;11(1):7662. Available from: https://doi.org/10.1038/s41598-021-87361-1. sourceSupported

May combine two claims.

NAD synthesis inhibition by NAMPT inhibition decreases cell growth and increases susceptibility to oxidative stress, emerging as a therapeutic concept for cancer treatment.

“For example, NAD synthesis inhibition due to NAMPT inhibition decreases cell growth and increases susceptibility to oxidative stress emerging as a therapeutic concept for cancer treatment [79].”

• cites [79] Xu R, Yuan Z, Lijuan Y, Li L, Li D, Lv C. Inhibition of NAMPT decreases cell growth and enhances susceptibility to oxidative stress. Oncol Rep. 2017;38(3):1767–73. sourceSupported

May combine two claims.

In an oncogenic mouse model, NMN supplementation at 500 mg/kg body weight daily for 13 days significantly increased the pro-inflammatory senescence secretory phenotype and promoted pancreatic ductal adenocarcinoma progression.

“In an oncogenic mouse model, the supplementation with NMN (500 mg/kg body weight daily for 13 days) significantly increased the secretory phenotype associated with pro-inflammatory senescence, promoting pancreatic ductal adenocarcinoma progression.”

• cites [81] Nacarelli T, Lau L, Fukumoto T, Zundell J, Fatkhutdinov N, Wu S, et al. NAD+ metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol [Internet]. 2019;21(3):397–407. Available from: https://doi.org/10.1038/s41556-019-0287-4. sourceSupported

May combine two claims.

NAAD was not detected in human blood before NR supplementation, while single doses of up to 1 g NR increased NAAD baseline by about 2,900% in healthy individuals.

“In another study, NAAD was not detected in human blood prior to NR supplementation, while there was a ∼2,900% increase in NAAD baseline in healthy individuals taking single doses of up to 1 g NR (100, 300, and 1000 mg) [63].”

• cites [63] Trammell SAJ, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016;7(1). sourceSupported

May combine two claims.

A single oral dose of NMN from 100 to 500 mg was safely and effectively metabolized in healthy subjects, with significant dose-dependent increases in plasma metabolites and no adverse effects or significant clinical changes.

“The first clinical trial reported that a single oral dose of NMN (from 100 to 500 mg) was safely and effectively metabolized in healthy subjects. It showed a significant increase of metabolites in plasma in a dose-dependent manner, without causing adverse effects or any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature [40].”

• cites [40] Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J. 2020;67(2):153–60. sourceSupported

May combine two claims.

In healthy subjects, NMN at 250 mg/day for 12 weeks elevated NAD+ levels in whole blood with no obvious adverse effects or abnormalities in physiological and clinical laboratory tests.

“In healthy subjects, NMN (250 mg/day for 12 weeks) elevated NAD+ levels in whole blood and no obvious adverse effects, no abnormalities in physiological and clinical laboratory tests were observed [84].”

• cites [84] Okabe K, Yaku K, Uchida Y, Fukamizu Y, Sato T, Sakurai T, et al. Oral administration of nicotinamide mononucleotide is safe and efficiently increases blood nicotinamide adenine dinucleotide levels in healthy subjects. Front Nutr. 2022;11:9. sourceSupported

May combine two claims.

Short telomeres show decreased expression and activity of sirtuins and marked mitochondrial dysfunction.

“Short telomeres showed decreased expression and activity of sirtuins and marked mitochondrial dysfunction.”

• cites [101] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194. sourcePartly supported

  The Mitochondrial Dysfunction section links telomere attrition in telomerase-deficient mice to reduced mitochondrial biogenesis and describes mitochondrial decline. It also discusses sirtuins’ roles in mitochondrial function, but does not say that short telomeres decrease sirtuin expression or activity. The claim also presents the mitochondrial finding more broadly than the mouse-specific example in the passage. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

NAD+ levels decrease in various tissues during aging and play a critical role in the pathophysiology of age-associated metabolic disorders, neurodegenerative diseases, and mental disorders.

“It is recognized the decrease of NAD+ levels in various tissues during aging [11, 13, 96, 97], playing a critical role in the pathophysiology of several diseases, including age-associated metabolic disorders, neurodegenerative diseases, and mental disorders [14].”

• cites [11] Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One [Internet]. 2012;7(7):e42357 Available from: https://doi.org/10.1371/journal.pone.0042357. sourceSupported
• cites [13] Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528–36. sourceSupported
• cites [96] McReynolds MR, Chellappa K, Chiles E, Jankowski C, Shen Y, Chen L, et al. NAD+ flux is maintained in aged mice despite lower tissue concentrations. Cell Syst [Internet]. 2021;12(12):1160–1172.e4. Available from: https://www.sciencedirect.com/science/article/pii/S2405471221003380. sourceSupported
• cites [97] Zhu X-H, Lu M, Lee B-Y, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci. 2015;112(9):2876–81. sourcePartly supported

  The Discussion reports that intracellular NAD+ declines in the human brain during healthy aging, supporting an age-related decrease in that tissue. The paper does not establish a decline across various tissues. In the citing sentence, the disease claim has a separate citation [14], so it is not assessed against this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [14] Johnson S, Imai S. NAD+ biosynthesis, aging, and disease [version 1; peer review: 2 approved]. F1000Research [Internet]. 2018;7(132). Available from: http://openr.es/a4e. sourceSupported

May combine two claims.

NR promoted metabolic flexibility by enhancing energy expenditure, attenuating high-fat diet-induced body weight gain and decreasing fat mass, with liver triglyceride levels decreasing by 40%.

“It promoted metabolic flexibility by enhancing energy expenditure, leading to a significant attenuation of high-fat diet-induced body weight gain and a decrease in fat mass, particularly in the liver, where triglyceride levels decreased by 40% [95].”

• cites [95] Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012;15(6):838–47. sourceSupported

May combine two claims.

NR protects cognitive function, synaptic plasticity, learning, memory, and motor function in Alzheimer disease models.

“NR demonstrated protective effects on cognitive function, synaptic plasticity, learning, memory, and motor function in Alzheimer’s disease models [24, 27].”

• cites [24] Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, et al. NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci [Internet]. 2018;115(8):E1876 LP–E1885. Available from: http://www.pnas.org/content/115/8/E1876.abstract. sourceSupported
• cites [27] Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging. 2013;34(6):1581–8. sourcePartly supported

  Results §3.1 reports improved object-recognition performance in NR-treated Tg2576 Alzheimer’s-model mice, supporting the cognitive, learning and memory aspects. Results §3.3 reports improved hippocampal long-term potentiation, supporting synaptic plasticity. The paper does not report a motor-function outcome, so it does not support that part of the claim. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

NAMPT protein and NAD+ levels decrease significantly in white adipose tissue and skeletal muscle of old mice, affecting NAD-dependent enzymes such as sirtuins.

“The NAMPT (nicotinamide phosphoribosyltransferase) protein and NAD+ levels decreased significantly in organs, such as white adipose tissue and skeletal muscle in old mice [13] affecting the activity of NAD+ -dependent enzymes such as sirtuins [15, 98].”

