Quantitative Analysis of NAD Synthesis-Breakdown Fluxes
Open accessAbstract
The redox cofactor nicotinamide adenine dinucleotide (NAD) plays a central role in metabolism and is a substrate for signaling enzymes including poly-ADP-ribose-polymerases (PARPs) and sirtuins. NAD concentration falls during aging, which has triggered intense interest in strategies to boost NAD levels. A limitation in understanding NAD metabolism has been reliance on concentration measurements. Here, we present isotope-tracer methods for NAD flux quantitation. In cell lines, NAD was made from nicotinamide and consumed largely by PARPs and sirtuins. In vivo, NAD was made from tryptophan selectively in the liver, which then excreted nicotinamide. NAD fluxes varied widely across tissues, with high flux in the small intestine and spleen and low flux in the skeletal muscle. Intravenous administration of nicotinamide riboside or mononucleotide delivered intact molecules to multiple tissues, but the same agents given orally were metabolized to nicotinamide in the liver. Thus, flux analysis can reveal tissue-specific NAD metabolism.
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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].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [83]
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 measuredNMN degrades very rapidly in blood at −80 °C.
“It has been reported that NMN degraded very rapidly in blood at − 80 °C [83].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [83]
In Results, under “Tracing the fate of NR and NMN” (page not provided), the paper reports that NMN degrades rapidly in whole blood, with a half-life of about three minutes. It does not say this degradation occurred at −80 °C; that temperature refers to the methanol used later to extract flash-frozen blood specimens. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMost cells are thought to maintain intracellular NAD mainly by recycling NAM through NAMPT.
“the prevailing thought is that the recycling of NAM via nicotinamide phosphoribosyltransferase (NAMPT) is the predominant pathway used by most cells to maintain intracellular NAD levels6.”
From Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages (2020) · cites this paper as [6]
Outside the liver, NAM is the major NAD precursor used by peripheral cells and tissues to maintain NAD levels.
“a recent study using stable-isotope tracing has demonstrated that, outside the liver, NAM is the major NAD precursor used by peripheral cells and tissues to maintain NAD levels6.”
From Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages (2020) · cites this paper as [6]
SIRT1 and SIRT2 are responsible for about one third of total NAD+ consumption under basal conditions.
“SIRT1 and SIRT2 seem to be responsible for about one third of the total NAD+ consumption under basal conditions5.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [5]
Besides the liver, the de novo biosynthetic pathway seems to be a more indirect mechanism contributing to system-wide NAD+ levels, with most NAD+ coming from the NAM salvage pathway.
“Thus, besides the liver, the de novo biosynthetic pathway seems to be a more indirect mechanism contributing to system-wide NAD+ levels, with most NAD+ coming from the NAM salvage pathway (BOX 1).”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [5]
Most tryptophan is metabolized to NAM in the liver, released into serum, taken up by peripheral cells and converted to NAD+ by the NAM salvage pathway.
“Most tryptophan is metabolized to NAM in the liver, where it is released into the serum, taken up by peripheral cells and converted to NAD+ by the NAM salvage pathway5.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [5]
PARP1 is one of the major NAD+ consumers not only in cells with acute DNA damage but also under normal and other pathophysiological conditions.
“However, PARP1 is one of the major NAD+ consumers not only in cells with acute DNA damage but also under normal and other pathophysiological conditions5, supporting a key role of PARP1 in regulating NAD+ homeostasis.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [5]
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Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells
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Boosting NAD+ with a small molecule that activates NAMPT
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NAD precursors cycle between host tissues and the gut microbiome
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NAD+ flux is maintained in aged mice despite lower tissue concentrations
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“Following protein digestion, most of the liberated tryptophan is absorbed in the small intestine and endogenously metabolized: up to 95% of ingested tryptophan is converted to kynurenic acid or nicotinamide adenine dinucleotide (NAD) (63, 64) via the kynurenine pathway, and 1-2% of ingested tryptophan is converted to…”
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Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis
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“The liver is the major site for synthesis of NAD from tryptophan and is a source of the nucleotide for other organs (57), explaining not only the prevention of liver disease of”
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“One of the important roles of the liver in NAD + metabolism is to supply NAM to other peripheral organs, including the skeletal muscle ( 40 , 51 ).”
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Role and Potential Mechanisms of Nicotinamide Mononucleotide in Aging
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- Authors
- Liu, L., Su, X., Quinn, W. J., Hui, S., Krukenberg, K., Frederick, D. W., Redpath, P., Zhan, L., Chellappa, K., White, E., Migaud, M., Mitchison, T. J., Baur, J. A., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- Rutgers, The State University of New Jersey (US)
- University of Pennsylvania (US)
- Harvard University (US)
- Queen's University Belfast (GB)
- Rutgers Cancer Institute (US)
- Corresponding author
- Mitchison, Timothy J.
- Baur, Joseph A.
- Rabinowitz, Joshua D.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 27
- Issue
- 5
- Pages
- 1067-1080.e5
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5932087
- OpenAlex
- W2800314655
- Cited by
- 564
- References
- 65
- Citations by year
- 2026: 61 · 2025: 65 · 2024: 84 · 2023: 77 · 2022: 87 · 2021: 77 · 2020: 57 · 2019: 38 · 2018: 17
- FWCI
- 26.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- Funders
- NIH (DP1DK113643, R01CA163591, R01DK098656, R01AG043483, R01 CA130893, R01 CA188096)
- University of Pennsylvania Diabetes Research Center (P30DK0s19525)
- Stand Up To Cancer- Pancreatic Cancer Dream Team Research (SU2CAACR-DT-20-16)
- Rutgers Cancer Institute of New Jersey (P30 CA72720)
- Biotechnology and Biological Sciences Research Council (BB/N001842/1)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Keywords
- NAD+ metabolism, NAD+ synthesis, isotope tracers, nicotinamide, tryptophan, liver, poly(ADP-ribose) polymerase, sirtuins, nicotinamide riboside, nicotinamide mononucleotide, tissue-specific metabolism, aging, oral versus intravenous administration
- MeSH terms
- Animals, Female, Humans, Intestine, Small, Liver, Mice, Inbred C57BL, NAD, Niacinamide, Poly(ADP-ribose) Polymerases, Spleen, Tryptophan, Muscle, Skeletal, Sirtuins, HCT116 Cells, Mice, Hep G2 Cells
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