Executive Summary
Nicotinamide Riboside (NR) is a clinically studied NAD+ precursor that has demonstrated a strong ability to elevate NAD+ levels in humans, with a favorable safety profile. While no human trials have yet proven a direct extension of lifespan, NR supplementation has been shown to support biological functions closely related to aging, including improved mitochondrial function, cardiovascular health, and cellular repair mechanisms. This whitepaper summarizes current scientific findings and justifies the inclusion of NR (300 mg/day) in an advanced anti-aging supplement.
Ingredient Overview
- Name: Nicotinamide Riboside (NR)
- Form: NR Chloride (e.g., NIAGEN® or other high-purity non-branded forms)
- Proposed Dosage: 300 mg per day
- Primary Function: NAD+ precursor, mitochondrial enhancer, sirtuin activator
Mechanism of Action
NR is converted in the body into NAD+ (nicotinamide adenine dinucleotide), a coenzyme essential for energy metabolism, DNA repair, mitochondrial health, and cellular signaling. NAD+ levels naturally decline with age, leading to increased oxidative stress, mitochondrial dysfunction, and cellular senescence. By restoring NAD+ levels, NR indirectly supports:
- Sirtuin activation (SIRT1, SIRT3)
- DNA repair (via PARPs)
- Autophagy and mitophagy
- Inflammation control
- Cellular energy production
Scientific Evidence
1. Martens et al., 2018
- Design: Randomized, double-blind, placebo-controlled crossover trial
- Participants: 30 healthy older adults (age 55–79)
- Intervention: 500 mg NR twice daily for 6 weeks (NIAGEN®)
- Results:
- ~60% increase in NAD+ in peripheral blood mononuclear cells (PBMCs)
- Nearly 5x increase in NAAD (Nicotinic Acid Adenine Dinucleotide)
- Trends toward reduced systolic (−3.9 mmHg) and diastolic (−2.0 mmHg) blood pressure
- No serious adverse events
- Link: https://doi.org/10.1038/s41467-018-03421-7
2. Heilbronn, 2017 (Review of Clinical Trials)
- Included Studies: Various trials using NIAGEN™ and BASIS™ (NR + Pterostilbene)
- Dosing Ranges: 100 mg to 1000 mg NR/day
- Outcomes:
- 40–90% increase in blood NAD+ levels
- Improved vascular endothelial function
- No reported serious adverse effects
- Link: https://doi.org/10.3233/NHA-170001
3. Airhart et al., 2017
- Design: Open-label, non-randomized study
- Participants: Healthy human volunteers
- Intervention: Single-dose NR and multiple-day administration
- Results:
- Rapid and sustained increases in NAD+ and its metabolites
- No significant adverse metabolic effects
- Supports bioavailability and safety of NR
- Link: Airhart SE et al., Nature Communications, 2017
4. Additional Supporting Research
- Zhang et al., 2016 (Cell Metabolism): NR enhances muscle regeneration in aged mice by restoring NAD+ levels. https://doi.org/10.1126/science.aaf2693
- Trammell et al., 2016 (Nature Communications): NR is orally bioavailable and elevates NAD+ in mice and humans. https://doi.org/10.1038/ncomms12948
Bioavailability & Comparisons
NR is more bioavailable and better tolerated than other NAD+ precursors such as:
- Nicotinamide: No flushing, but inhibits sirtuins at high doses
- Nicotinic Acid (Niacin): Effective but causes flushing
- Nicotinamide Mononucleotide (NMN): Less stable; more data needed in humans
NR offers a favorable safety-efficacy balance, making it ideal for long-term supplementation.
Safety Profile
- GRAS Status: Nicotinamide Riboside Chloride has GRAS status in the U.S. (GRN No. 635)
- Adverse Events: No serious adverse events reported in human trials up to 2000 mg/day
- Mild Events: Occasional mild nausea or digestive discomfort
Impact on the 12 Hallmarks of Aging
The 12 hallmarks of aging describe interconnected biological mechanisms that contribute to age-related decline. Below is how NR, as well as other ingredients commonly found in advanced longevity formulas, support these hallmarks:
| Hallmark of Aging | Supporting Ingredients and Roles |
|---|---|
| Genomic Instability | NR activates DNA repair enzymes (PARPs); Zinc supports DNA stability; Apigenin offers antioxidant protection |
| Telomere Attrition | Astragalus Extract may support telomerase activity and telomere maintenance (preclinical) |
| Epigenetic Alterations | NR, Resveratrol, and Pterostilbene activate sirtuins, influencing gene expression and chromatin remodeling |
| Loss of Proteostasis | NR, Urolithin A, and Spermidine promote autophagy and proper folding of damaged proteins |
| Deregulated Nutrient Sensing | NR, Resveratrol, and Pterostilbene regulate metabolic pathways (e.g., SIRT1, AMPK); Zinc supports insulin and IGF-1 sensitivity |
| Mitochondrial Dysfunction | NR restores NAD+ for mitochondrial function; Urolithin A supports mitophagy; CoQ10 improves energy output; Spermidine preserves mitochondrial membrane potential |
| Cellular Senescence | Fisetin, Quercetin, and Apigenin act as senolytics and anti-inflammatory agents |
| Stem Cell Exhaustion | NR supports cellular energy and DNA repair; Astragalus may promote stem cell regeneration; Urolithin A enhances stem cell mitochondrial fitness |
| Altered Intercellular Communication | NR helps regulate NAD+-dependent signaling; Fisetin, Quercetin, and Apigenin reduce SASP and systemic inflammation |
| Disabled Macroautophagy | Spermidine and Urolithin A stimulate autophagic pathways; NR supports energy required for autophagy |
| Chronic Inflammation | Quercetin, Apigenin, Fisetin, and NR downregulate pro-inflammatory cytokines |
| Microbiome Dysbiosis | NR indirectly improves gut health via immune balance and mitochondrial support |
Conclusion & Justification
Nicotinamide Riboside is one of the most well-researched and effective compounds for NAD+ restoration. Human clinical trials consistently demonstrate its ability to boost NAD+ safely and improve biomarkers associated with aging and cardiovascular function. At a daily dose of 300 mg, NR provides a scientifically supported foundation for any advanced longevity formulation.
References
- Martens CR et al. (2018). Chronic Nicotinamide Riboside Supplementation Is Well-Tolerated and Elevates NAD+ in Healthy Middle-Aged and Older Adults. Nature Communications. https://doi.org/10.1038/s41467-018-03421-7
- Heilbronn L. (2017). Clinical Trials Corner. Nutrition and Healthy Aging. https://doi.org/10.3233/NHA-170001
- Trammell SAJ et al. (2016). Nicotinamide Riboside Is Orally Bioavailable and Elevates NAD+ in Mice and Humans. Nature Communications. https://doi.org/10.1038/ncomms12948
- Zhang H et al. (2016). NAD+ Repletion Improves Mitochondrial and Stem Cell Function and Enhances Life Span in Mice. Science. https://doi.org/10.1126/science.aaf2693
- Airhart SE et al. (2017). An Open-Label, Non-Randomized Study of the Pharmacokinetics of the NAD+ Precursor Nicotinamide Riboside (NR) and Its Effects on Blood NAD+ Levels in Healthy Volunteers. Nature Communications. https://www.nature.com/articles/ncomms12948