• cites [13] Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528–36. sourcePartly supported

  The Results section on age-induced diabetes reports significant NAD+ decreases in white adipose tissue and skeletal muscle of old mice and says NAMPT protein levels also decreased in those tissues. It does not state that the NAMPT decreases were statistically significant. The sirtuin-activity clause is attached to different citations, so it is not assessed here; no page number is available in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [15] Imai S ichiro, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464–71. sourcePartly supported

  The sections “NAD+ declines with aging” and “Possible mechanisms for how NAD+ levels decline in aging” report lower NAD+ in aged mouse skeletal muscle and some evidence that NAMPT declines with age. They also link declining NAD+ to reduced sirtuin activity. The copy does not establish a significant decline in both NAMPT protein and NAD+ in white adipose tissue and skeletal muscle of old mice. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [98] Ramsey KM, Mills KF, Satoh A, Imai SI. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell. 2008;7(1):78–88. sourceNot checked — no full text of the source

May combine two claims.

Telomere shortening and a decrease in naïve lymphocytes impair immune function and increase circulating pro-inflammatory cytokines, contributing to worsening of COVID-19.

“The shortening of telomeres and decrease in naïve lymphocytes leading to impaired immune function and a rise in circulating pro-inflammatory cytokines are factors contributing to the worsening of COVID-19 cases [105, 106].”

• cites [105] Mueller AL, McNamara MS, Sinclair DA. Why does COVID-19 disproportionately affect older people? Aging (Albany NY) [Internet]. 2020;12(10):9959–81. Available from: https://doi.org/10.18632/aging.103344. sourcePartly supported

  In “The aging adaptive immune system” (page unavailable), the paper links telomere shortening to T-cell exhaustion and reduced naïve T cells to defective immunosurveillance, and describes immunosenescence as a likely factor in severe COVID-19. In “Increased inflammation and cytokine storms in the aged” (page unavailable), it separately links aging to higher circulating pro-inflammatory cytokines and cytokine storms. It does not establish that telomere shortening or the loss of naïve lymphocytes causes the rise in circulating cytokines implied by the citing sentence. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [106] Omran HM, Almaliki MS. Influence of NAD+ as an ageing-related immunomodulator on COVID 19 infection: a hypothesis. J Infect Public Health. 2020;13(9):1196–201. sourceSupported

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

It remains unclear why NR administration raises NAD+ levels more than NAM and NA treatment, while NMN and NAM administration show no difference in blood and liver NAD levels.

“It is still unclear why NR administration increases NAD+ levels more than NAM and NA treatment [63], while NMN and NAM administration showed no difference in NAD levels in blood and liver [90].”

• cites [63] Trammell SAJ, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016;7(1). sourceSupported
  Experimental — accuracy not yet measured
• cites [90] Kawamura T, Mori N, Shibata K. β-Nicotinamide mononucleotide, an anti-aging candidate compound, is retained in the body for longer than nicotinamide in rats. J Nutr Sci Vitaminol (Tokyo). 2016;62(4):272–6. sourceSupported
  Experimental — accuracy not yet measured

May combine two claims.

NMN promoted telomere lengthening in aged mice, pre-aging mice, and humans.

“NMN promoted telomere lengthening in aged mice [36], pre-aging mice and humans [37•].”

• cites [36] Amano H, Chaudhury A, Rodriguez-Aguayo C, Lu L, Akhanov V, Catic A, et al. Telomere dysfunction induces sirtuin repression that drives telomere-dependent disease. Cell Metab [Internet]. 2019;29(6):1274–1290.e9. Available from: https://doi.org/10.1016/j.cmet.2019.03.001. sourcePartly supported

  The Results (Fig. 6f) report significantly longer telomeres after NMN treatment in G4 mice with dysfunctional telomeres, but not a significant increase in wild-type mice. The Methods describe the mice as 8–16 weeks old, so this does not establish lengthening in aged mice. The sentence assigns the pre-aging-mouse and human claims to a different citation [37•], not this paper. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [37•]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

NR increased hepatic β-oxidation and mitochondrial content, reversing glucose intolerance, insulin resistance, liver lipid accumulation, and hepatic fibrosis.

“NR increased hepatic β-oxidation and mitochondrial content reversing glucose intolerance, insulin resistance, liver lipid accumulation, and hepatic fibrosis [21].”

• cites [21] Gariani K, Menzies KJ, Ryu D, Wegner CJ, Wang X, Ropelle ER, et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology [Internet]. 2016;63(4):1190–204. Available from: https://doi.org/10.1002/hep.28245. sourceSupported

May combine two claims.

NR significantly reduced neuroinflammation, hippocampal neuron apoptosis, phosphorylated Tau, and DNA damage, while increasing neurogenesis by almost 20%.

“Futhermore, NR significantly reduced neuroinflammation, apoptosis of hippocampal neurons, phosphorylated Tau and DNA damage, while also increasing neurogenesis by almost 20% [24].”

• cites [24] Hou Y, Lautrup S, Cordonnier S, Wang Y, Croteau DL, Zavala E, et al. NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci [Internet]. 2018;115(8):E1876 LP–E1885. Available from: http://www.pnas.org/content/115/8/E1876.abstract. sourcePartly supported

  The Results (pp. 6–7) report reduced phosphorylated Tau, DNA damage, and apoptosis after NR treatment; the Discussion (p. 7) reports reduced neuroinflammation. The Results (p. 4) also report increased proliferation of neuronal progenitor cells, but our copy does not give an almost-20% increase in neurogenesis. The findings concern AD mouse models and cultured mouse cells, rather than an unqualified effect. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Age is a risk factor for COVID-19, increasing the chances of severe disease and death.

“Age is also a risk factor for patients with COVID-19, increasing the chances of severe disease and death [105].”

• cites [105] Mueller AL, McNamara MS, Sinclair DA. Why does COVID-19 disproportionately affect older people? Aging (Albany NY) [Internet]. 2020;12(10):9959–81. Available from: https://doi.org/10.18632/aging.103344. sourceSupported

May combine two claims. The quote only partly states this claim.

NMN has been proposed as a nutraceutical to prevent age-related physiological decline and has been shown to improve diabetes and Alzheimer disease, enhance aerobic capacity, and exert cardio- and vasoprotective, anti-inflammatory, antioxidant, endothelial-protective, heart failure-protective, and ischemia/reperfusion-protective effects.

“Proposed as a nutraceutical to prevent age-related physiological decline [1••, 91], NMN has shown to improve diabetes [13, 20, 38] and Alzheimer’s disease [22, 23], enhance aerobic capacity [92], and exhibit cardio- and vasoprotective actions. It inhibits inflammation and decreases oxidative stress, preventing arterial and endothelial dysfunction [32, 93], and protecting against heart failure [94]”

• cites [1••, 91]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [13] Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528–36. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [20] Caton PW, Kieswich J, Yaqoob MM, Holness MJ, Sugden MC. Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function. Diabetologia [Internet]. 2011;54(12):3083–92. Available from: https://doi.org/10.1007/s00125-011-2288-0. sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites [38] Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science (80-). 2021;372(6547):1224–9. sourceNot checked — no full text of the source
• cites [22] Wang X, Hu X, Yang Y, Takata T, Sakurai T. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 2016;1643:1–9. sourceNot checked — no full text of the source
• cites [23] Yao Z, Yang W, Gao Z, Jia P. Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci Lett. 2017;647:133–40. sourceNot checked — no full text of the source

May combine two claims.

Intraperitoneal injection of NR at 400 mg/kg once daily for 1 week before facial nerve axotomy delayed axon degeneration and demyelination and significantly increased facial nucleus and facial nerve NAD+ levels in wild-type mice.

