NOT FOR HUMAN CONSUMPTION

Nicotinamide adenine dinucleotide (NAD⁺) is a universal redox cofactor and enzyme substrate central to energy metabolism (NAD⁺/NADH) and cell signalling. As a co-substrate, NAD⁺ fuels sirtuins (SIRT1–7), PARPs, CD38/CD157, and SARM1, thereby governing mitochondrial biogenesis, DNA repair, circadian timing, immune tone, and axon integrity. Tissue NAD⁺ falls with aging and cardiometabolic stress due to increased consumption (PARPs/CD38) and impaired salvage. Augmentation strategies include dietary precursors (nicotinamide riboside, NR; nicotinamide mononucleotide, NMN; niacin/NA; nicotinamide/NAM; tryptophan→kynurenine pathway), enzyme targeting (boost NAMPT, inhibit CD38/PARP), and parenteral NAD⁺ (investigational). No NAD⁺-raising therapy is FDA/EMA-approved for disease modification; NR is widely sold as a supplement; NMN has variable regulatory status by country; IV NAD⁺ is not an approved drug.

Additional Benefits of NAD⁺ Repletion Now Under Investigation

2. Molecular Mechanism of Action

2.1 Enzyme Pharmacodynamics

• Sirtuins (SIRT1–7): NAD⁺-dependent deacylases → PGC-1α activation, mitochondrial biogenesis, NF-κB dampening, improved insulin signalling.

• PARPs (PARP1/2): DNA-damage sensors; high activity consumes NAD⁺ and limits ATP; controlled activity supports genome stability.

• CD38/CD157: Ecto-enzymes that hydrolyze NAD⁺ to cyclic/linear ADPR; upregulated with age/inflammation.

• SARM1: Pro-degenerative axonal NADase; inhibition/offset by higher NMNAT and NAD⁺ supports axon survival.

2.2 Upstream/Downstream Biology

3. Pharmacokinetics (augmentation strategies)

• Oral NR: Rapid absorption; increases blood/tissue NAD⁺ within hours; half-life minutes; excreted as MeNAM → 2PY/4PY in urine.

• Oral NMN: Converted to NAD⁺ via NRK/NMNAT; a putative SLC12A8 transporter is described in mice; human transport remains debated; raises blood NAD⁺ within hours.

• Niacin (NA) / Nicotinamide (NAM): Classical precursors; NA causes flush, improves lipids at pharmacologic doses; NAM raises NAD⁺ but at high doses increases MeNAM/2PY/4PY (methylation sink).

• IV NAD⁺ (investigational): Transient plasma rise with downstream NAM/MeNAM; intracellular access largely via extracellular breakdown→precursors.

• Clearance: Predominantly urinary MeNAM/2PY/4PY; high doses tax methyl donors (SAM).

4. Pre-clinical and Translational Evidence

4.1 Human trials (selected themes)

• NR: In mid-life/older adults, raises NAD⁺ and reduces aortic stiffness/BP; variable effects on insulin sensitivity and lipids; generally well tolerated.

• NMN: In overweight/prediabetic adults, improved muscle insulin sensitivity and skeletal-muscle NAD⁺ signalling over 10–12 weeks.

• Niacin/NAM: Robust lipid effects for niacin but limited by flush, insulin resistance, and gout risk; high-dose NAM limited by GI/hepatic tolerability.

• IV NAD⁺: Used in clinics for wellness/withdrawal claims; rigorous RCT data are lacking.

Evidence quality note: Strong mechanistic and animal data; human RCTs show reliable biochemical NAD⁺ rises and signal-level clinical effects (vascular/insulin sensitivity) but mixed results for performance, weight, and hard outcomes. Larger, longer trials are in progress.

5. Emerging Clinical Interests

6. Safety and Tolerability

• NR/NMN (oral, usual trial doses): Generally well tolerated (flushing uncommon). GI upset, headache, fatigue, pruritus occur in a minority.

• Niacin (NA): Flushing, itching, hypotension, ↑ uric acid/gout, ↑ glucose/insulin resistance, hepatotoxicity risk (especially sustained-release forms).

• Nicotinamide (NAM): Better tolerated than niacin; hepatotoxicity at high doses (≥3 g/day), nausea, headache; increases MeNAM/2PY/4PY (methyl-sink)—consider folate/B₁₂/betaine sufficiency.

• IV NAD⁺: Infusion-rate related nausea, chest/abdominal tightness, lightheadedness; sterile-prep and monitoring required; no disease indication approved.

• Biologic cautions:

  • Active malignancy: Some tumors are NAMPT/NAD⁺-addicted; indiscriminate NAD⁺ boosting could be counterproductive—oncology oversight advised.

  • Drug interactions: Theoretical with PARP inhibitors, chemotherapy (DNA-repair), and immunotherapies; monitor in trials.

  • Methylation burden: High NAM/NR intake increases methylated metabolites; watch homocysteine and methyl-donor status.

Comparative safety matrix

7. Regulatory Landscape

• Approved drugs: None for “NAD⁺ repletion” as a disease therapy.

• Dietary supplements (US/EU varies): NR broadly marketed; NMN status varies/contested; niacin/NAM are established vitamins.

• Parenteral NAD⁺: Not FDA-approved; clinic use is off-label/wellness without disease claims.

• Quality: Use GMP sources; third-party testing helps reduce adulteration and label-claim gaps.

8. Future Directions

• Phenotype-targeted trials: Visceral-obese NAFLD, pre-diabetes, hypertensive mid-life adults, CKD, and early neurodegeneration with biomarker-anchored endpoints.

• Mechanism-guided combos: NR/NMN + exercise, caloric periodization, SGLT2/GLP-1 co-therapy; CD38 inhibition to preserve NAD⁺; methyl-donor support when using high NAM/NR.

• Outcome end-points: Hard outcomes (fractures, MACE, CKD progression), not just NAD⁺ levels.

• Compartmental NADomics: Distinguish cytosolic vs mitochondrial pools, tissue targeting, and clock-time dosing to align with circadian NAD⁺ oscillations.

• Safety science: Long-term oncology surveillance, hepatobiliary panels, homocysteine/methylation monitoring at higher doses, and standardized IV NAD⁺ protocols.

Selected References

• Trammell S.A.J. et al. Human NR pharmacokinetics and NAD⁺ metabolome. Cell Metabolism.

• Martens C.R. et al. NR lowers aortic stiffness and blood pressure in older adults. Nature Communications.

• Yoshino J. et al. NMN improves insulin sensitivity in prediabetic women. Science.

• Mills K.F. et al. NAD⁺ repletion improves mitochondrial function and lifespan in models. Cell Metabolism.

• Camacho-Pereira J. et al. CD38 drives age-related NAD⁺ decline; inhibition restores function. Nature Medicine.

• Lautrup S. et al. NAD⁺ in brain aging and disease. Nature Reviews Neurology.

• Rajman L., Chwalek K., Sinclair D. Therapeutic potential of NAD⁺ precursors. Cell Metabolism.

• Canto C., Auwerx J. NAD⁺ and sirtuins in metabolic control. Cold Spring Harbor Perspectives in Medicine.

• Katsyuba E., Auwerx J. NAD⁺ homeostasis: from tryptophan to therapy. Nature Metabolism