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Preclinical mechanistic study

Quantitative Analysis of NAD Synthesis-Breakdown Fluxes

Ling Liu, Xiaoyang Su, William J Quinn III, Sheng Hui, Kristin Krukenberg, David W Frederick, Philip Redpath, Le Zhan, Karthikeyani Chellappa, Eileen White, Marie Migaud, Timothy J Mitchison, Joseph A Baur, Joshua D Rabinowitz

Cell Metabolism · 2018 · 27(5):1067–1080.e5

Original publication PubMed Full text on PMC

Study at a glance

Design
Stable-isotope tracer and metabolic-flux study in cell lines and mouse tissues
Population or model
Cultured mammalian cells and mice
Sample size
Multiple cell and animal experiments; see publication
Intervention
Isotope-labeled NAD precursors including NMN and NR administered through different routes
Publication type
Metabolic flux study
Evidence class
preclinical-mechanistic
Research area
NAD synthesis and precursor flux
Trial registration
Not applicable.

Study endpoints

  • NAD synthesis and breakdown flux
  • Tissue-specific NAD turnover
  • Fate of oral versus intravenous NMN and NR
  • Nicotinamide production and tissue precursor use

Plain-language summary

This study developed isotope-tracing methods to quantify how NAD is made and broken down across cells and mouse tissues.

NAD turnover differed substantially by tissue. In mice, intravenously administered NMN or NR could deliver intact precursor to multiple tissues, while oral precursor was extensively converted through hepatic metabolism, including to nicotinamide.

The study is important for understanding why route of administration matters, but its in-vivo oral data are from mice and cannot by themselves define human NMN bioavailability.

Key findings

  • NAD synthesis and breakdown rates varied widely across tissues.
  • Nicotinamide was a major NAD source in many tissues.
  • Intravenous precursor delivery differed from oral delivery.
  • Orally administered NMN and NR were substantially metabolized before reaching peripheral tissues intact in the mouse model.

Limitations

  • In-vivo precursor-routing experiments were in mice.
  • Tracer conditions may not reproduce chronic supplement use.
  • Tissue-specific metabolism may differ between mice and humans.
  • The study addresses metabolic fate rather than clinical benefits.

Funding and transparency

Funding

Supported by NIH grants DP1DK113643 (to J.D.R.), R01CA163591 (to E.P.W. and J.D.R.), R01DK098656 (to J.A.B.), R01AG043483 (to J.A.B.), P30DK019525 (University of Pennsylvania Diabetes Research Center), SU2CAACR-DT-20-16 (Stand Up To Cancer–Pancreatic Cancer Dream Team Research Grant to J.D.R.), R01CA130893 (to E.P.W.), and P30CA72720 (Rutgers Cancer Institute of New Jersey); Biotechnology and Biological Sciences Research Council grant BB/N001842/1 (to M.E.M. and P.R.); S.H. was a Merck Fellow of the Life Sciences Research Foundation.

Competing interests

The authors declare no competing financial interests.

HealthspanX observation

This paper is essential context for oral-bioavailability claims because intact intravenous delivery does not imply identical oral precursor handling.

Interpretive weight

Mechanistic context

Isotope-tracer work provides important quantitative precursor-metabolism context, but oral findings are from mice and cannot be assumed to define human NMN pharmacokinetics.

This record summarizes a publication; it is not medical advice or a claim that a HealthspanX product reproduces the study's results. Report a correction.

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