“Correspondingly, intraperitoneal injection of NR (400 mg/kg) once daily for 1 week prior to facial nerve axotomy, delayed axon degeneration, and demyelination, increasing significantly facial nucleus and facial nerve NAD+ levels in wild-type mice [100].”

• cites [100] Takaso Y, Noda M, Hattori T, Roboon J, Hatano M, Sugimoto H, et al. Deletion of CD38 and supplementation of NAD+ attenuate axon degeneration in a mouse facial nerve axotomy model. Sci Rep. 2020;10(1). sourceSupported

May combine two claims.

NMN treatment with 5 mM drinking water for 8 weeks promoted telomere lengthening in G4 mice, dampened the DNA damage response and p53, rescued liver fibrosis, and improved mitochondrial biogenesis and function in a partially SIRT1-dependent manner.

“Treatment with NMN (dissolved in 5-mM drinking water for 8 weeks) promoted telomere lengthening in generation 4 (G4) mice, dampened the DNA damage response and p53, functionally rescued liver fibrosis, and improved the mitochondrial biogenesis and function in a partially SIRT1-dependent manner [36].”

• cites [36] Amano H, Chaudhury A, Rodriguez-Aguayo C, Lu L, Akhanov V, Catic A, et al. Telomere dysfunction induces sirtuin repression that drives telomere-dependent disease. Cell Metab [Internet]. 2019;29(6):1274–1290.e9. Available from: https://doi.org/10.1016/j.cmet.2019.03.001. sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

This affects the balance of cellular redox reactions and leads to functional decline.

“As consequence, affect the balance of redox reactions in the cell, leading to functional decline [14].”

• cites [14] Johnson S, Imai S. NAD+ biosynthesis, aging, and disease [version 1; peer review: 2 approved]. F1000Research [Internet]. 2018;7(132). Available from: http://openr.es/a4e. sourceSupported

May combine two claims.

NR reduced beta-amyloid levels and increased the chance of recognizing a novel object by 20% in NR-treated Tg2576 mice.

“It reduced the beta-amyloid levels, increasing the chance of recognizing a novel object by 20% in NR-treated Tg2576 mice [27].”

• cites [27] Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging. 2013;34(6):1581–8. sourceSupported

May combine two claims.

During aging, DNA damage accumulates in the cell nucleus, causing PARP activation and reducing both NAD+ levels and SIRT1 activity.

“During the aging process, DNA damage accumulates in the cell nucleus causing PARPs activation and reducing both NAD+ levels and SIRT1 activity [15].”

• cites [15] Imai S ichiro, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 2014;24(8):464–71. sourcePartly supported

  In “Possible mechanisms for how NAD+ levels decline in aging” (page not provided), the paper reports chronic PARP activation in aging animals alongside reduced NAD+ and evidence of lower SIRT1 activity. It presents accumulated nuclear DNA damage as a possible explanation for PARP-mediated NAD+ depletion, not as an established cause of the entire chain stated in the claim. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

NR prevents and improves metabolic disorders such as high-fat diet-induced obesity and non-alcoholic fatty liver disease.

“Additionally, NR has been shown to prevent and improve metabolic disorders such as high-fat diet- induced obesity and non-alcoholic fatty liver disease (NAFLD).”

• cites [95] Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012;15(6):838–47. sourcePartly supported

  In Results, under “NR supplementation enhances energy expenditure” (page unavailable), NR significantly attenuated high-fat-diet-induced weight gain in mice, and their livers contained 40% less triglyceride. The paper does not establish that NR prevents or improves diagnosed NAFLD, nor does this prevention study show improvement of an existing disorder. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [21] Gariani K, Menzies KJ, Ryu D, Wegner CJ, Wang X, Ropelle ER, et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology [Internet]. 2016;63(4):1190–204. Available from: https://doi.org/10.1002/hep.28245. sourceSupported

May combine two claims.

Aging leads to dysfunctional mitochondria with defective mitophagy and bioenergetics, producing excess free radicals that damage the cellular environment.

“As we age, mitochondria become increasingly dysfunctional, with defective mitophagy and bioenergetic capabilities which end up producing excess free radicals inside the cell, damaging the global cellular environment [101].”

• cites [101] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194. sourcePartly supported

  The Mitochondrial Dysfunction section describes declining respiratory-chain efficiency with age, and its Mitochondrial integrity and biogenesis subsection identifies defective mitophagy as a cause of impaired bioenergetics. The Reactive oxygen species subsection says ROS levels can rise with age and eventually aggravate cellular damage. But the paper does not present excess ROS as an inevitable result of mitochondrial dysfunction: its Genomic Instability > Mitochondrial DNA subsection reports impaired mitochondrial function without increased ROS production. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

CMAs reinforced immune response and regulated amino acid and lipid metabolism.

“CMAs were found to reinforce immune response and regulate amino acid and lipid metabolism.”

• cites [109] Altay O, Arif M, Li X, Yang H, Aydın M, Alkurt G, et al. Combined metabolic activators accelerates recovery in mild-to-moderate COVID-19. Adv Sci. 2021;8(17):2101222. sourcePartly supported

  The Results sections on global metabolism report CMA-associated changes in amino-acid and lipid metabolites. The cytokine Results section reports improved inflammation-related cytokine levels during COVID-19 recovery, but it does not establish that CMA reinforced the immune response; that part overstates the measured finding. The copy provides no page numbers for these sections. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

NMN was beneficial for glucose tolerance only in the most metabolically compromised mice group (HFD and from obese progenitress); it impaired glucose tolerance in mice from lean progenitress consuming chow and had no additional impact in offspring consuming HFD.

“However, in relation to glucose tolerance, NMN was beneficial only for the most metabolically compromised mice group (feed HFD and from obese progenitress). In addition, NMN impaired glucose tolerance in mice from lean progenitress consuming chow and had no additional impact in offspring consuming HFD [115].”

• cites [115] Uddin GM, Youngson NA, Chowdhury SS, Hagan C, Sinclair DA, Morris MJ. Administration of nicotinamide mononucleotide (NMN) reduces metabolic impairment in male mouse offspring from obese mothers. Cells. 2020;9(4). sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

May combine two claims.

Declining NAD+ levels is a signature of imbalance in energy homeostasis, making NAD+ an energy-sensing metabolite.

“Declining NAD+ levels is a signature of an imbalance in energy homeostasis [114], which makes it an energy-sensing metabolite.”

• cites [114] Fan L, Cacicedo JM, Ido Y. Impaired nicotinamide adenine dinucleotide (NAD+) metabolism in diabetes and diabetic tissues: implications for nicotinamide-related compound treatment. J Diabetes Investig [Internet]. 2020;11(6):1403–19. Available from: https://doi.org/10.1111/jdi.13303. sourceSupported

May combine two claims.

Proteomics analysis identified that NMN downregulated COX-2 expression and markedly decreased mRNA expression and extracellular secretion of IL-6 and IL-1β, and cellular PGE2 levels.

“Proteomics analysis identified that NMN downregulated the expression of cyclooxygenase-2 (COX-2) and markedly decreased mRNA expressions and extracellular secretion of IL-6 and IL-1β, and the cellular levels of prostaglandin E2 (PGE2).”

• cites [31] Liu J, Zong Z, Zhang W, Chen Y, Wang X, Shen J, et al. Nicotinamide mononucleotide alleviates lps-induced inflammation and oxidative stress via decreasing COX-2 expression in macrophages. Front Mol Biosci. 2021;6:8. sourceSupported

May combine two claims.

