NAD+ Salvage Pathway (NMN, NR, CD38 Inhibition) — References

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• Parent Topic: NAD+ Salvage Pathway (NMN, NR, CD38 Inhibition)
• Reference Hub: 04 - Longevity & Environment References MOC

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Primary Literature Dossier

1. Yoshino et al. (2021) — NMN Enhances Human Skeletal Muscle Insulin Sensitivity

• Citation: Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, Sindelar M, Pietka T, Patterson BW, Imai SI, Klein S. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021 Jun 11;372(6547):1224-1229.
• Identifiers: PMID: 33888596 (PubMed · Europe PMC) | DOI: 10.1126/science.abe9985 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Randomized, placebo-controlled, double-blind clinical trial ($n=25$ postmenopausal women with prediabetes and overweight/obesity; 10 weeks of $250\text{ mg/day}$ oral NMN vs. placebo).
• Key Quantitative Outcomes:
  • Hyperinsulinemic-euglycemic clamp showed a $25\pm 7\%$ increase in skeletal muscle insulin-stimulated glucose disposal rate ($p<0.01$) in the NMN group vs. no change in placebo.
  • PBMC ${\text{NAD}}^{+}$ levels increased by 43% ($p<0.001$), and muscle ${\text{NAD}}^{+}$ turnover metabolites ($N^1$-methylnicotinamide and $N^1$-methyl-2-pyridone-5-carboxamide) rose 3- to 4-fold.
  • Upregulated muscle $\text{AKT}$ and $\text{mTOR}$ phosphorylation and $\text{PDGF}$ receptor signaling for myofibrillar remodeling.

2. Martens et al. (2018) — Chronic Nicotinamide Riboside Supplementation in Older Adults

• Citation: Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonoles Imlay K, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications. 2018 Mar 29;9(1):1286.
• Identifiers: PMID: 29599478 (PubMed · Europe PMC) | DOI: 10.1038/s41467-018-03421-7 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Randomized, double-blind, placebo-controlled crossover trial ($n=24$ lean, healthy adults aged 55–79 years; $1,000\text{ mg/day}$ NR ($500\text{ mg}$ BID) for 6 weeks).
• Key Quantitative Outcomes:
  • PBMC ${\text{NAD}}^{+}$ concentration increased by ~60% ($p=0.0009$), and nicotinic acid adenine dinucleotide ($\text{NAAD}$, a sensitive biomarker of ${\text{NAD}}^{+}$ bioavailability) rose nearly 5-fold.
  • In individuals with Stage 1 hypertension/elevated BP, systolic blood pressure dropped by $3.9\text{ mmHg}$ (and $9.0\text{ mmHg}$ in hypertensive subgroup) alongside a $41.5\text{ cm/s}$ reduction in carotid-femoral pulse wave velocity (aortic stiffness).

3. Camacho-Pereira et al. (2016) — CD38 Dictates Age-Related NAD+ Decline

• Citation: Camacho-Pereira J, Tarragó MG, Chini CCS, Nin V, Escande C, Warner GM, Puranik AS, Schoon RA, Reid JM, Galina A, Chini EN. CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metabolism. 2016 Jun 14;23(6):1127-1139.
• Identifiers: PMID: 27304511 (PubMed · Europe PMC) | DOI: 10.1016/j.cmet.2016.05.006 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Preclinical mechanistic & human adipose tissue translational study (wild-type vs. $\text{CD38}$ knockout mice aged 3–32 months + human white adipose tissue biopsies).
• Key Quantitative Outcomes:
  • Demonstrated that $\text{CD38}$ protein and $\text{NADase}$ activity increase 2.5- to 4.5-fold across liver, adipose, spleen, and skeletal muscle during aging, whereas $\text{PARP1}$ and $\text{NAMPT}$ changes alone could not account for tissue ${\text{NAD}}^{+}$ loss.
  • Aged $\text{CD38}$ knockout mice retained 2-fold higher tissue ${\text{NAD}}^{+}$ levels, preserved mitochondrial oxygen consumption rate (OCR), and maintained $\text{SIRT3}$ deacetylase activity at 24–32 months of age.
  • Identified that $\text{CD38}$ directly degrades extracellular NMN before cellular uptake unless $\text{CD38}$ is pharmacologically inhibited (e.g., via apigenin or 78c).

4. Yi et al. (2023) — Dose-Dependent Efficacy and Safety of Oral NMN in Middle-Aged Adults

• Citation: Yi L, Maier AB, Tao R, Lin Z, Vaidya A, Pendse S, Thasma S, Andhalkar N, Avhad G, Kumbhar V. The efficacy and safety of $\beta$-nicotinamide mononucleotide (NMN) supplementation in healthy middle-aged adults: a randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent clinical trial. GeroScience. 2023 Feb;45(1):29-43.
• Identifiers: PMID: 36482258 (PubMed · Europe PMC) | DOI: 10.1007/s11357-022-00705-1 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Randomized, double-blind, placebo-controlled parallel-group trial ($n=80$ healthy adults aged 40–65 years; placebo, $300\text{ mg}$, $600\text{ mg}$, or $900\text{ mg/day}$ oral NMN for 60 days).
• Key Quantitative Outcomes:
  • Serum ${\text{NAD}}^{+}$ concentrations increased in a dose-dependent curve, peaking in the $600\text{ mg}$ ($+4.7\text{-fold}$) and $900\text{ mg}$ ($+5.1\text{-fold}$) arms ($p<0.001$) vs. baseline.
  • Six-minute walking test (6MWT) distance increased by $+48\text{ m}$ ($+14.5\%$) in the $600\text{ mg}$ group and $+51\text{ m}$ in the $900\text{ mg}$ group ($p<0.01$), while biological age blood composite score remained stable vs. $+1.6\text{ year}$ drift in placebo.