Excessive PARP activation compensates for ADPR hydrolysis and consumes NAD+, suggesting that increasing NAD+ may restore antiviral PARP functions to support immunity to SARS-CoV-2.

“Consequently, excessive activation of PARPs occurs to compensate for ADPR hydrolysis, accompanied by NAD+ consumption, suggesting that increasing NAD+ levels may restore the antiviral functions of PARPs to support immunity to SARS-CoV-2 [16, 106].”

• cites [16] Heer CD, Sanderson DJ, Voth LS, Alhammad YMO, Schmidt MS, Trammell SAJ, et al. Coronavirus infection and PARP expression dysregulate the NAD metabolome: an actionable component of innate immunity. J Biol Chem. 2020;295(52):17986–96. sourcePartly supported

  The Results report that coronavirus infection induces antiviral PARPs, PARP10 expression lowers cellular NAD+, and NAD boosting can enhance PARP activity. The Discussion proposes testing NAD boosters for COVID-19, but the paper does not establish that PARPs are excessively activated to compensate for ADPR hydrolysis or that boosting NAD+ restores immunity to SARS-CoV-2; its viral-replication test used a hydrolase-mutant MHV. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [106] Omran HM, Almaliki MS. Influence of NAD+ as an ageing-related immunomodulator on COVID 19 infection: a hypothesis. J Infect Public Health. 2020;13(9):1196–201. sourcePartly supported

  In “Role of NAD+ in infection and autoimmune diseases” (page unavailable), the paper says coronavirus-mediated ADP-ribose hydrolysis can prompt excessive PARP-1 activation and NAD+ consumption. It also describes PARP-1 as antiviral and says exogenous NAD+ can reverse its overactivation, but it does not say that increasing NAD+ restores PARP’s antiviral function against SARS-CoV-2; it emphasizes inhibiting PARP-1 overactivation and inflammation. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in deacetylation and modulation of energy metabolism-related downstream SIRT1 targets including PGC1α, FOXO1, and FOXO3a.

“Thus, AMPK enhances the SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of energy metabolism-related downstream SIRT1 targets, which include the PGC1α, the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors [102].”

• cites [102] Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature [Internet]. 2009;458(7241):1056–60. Available from: https://doi.org/10.1038/nature07813. sourceSupported

May combine two claims.

NR (450 mg/kg body weight for 45 days) stabilized myocardial NAD+ levels, increased glycolysis and citrate and acetyl-coenzyme A metabolism, attenuating heart failure development in a mouse model with dilated cardiomyopathy.

“NR (450 mg/kg body weight for 45 days) stabilized myocardial NAD+ levels, increased glycolysis, and citrate and acetyl-coenzyme A metabolism, attenuating the development of heart failure in a mouse model with dilated cardiomyopathy [35].”

• cites [35] Diguet N, Trammell SAJ, Tannous C, Deloux R, Piquereau J, Mougenot N, et al. Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation [Internet]. 2018;137(21):2256–73. Available from: https://doi.org/10.1161/CIRCULATIONAHA.116.026099. sourcePartly supported

  The Results sections on the SRFHKO heart and cardiac NAD+ metabolome report that dietary NR preserved myocardial NAD+ and attenuated heart-failure development in mice with dilated cardiomyopathy. The reported dose was 400 mg/kg/day from day 5 to day 50, not 450 mg/kg. NR improved cardiac citrate synthase and ATP-citrate lyase activity, but the reported increase in glycolysis was measured in cultured cardiomyocytes, not in the treated mice. Page numbers were not available in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

NR protected against detrimental metabolic effects of a high-fat diet including hyperinsulinemia, elevated total and LDL cholesterol, and weight gain, but had no effect on body weight when given with a normal chow diet.

“In addition, NR protected against the detrimental metabolic effects of a high-fat diet, including hyperinsulinemia, elevated levels of total and LDL cholesterol, and weight gain, although it had no effect on body weight when given with a normal chow diet [95].”

• cites [95] Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012;15(6):838–47. sourceSupported

May combine two claims.

NR reduced acetylation of SOD2 and isocitrate dehydrogenase 2 while increasing mitochondrial SOD2 activity, thereby reducing mitochondrial ROS levels.

“NR reduced acetylation of SOD2 and isocitrate dehydrogenase 2, while increasing mitochondrial SOD2 activity, thereby reducing mitochondrial ROS levels.”

• cites [30] Traba J, Kwarteng-Siaw M, Okoli TC, Li J, Huffstutler RD, Bray A, et al. Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects. J Clin Invest. 2015;125(12):4592–600. sourceSupported

May combine two claims.

AMPK senses changes in intracellular AMP/ATP ratio; during energy limitation, low ATP activates AMPK to maintain cellular energy stores.

“The adenosine monophosphate-activated protein kinase (AMPK) is a cellular energy regulator which senses changes in the intracellular AMP/ATP ratio. During energy limitation, low levels of ATP activate AMPK, which acts to maintain cellular energy stores.”

• cites [102] Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature [Internet]. 2009;458(7241):1056–60. Available from: https://doi.org/10.1038/nature07813. sourceSupported

May combine two claims.

NR decreased IL-1β and TNF-α secretion in monocytes and macrophages from healthy volunteers, with the largest reductions in monocytes (>50% for IL-1β and >75% for TNF-α) and smaller reductions in macrophages (~20% for IL-1β and ~45% for TNF-α).

“Additionally, NR decreased Interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) secretion in monocytes and macrophages from healthy volunteers, with the most significant reductions in monocytes of over 50% for IL-1β (from approximately 22,000 to 10,000 pg/mL) and over 75% for TNF-α (from above 2000 to less than 500 pg/mL). In macrophages, the most pronounced reduction was around 20% for”

• cites [30] Traba J, Kwarteng-Siaw M, Okoli TC, Li J, Huffstutler RD, Bray A, et al. Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects. J Clin Invest. 2015;125(12):4592–600. sourcePartly supported

  The Discussion (page unavailable) says NR decreased cytokine release in monocytes and primary macrophages from healthy volunteers. It does not give the claimed IL-1β and TNF-α reductions for each cell type, or establish that the reductions were larger in monocytes. The cited Supplemental Figure 4 values are not present in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

NR supplementation (400 mg/kg/day) in mice increased NAD+ levels in liver and muscle, stimulated SIRT1 and SIRT3 activity, and enhanced mitochondrial function, oxidative metabolism, energy expenditure, and endurance performance.

“By increasing NAD+ levels in mice’s liver and muscle, NR supplementation (400 mg/kg/day) stimulated SIRT1 and SIRT3 activity, enhancing the mitochondrial function, oxidative metabolism, energy expenditure, and endurance performance [95].”

• cites [95] Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012;15(6):838–47. sourcePartly supported

  The Results sections report that 400 mg/kg/day NR increased liver and muscle NAD+, increased readouts of SIRT1 and SIRT3 activity, and improved measures of mitochondrial function and oxidative metabolism (page numbers unavailable). The energy-expenditure and endurance Results qualify the performance findings: both showed a tendency on chow but a significant improvement on a high-fat diet. The sentence omits that condition and presents sirtuin activity as the established cause of all the outcomes, whereas the Discussion notes that other NR actions may contribute. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

NMN treatment suppressed other inflammation-associated pathways such as prostanoid biosynthesis, LPS/IL-1 mediated inhibition of RXR function, IL-6 signaling, and NF-κB signaling.

“NMN treatment also suppressed other inflammation-associated pathways such as prostanoid biosynthesis, LPS/IL-1 mediated inhibition of RXR function, IL-6 signaling, and NF-κB signaling [31].”

• cites [31] Liu J, Zong Z, Zhang W, Chen Y, Wang X, Shen J, et al. Nicotinamide mononucleotide alleviates lps-induced inflammation and oxidative stress via decreasing COX-2 expression in macrophages. Front Mol Biosci. 2021;6:8. sourceSupported

May combine two claims.

NAD+/NADH ratio imbalance (pseudohypoxia) causes reductive stress, mitochondrial overload, and dysfunction, leading to oxidative stress and damage to DNA, lipids, and proteins.

“This NAD+ /NADH ratio imbalance, also known as pseudohypoxia, initially causes reductive stress, mitochondrial overload, and dysfunction, which lead to oxidative stress and oxidative damage to macromolecules, including DNA, lipids, and proteins.”

• cites [117] Wu J, Jin Z, Zheng H, Yan L-J. Sources and implications of NADH/NAD(+) redox imbalance in diabetes and its complications. Diabetes Metab Syndr Obes [Internet]. 2016;9:145–53. Available from: https://pubmed.ncbi.nlm.nih.gov/27274295. sourcePartly supported

  The Abstract states that NADH/NAD+ imbalance initially produces reductive stress and eventually oxidative stress and damage to DNA, lipids, and proteins. “Detrimental effects of redox imbalance in diabetes” describes NADH overloading the mitochondrial electron transport chain, with ROS production and mitochondrial dysfunction. The paper does not itself identify NADH/NAD+ imbalance as “pseudohypoxia”; that term appears only in a cited reference title. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Daily oral gavage of NR 400 mg/kg/day for 4 weeks alleviated diabetes-induced cardiomyopathy and improved cardiac function in diabetic mice.

“Daily oral gavage of NR 400 mg/kg/day for 4 weeks alleviated diabetes-induced cardiomyopathy improving cardiac function in diabetic mice.”

• cites [19] Hu L, Guo Y, Song L, Wen H, Sun N, Wang Y, et al. Nicotinamide riboside promotes Mfn2-mediated mitochondrial fusion in diabetic hearts through the SIRT1-PGC1α-PPARα pathway. Free Radic Biol Med. 2022;1(183):75–88. sourceSupported

May combine two claims.

Hyperglycemia of diabetes causes a redox imbalance between NAD+ and NADH, which can lead to oxidative stress and metabolic syndromes.

“The hallmark hyperglycemia of diabetes mellitus causes a redox imbalance between NAD+ and NADH ratio, which can lead to oxidative stress and a variety of metabolic syndromes.”

• cites [117] Wu J, Jin Z, Zheng H, Yan L-J. Sources and implications of NADH/NAD(+) redox imbalance in diabetes and its complications. Diabetes Metab Syndr Obes [Internet]. 2016;9:145–53. Available from: https://pubmed.ncbi.nlm.nih.gov/27274295. sourceSupported

May combine two claims.

Bifidobacterium and Lactobacillus are associated with improved gut health, including prevention of diarrhea, improved gut barrier function, reduced inflammation, and immune system support.

“These bacteria have been associated with improved gut health, including prevention of diarrhea, improved gut barrier function, reduced inflammation, and immune system support [127].”

• cites [127] Turroni F, Ventura M, Buttó LF, Duranti S, O’Toole PW, Motherway MO, et al. Molecular dialogue between the human gut microbiota and the host: a Lactobacillus and Bifidobacterium perspective. Cell Mol Life Sci. 2014;71(2):183–203. sourceSupported

May combine two claims.

In diet- and age-induced diabetic models, intraperitoneal NMN (500 mg/kg/day for 11 days) ameliorated impaired glucose tolerance substantially and enhanced hepatic insulin sensitivity.

“In both diet- and age-induced diabetic models, the administration of NMN via intraperitoneal (500 mg/kg body weight/day for 11 days) ameliorated impaired glucose tolerance substantially and enhanced hepatic insulin sensitivity.”

• cites [13] Yoshino J, Mills KF, Yoon MJ, Imai SI. Nicotinamide mononucleotide, a key NAD + intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011;14(4):528–36. sourcePartly supported

  The Results report improved glucose tolerance in diet- and age-induced diabetic mice and improved hepatic insulin sensitivity in HFD-fed diabetic females. The 500 mg/kg/day intraperitoneal dose is supported, but 11 injections were used for aged diabetic females; HFD-fed males and females received 10 and 7 days, respectively, and aged diabetic males improved after one dose. The claim also extends the hepatic insulin-sensitivity finding beyond the females in whom it was assessed. Page numbers are not available in the supplied passages. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

Gut microbiota has an important physiological role in metabolic homeostasis, hormone secretion, and brain function of the host.

“It is also already known the important physiological role of gut microbiota in the metabolic homeostasis, hormones secretion, and brain function of the host [118–121].”

• cites [118] Blacher E, Bashiardes S, Shapiro H, Rothschild D, Mor U, Dori-Bachash M, et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature [Internet]. 2019;572(7770):474–80. Available from: https://doi.org/10.1038/s41586-019-1443-5. sourcePartly supported

  The introductory passage links gut-microbiome metabolites to neuronal processes, and the ‘AM attenuates ALS in mice by increasing NAM levels’ section reports microbiome-associated changes in circulating metabolites. These support roles in brain function and metabolism, chiefly in an ALS mouse model, but the passages do not establish metabolic homeostasis generally or a role in hormone secretion. Page numbers were not provided in our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [119] Sun L-J, Li J-N, Nie Y-Z. Gut hormones in microbiota-gut-brain cross-talk. Chin Med J (Engl). 2020;133(7):826–33. sourceSupported
• cites [120] Mishra AK, Dubey V, Ghosh AR. Obesity: an overview of possible role(s) of gut hormones, lipid sensing and gut microbiota. Metabolism. 2016;65(1):48–65. sourceNot checked — no full text of the source
• cites [121] Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021;19(1):55–71. sourceSupported

May combine two claims.

NMN demonstrated a protecting effect on IBD in an experimental mice model of colitis, reversing intestinal dysbiosis.

“NMN also demonstrated protecting effect on IBD in an experimental mice model of colitis, reversing the intestinal dysbiosis [46].”

• cites [46] Huang P, Wang X, Wang S, Wu Z, Zhou Z, Shao G, et al. Treatment of inflammatory bowel disease: potential effect of NMN on intestinal barrier and gut microbiota. Curr Res Food Sci. 2022;5:1403–11. sourceSupported
  Experimental — accuracy not yet measured

May combine two claims.

Sirtuins are involved in regulating gut microbiota and in protecting intestinal endothelial cells against oxidative injury.

“Sirtuins are involved in regulating the gut microbiota [128, 129] and in protecting intestinal endothelial cells against oxidative injury [130].”

• cites [128] Wellman AS, Metukuri MR, Kazgan N, Xu X, Xu Q, Ren NSX, et al. Intestinal epithelial sirtuin 1 regulates intestinal inflammation during aging in mice by altering the intestinal microbiota. gastroenterology. 2017;153(3):772–86. sourceSupported
• cites [129] Zhang Y, Wang X, Zhou M, Kang C, Lang H, Chen M, et al. Crosstalk between gut microbiota and sirtuin-3 in colonic inflammation and tumorigenesis. Exp Mol Med. 2018;50(4):1–11. sourceSupported
• cites [130] Zhang X, Tian B, Deng Q, Cao J, Ding X, Liu Q, et al. Nicotinamide riboside relieves the severity of experimental necrotizing enterocolitis by regulating endothelial function via eNOS deacetylation. Free Radic Biol Med. 2022;184:218–29. sourceNot checked — no full text of the source

May combine two claims.

Mice fed 60% HFD supplemented with 0.4% NR for 168 days had almost 16% reduction in weight gain and reduced fasting blood glucose compared to vehicle.

“Mice fed with 60% HFD supplemented with 0.4% NR (for 168 days) had almost a 16% reduction in weight gain and a reduction in fasting blood glucose levels compared to the control supplemented with vehicle (water).”

• cites [131] Lozada-Fernández VV, DeLeon O, Kellogg SL, Saravia FL, Hadiono MA, Atkinson SN, et al. Nicotinamide riboside-conditioned microbiota deflects high-fat diet-induced weight gain in mice. mSystems. 2022;7(1). sourceSupported

May combine two claims.

NAD+ can indirectly affect gut microbes by regulating colon movement through β-NAD and by affecting synthesis of host bile acids, which can be antimicrobial.

“Furthermore, NAD+ can indirectly affect gut microbes by regulating the movement of the colon through the key inhibitory neurotransmitter β-NAD and by affecting the synthesis of host bile acids [45], which can be antimicrobial when they destroy the bacterial cell membrane [134].”

• cites [45] Huang P, Jiang A, Wang X, Zhou Y, Tang W, Ren C, et al. NMN maintains intestinal homeostasis by regulating the gut microbiota. Front Nutr. 2021;29:8. sourcePartly supported

  The Introduction (page unavailable) says bile acids regulate gut microbiota, supporting the broad bile-acid link. But the Discussion (page unavailable) speculates that the higher fecal bile-acid levels after NMN treatment reflect decreased ileal reabsorption, not increased synthesis. The paper does not describe β-NAD regulating colon movement; the antimicrobial cell-membrane mechanism is attached to a different citation. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [134] Ren Z, Xu Y, Li T, Sun W, Tang Z, Wang Y, et al. NAD+ and its possible role in gut microbiota: Insights on the mechanisms by which gut microbes influence host metabolism. Anim Nutr. 2022;10:360–71. sourceSupported

May combine two claims.

NAD+ can directly affect metabolism of intestinal microorganisms; because NAD+ is an important component in energy metabolism, boosting NAD+ may promote microbial energy production.

“And indeed NAD+ can directly affect the metabolism of intestinal microorganisms. Because NAD+ is an important component in the energy metabolism of all living organisms, mainly to be a cofactor for many key enzymes involved in the production of cellular ATP, boosting NAD+ may promote microbial energy production [134].”

• cites [134] Ren Z, Xu Y, Li T, Sun W, Tang Z, Wang Y, et al. NAD+ and its possible role in gut microbiota: Insights on the mechanisms by which gut microbes influence host metabolism. Anim Nutr. 2022;10:360–71. sourceSupported

May combine two claims.

NMN increased microbial abundance and diversity, improved mucus secretion and tight-junction protein expression, attenuating intestinal mucosal permeability.

“In addition to increasing microbial abundance and diversity, NMN improved the mucus secretion and tight-junction proteins’ expression, which helped to attenuate intestinal mucosal permeability [46].”

• cites [46] Huang P, Wang X, Wang S, Wu Z, Zhou Z, Shao G, et al. Treatment of inflammatory bowel disease: potential effect of NMN on intestinal barrier and gut microbiota. Curr Res Food Sci. 2022;5:1403–11. sourceSupported
  Experimental — accuracy not yet measured

May combine two claims.

Although NMN reduced diversity of intestinal species, it increased abundance of butyric acid-producing bacteria (Ruminococcae_UCG-014 and Prevotellaceae_NK3B31_group) and probiotics such as Akkermansia muciniphila, while decreasing harmful bacteria (Bilophila and Oscillibacter).

“Although NMN reduced the diversity of intestinal species, it increased the abundance of butyric acid-producing bacteria (Ruminococcae_UCG-014 and Prevotellaceae_NK3B31_group) and other probiotics such as Akkermansia muciniphila, while the abundance of several harmful bacteria (Bilophila and Oscillibacter) were decreased [45].”

• cites [45] Huang P, Jiang A, Wang X, Zhou Y, Tang W, Ren C, et al. NMN maintains intestinal homeostasis by regulating the gut microbiota. Front Nutr. 2021;29:8. sourceSupported

May combine two claims.

NMN increased bile acid-related metabolites and beneficial metabolites, number of goblet cells, mucus thickness, and tight junction protein expression, maintaining intestinal epithelium integrity and reducing mucosal permeability.

“In addition, NMN increased the level of bile acid-related metabolites and beneficial metabolites, the number of goblet cells, mucus thickness, and expression of tight junction protein, maintaining the integrity of the intestinal epithelium and reducing mucosal permeability [45].”

• cites [45] Huang P, Jiang A, Wang X, Zhou Y, Tang W, Ren C, et al. NMN maintains intestinal homeostasis by regulating the gut microbiota. Front Nutr. 2021;29:8. sourceSupported

May combine two claims.

Dietary NAD+ precursors can promote NAD+ biosynthesis and raise intracellular NAD+ levels, and this may be a strategy to reverse physiological decline and prevent disease.

“Dietary precursors can promote NAD+ biosynthesis and increase intracellular levels, being a potential strategy for reversing physiological decline and preventing diseases.”

May combine two claims.

Gut bacteria convert NMN to NAMN by deamidation, after which NAMN enters the Preiss-Handler pathway to NAD+ synthesis.

“Unlike mammals, the bacteria present in the gut possess enzymes that convert NMN to nicotinic acid mononucleotide (NAMN) through a process of deamidation [62]. After that, NAMN follows via the Preiss-Handler pathway to NAD+ synthesis.”

• cites [62] Galeazzi L, Bocci P, Amici A, Brunetti L, Ruggieri S, Romine M, et al. Identification of nicotinamide mononucleotide deamidase of the bacterial pyridine nucleotide cycle reveals a novel broadly conserved amidohydrolase family. J Biol Chem. 2011;286(46):40365–75. sourceNot checked — no full text of the source

May combine two claims.

In mammals, NAD+ can be produced de novo from tryptophan, through the NAM salvage pathway, or from NA via the Preiss-Handler pathway.

“In mammals, NAD can be produced in different ways: by de novo generation from the amino acid tryptophan, by the nicotinamide (NAM) in the salvage pathway which is released from these consuming reactions as a NAD recycling system, or by niacin/nicotinic acid (NA) in the Preiss-Handler pathway (Fig. 2A).”

May combine two claims.

NR and NMN occur in vegetables, meat, and milk, and microorganisms in fermented beverages can produce them.

“NR and NMN have been found in vegetables, meat, and milk, and microorganisms in fermented beverages can also produce them.”

• cites [1••, 41, 42]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [77•]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

NMN and NR affect gut microbiota composition, reversing dysbiosis and promoting intestinal and extraintestinal benefits.

“NMN and NR also affect the composition of the gut microbiota, reversing dysbiose and promoting beneficial effects at both intestinal and extraintestinal levels [45–47•].”

• cites [45–47•]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

NAD+ decline can result from reduced NAD-synthesizing enzymes, increased NAD-consuming enzymes, or both.

“In summary, NAD+ decline can result from reduced NAD-synthesizing enzymes, increased NAD-consuming enzymes, or a combination of both.”

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

NR has been named the third NAD+ vitamin precursor alongside NAM and NA.

“NR has been named as the third NAD+ vitamin precursor, alongside NAM and NA [65].”

• cites [65] Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr [Internet]. 2008;28(1):115–30. Available from: https://doi.org/10.1146/annurev.nutr.28.061807.155443. sourceNot checked — no full text of the source

May combine two claims.

NAD+ is a molecule essential for living organisms and cellular health, serving as a redox cofactor and as a substrate in cellular signaling.

“NAD+ is a vital molecule that takes part as a redox cofactor in several metabolic reactions besides being used as a substrate in important cellular signaling in regulation pathways for energetic, genotoxic, and infectious stress.”

• Also stated in: § Introduction · plain

  “NAD+ is the oxidized form of nicotinamide adenine dinucleotide, a molecule essential for living organisms for maintaining cellular health.”

• cites [1••, 2–6]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [7] Berger F, Ramírez-Hernández MH, Ziegler M. The new life of a centenarian: signalling functions of NAD(P). Trends Biochem Sci. 2004;29(3):111–8. sourceNot checked — no full text of the source

May combine two claims.

NMN and NR are present in foods and may have a dietary therapeutic role similar to other bioactive food compounds.

“However, these NAD+ precursors are also present in foods and may have a potential dietary therapeutic role, similar to that of phenolic groups and other bioactive food compounds.”

• cites [1••, 41, 42]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Under hot acid or alkaline extraction, NR and NMN hydrolyze to NA and can account for total niacin in analyzed milk samples.

“And indeed, NR and NMN molecules were hydrolyzed to NA and could account for the total niacin content in the milk samples analyzed [42].”

• cites [42] Ummarino S, Mozzon M, Zamporlini F, Amici A, Mazzola F, Orsomando G, et al. Simultaneous quantitation of nicotinamide riboside, nicotinamide mononucleotide and nicotinamide adenine dinucleotide in milk by a novel enzyme-coupled assay. Food Chem. 2017;15(221):161–8. sourceNot checked — no full text of the source

May combine two claims.

NMN and NR reverse gut dysbiosis and produce beneficial effects at intestinal and extraintestinal levels.

“They also reverse gut dysbiosis and promote beneficial effects at intestinal and extraintestinal levels.”

• cites [45–47•]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The dietary contribution of NR and NMN to increasing NAD+ levels and the search for their food sources remain largely unexplored.

“The prospection of NR and NMN to find potential food sources and their dietary contribution in increasing NAD+ levels are still an unexplored field of research.”

May combine two claims.

Muscle NAD+ content did not change after 10 weeks, but NMN treatment increased muscle metabolites MeNAM, Me-2py, and Me-4py.

“Although muscle NAD+ content did not change after 10 weeks, NMN treatment increased muscle metabolites N1-methylnicotinamide (MeNAM), N1-methyl-2-pyridone-5-carboxamide (Me-2py), and N1-methyl-4-pyridone-5-carboxamide (Me-4py).”

• cites [38] Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science (80-). 2021;372(6547):1224–9. sourceNot checked — no full text of the source

May combine two claims.

Among investigated foods, edamame had the highest NMN amount at 0.47-1.88 mg/100 g and avocado at 0.36-1.60 mg/100 g, with lower amounts in seafood and raw meats at 0.06-0.42 mg/100 g.

“Among the investigated sources, the highest amount was found in edamame ranging at 0.47–1.88 (mg/100 g) and avocado at 0.36–1.60 (mg/100 g), and at smaller amounts in seafood and raw meats (0.06–0.42 mg/100 g) [1••].”

• cites [1••]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

Plasma NMN levels may be kept low and constant by balanced distribution of NMN from plasma to tissues.

“Suggesting plasma NMN levels may also be kept low and constant due to balanced NMN distribution from plasma to tissues.”

• cites [1••]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

NA at pharmacological doses reduced serum cholesterol levels in humans, but its use is limited by skin flushing, warmth, and itching.

“NA at pharmacological doses reduced serum cholesterol levels in humans; however, its use is limited due to the side effect causing skin flushing, accompanied by an unpleasant warmth sensation, and often itching [87].”

• cites [87] Capuzzi DM, Morgan JM, Brusco OA, Intenzo CM. Niacin dosing: relationship to benefits and adverse effects. Curr Atheroscler Rep [Internet]. 2000;2(1):64–71. Available from: https://doi.org/10.1007/s11883-000-0096-y. sourceNot checked — no full text of the source

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

The optimal dose of NMN and NR supplements for humans is not yet fully understood.

“However, it is important to note that the optimal dose of NMN and NR supplements for humans is not yet fully understood and further research is needed to determine the most effective and safe dosage.”

May combine two claims.

NMN and NR reversed cell death induced by a NAMPT inhibitor, CD38 favored cell death, and CD73 allowed cell viability by degrading NAD and NMN into NAM and NMN into NR, respectively, sustaining NAD+ synthesis.

“While the NAD+ precursors, NMN and NR, reversed cell death induced by the NAMPT inhibitor, the CD38 favored cell death, and CD73 allowed cell viability by degrading NAD and NMN into NAM, and NMN into NR, respectively, thus sustaining NAD+ synthesis [80].”

• cites [80] Grozio A, Sociali G, Sturla L, Caffa I, Soncini D, Salis A, et al. CD73 Protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated Tumor Cells. J Biol Chem. 2013;288(36). sourceNot checked — no full text of the source

May combine two claims.

Bovine milk has the highest NR content at 0.5-3.6 μM, and human milk is the richest NMN source at 2.1-9.8 μM.

“with bovine milk having the highest NR content (0.5–3.6 μM,) and human milk as the richest NMN source (2.1–9.8 μM) [42].”

• cites [42] Ummarino S, Mozzon M, Zamporlini F, Amici A, Mazzola F, Orsomando G, et al. Simultaneous quantitation of nicotinamide riboside, nicotinamide mononucleotide and nicotinamide adenine dinucleotide in milk by a novel enzyme-coupled assay. Food Chem. 2017;15(221):161–8. sourceNot checked — no full text of the source

• AssumptionThe authors state this as an assumption: The NR and NMN concentrations reported for milk are per 1 L volume.

May combine two claims.

Yeast-mediated NR and NMN production in craft beers has been demonstrated, and hops may enhance NR levels during fermentation.

“Recently, yeast-mediated NR and NMN production in craft beers was demonstrated, and hop indicated a role in the enhancement of NR levels during fermentation [77•]”

• cites [77•]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

NAD+ is essential for plant adaptation to environmental stresses such as UV irradiation, salinity, heat shock, and drought.

“NAD+ is essential for plants’ adaptation to environmental stresses such as UV irradiation, salinity, heat shock, and drought stress [66, 67].”

• cites [66] Gakière B, Hao J, de Bont L, Pétriacq P, Nunes-Nesi A, Fernie AR. NAD+ biosynthesis and signaling in plants. CRC Crit Rev Plant Sci [Internet]. 2018;37(4):259–307. Available from: https://doi.org/10.1080/07352689.2018.1505591. sourceNot checked — no full text of the source
• cites [67] Hashida S, Takahashi H, Uchimiya H. The role of NAD biosynthesis in plant development and stress responses. Ann Bot [Internet]. 2009;103(6):819–24. Available from: https://doi.org/10.1093/aob/mcp019. sourceNot checked — no full text of the source

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

NMN and NR are marketed in capsule or powder form at high prices, with daily doses of 100-1000 mg used in studies.

“Last, NMN, and NR are marketed at high prices in capsule or powder form, with dosages ranging from 100 to 1000 mg, which are doses utilized per day in the studies.”

May combine two claims.

In that 60-day trial, the difference between NMN and placebo groups was not statistically significant, but serum NAD+/NADH levels increased by 38%, from 6.57 pmol/ml at baseline to 9.07 pmol/ml at the end.

“Although the difference between the NMN and placebo groups was not statistically significant, NAD+ /NADH levels in the serum increased by 38% (from 6.57 pmol/ml baseline to 9.07 pmol/ml at the end of the study) [85].”

• cites [85] Huang H. A multicentre, randomised, double blind, parallel design, placebo controlled study to evaluate the efficacy and safety of uthever (NMN supplement), an orally administered supplementation in middle aged and older adults. Front Aging. 2022;5:3.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

After oral gavage of NMN at 300 mg/kg in mice, NMN was quickly absorbed from the intestine into the bloodstream and eliminated from circulation within 15 minutes, with a consistent increase in hepatic NAD+ levels at 15 to 30 minutes.

“After oral gavage (300 mg/kg body weight), NMN was quickly absorbed from the intestine into the bloodstream and eliminated from circulation within 15 min, with a consistent increase in hepatic NAD+ levels at 15 to 30 min [1••].”

• cites [1••]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

In plants, NAD is synthesized by the de novo pathway from aspartate and by the salvage pathway, with NA as a key metabolite of the pyridine nucleotide cycle.

“In plants, NAD is synthesized by the de novo pathway from the amino acid aspartate and by the salvage pathway [66]; however, nicotinic acid (NA) is the key metabolite of the pyridine nucleotide cycle [70]”

• cites [66] Gakière B, Hao J, de Bont L, Pétriacq P, Nunes-Nesi A, Fernie AR. NAD+ biosynthesis and signaling in plants. CRC Crit Rev Plant Sci [Internet]. 2018;37(4):259–307. Available from: https://doi.org/10.1080/07352689.2018.1505591. sourceNot checked — no full text of the source
• cites [70] Ashihara H, Stasolla C, Yin Y, Loukanina N, Thorpe TA. De novo and salvage biosynthetic pathways of pyridine nucleotides and nicotinic acid conjugates in cultured plant cells. Plant Sci [Internet]. 2005;169(1):107–14. Available from: https://www.sciencedirect.com/science/article/pii/S0168945205000828. sourceNot checked — no full text of the source

May combine two claims.

Only a few studies have measured NMN and NR in foods, so the best food sources have not been clearly identified.

“To date, only a few studies have measured NMN and NR in foods, and as a result, the best sources have not been clearly identified.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

Obtaining NAD+ precursors through the diet may be a more accessible and natural alternative to supplements, despite their lower content in foods.

“Obtaining NAD+ precursors through the diet may be a more accessible and natural alternative, despite their lower content in food sources compared to supplements.”

May combine two claims.

Oral NMN improved energy expenditure, oxygen consumption, insulin sensitivity, lipid plasma profile, eye function, bone density, and myeloid-lymphoid composition in aged mice.

“improving energy expenditure, oxygen consumption, insulin sensitivity, lipid plasma profile, eye function, bone density, and myeloid-lymphoid composition in aged mice [1••].”

• cites [1••]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

PGC1α is a transcriptional co-regulator of mitochondrial genes and detoxifies enzymes that eliminate reactive oxygen species, leading to metabolism improvement and antioxidant protection.

“PGC1α is a transcriptional co-regulator of mitochondrial genes and detoxifies enzymes that eliminate ROS (reactive oxygen species), leading to metabolism improvement and antioxidant protection [103].”

• cites [103] St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell [Internet]. 2006;127(2):397–408. Available from: https://www.sciencedirect.com/science/article/pii/S0092867406012281. sourceNot checked — no full text of the source

May combine two claims.

CD38 regulates NAD+, NMN, and SIRT1 activity and plays a critical role in the onset of age-related diseases.

“Thus, CD38 regulates the levels of NAD+, NMN, and additionally to SIRT1 activity, playing a critical role in the onset of age-related diseases.”

• cites [99] Camacho-Pereira J, Tarragó MG, Chini CCS, Nin V, Escande C, Warner GM, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 2016;23(6):1127–39. sourceNot checked — no full text of the source

May combine two claims.

Orally administered NMN was quickly absorbed, transported into blood, and converted to NAD+ in liver and soleus muscle in aged mice.

“In addition, the orally administered NMN was quickly absorbed, transported into blood circulation, and immediately converted to NAD+ in major metabolic tissues such as the liver and soleus muscle”

• cites [1••]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Long-term NMN administration (100 or 300 mg/kg/day in drinking water for 12 months) increased mitochondrial respiratory ability in skeletal muscle and reversed age-associated gene expression changes in a tissue-specific manner in mice.

“A long-term NMN administration (given in drinking water ad libitum at either 100 or 300 mg/kg/day for 12 months) increased mitochondrial respiratory ability in skeletal muscle and reversed age-associated gene expression changes in a tissue-specific manner [1••].”

• cites [1••]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

CD38 levels and activity increase with aging and are necessary for NAD decline and mitochondrial dysfunction.

“The levels and activity of CD38 increase with aging and are necessary for NAD decline and mitochondrial dysfunction [99].”

• cites [99] Camacho-Pereira J, Tarragó MG, Chini CCS, Nin V, Escande C, Warner GM, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 2016;23(6):1127–39. sourceNot checked — no full text of the source

May combine two claims.

In that case study, patients had low oxygen saturation, pulmonary infiltrates, and inflammation before treatment, and showed rapid improvement in bilateral pulmonary infiltrates, fever resolution, and lower inflammation biomarkers after treatment.

“Before treatment, patients had low-oxygen saturation, pulmonary infiltrates, and inflammation. Post-treatment, there was rapid improvement in bilateral pulmonary infiltrates, fever resolution, and lower inflammation biomarkers.”

• cites [17] Huizenga R. Dramatic clinical improvement in nine consecutive acutely Ill elderly COVID-19 patients treated with a nicotinamide mononucleotide cocktail: a case series. SSRN Electron J [Internet]. 2020; Available from: https://ssrn.com/abstract=3677428.Not checked yet

  Not checked in the free run.

May combine two claims.

One patient in the case study stopped treatment after 3 days and experienced relapse with fever and pulmonary infiltrates 8 days later.

“However, one patient stopped the treatment after 3 days due to miscommunication and experienced a relapse with fever and pulmonary infiltrates 8 days later [17].”

• cites [17] Huizenga R. Dramatic clinical improvement in nine consecutive acutely Ill elderly COVID-19 patients treated with a nicotinamide mononucleotide cocktail: a case series. SSRN Electron J [Internet]. 2020; Available from: https://ssrn.com/abstract=3677428.Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The link between intestinal microorganisms and NAD+ metabolites suggests an important axis for beneficial physiological effects.

“In the same way, link between intestinal microorganisms and NAD+ metabolites suggests an important axis for beneficial physiological effects.”

May combine two claims.