We’ve heard countless “myths” about NAD+ from animal studies, but when it comes to real-world applications, the questions people care most about remain: How far has NAD+ research advanced in human trials? Is it safe? Does it work for humans?
Recently, a landmark review published in Nature Aging has systematically answered these questions. The corresponding author of this review is Prof. Evandro Fei Fang from the University of Oslo, Norway.
1. Clinical Progress by Medical Specialty
Think of NAD+ clinical research as a “hospital corridor,” where each department represents a disease area. The “traffic lights” next to each department indicate the trial phase (🟢 = completed, 🟡 = ongoing):
- 🟢🟡🟡 Phase Ⅰ: Focuses solely on safety.
- 🟢🟢🟡 Phase Ⅱ: Begins exploring efficacy signals.
- 🟢🟢🟢 Phase Ⅲ: Large-scale, long-term trials to confirm efficacy and safety.
1.1 Neurology
🟢🟢🟡 Alzheimer’s Disease (AD) & Mild Cognitive Impairment (MCI)
- A randomized, double-blind, placebo-controlled Phase Ⅱ trial (60 patients) used NR (nicotinamide riboside)-containing combination therapy, showing improved memory over 84 days.
- A 10-week study (20 participants) using NR alone increased blood NAD+ levels and reduced epigenetic age—though no cognitive changes were observed.
- Due to small sample sizes and unclear mechanisms, AD research is currently paused at Phase Ⅱ.
🟢🟡🟡 Parkinson’s Disease (PD)
- Clinical trials of NAD+ supplementation for PD have yielded promising results: Daily supplementation with 1g NR increased total brain NAD+ levels, improved brain metabolism, reduced inflammatory markers, and enhanced motor function.
- The NR-SAFE trial confirmed the highest safe NR dose tested to date: 3g per day, verifying its safety and peripheral metabolic response—setting a clear safety limit for future dosage studies.
Key Finding: NR increased NAD+ metabolites in the cerebrospinal fluid (CSF) and muscles of PD patients (see original study for metabolite quantification: Me-2-PY, Me-4-PY).
🟢🟢🟡 Amyotrophic Lateral Sclerosis (ALS)
- Most ALS clinical studies use a combination therapy of 1000mg NR + 200mg pterostilbene, which initially showed improvements in muscle strength.
- A large-scale trial involving 320 ALS patients is expected to be completed by the end of 2025.
1.2 Cardiology
🟢🟢🟡 Hypertension
- A clinical trial showed that 30 days of NMN (β-nicotinamide mononucleotide) supplementation reduced both systolic and diastolic blood pressure in hypertensive patients.
NAD+ Precursor NA (Niacin) in Cardiovascular Diseases
- NA, a “veteran” NAD+ precursor, has entered Phase Ⅲ trials for cardiovascular diseases, showing a 26% reduction in recurrent myocardial infarction and an 11% reduction in all-cause mortality during long-term follow-up. It also works well in combination with other drugs.
- However, recent trials identified safety concerns: NA may affect glucose metabolism and significantly increase the risk of ischemic stroke—halting its use in cardiovascular care.
1.3 Endocrinology
🟢🟢🟡 Metabolic Syndrome/Diabetes
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Gender Differences Observed:
- In a 12-week trial of obese men with insulin resistance, NR supplementation increased urinary biomarkers of NAD+ metabolism but did not improve insulin sensitivity.
- In prediabetic postmenopausal women, NMN supplementation significantly improved muscle insulin sensitivity (measured by glucose disposal rate: Under insulin stimulation, glucose handling capacity was markedly enhanced in the NMN group vs. placebo, P<0.01).
- Individual Heterogeneity: Even identical twins showed different responses to NR supplementation due to differences in metabolic health and BMI. This highlights the need for personalized approaches—future large-scale trials should clarify which patients benefit most and which NAD+ precursor suits specific metabolic conditions.
🟢🟡🟡 Sarcopenia & Related Muscle Diseases
- A trial of NA supplementation (5 patients with mitochondrial myopathy, 10 healthy elderly participants) showed divergent results:
- Muscle NAD+ levels in patients rebounded, even reaching levels close to those of healthy controls.
- No effect was observed in healthy participants.
- This suggests NAD+ precursors may be more effective in individuals with metabolic dysfunction, while their benefits in normally aging individuals require further evaluation.
1.4 Respiratory Medicine
🟢🟡🟡 Chronic Obstructive Pulmonary Disease (COPD)
- COPD is a key intersection of aging and respiratory impairment, and NR shows therapeutic potential:
- After 6 weeks of NR supplementation, blood NAD+ levels in COPD patients doubled, and inflammatory factors decreased.
- No significant effects were seen in healthy individuals.
2. Preclinical Research (Animal & Cellular Studies)
At the end of the “corridor,” research remains in preclinical stages (🟡🟡🟡)—providing “blueprints” for future clinical trials.
2.1 Animal Studies
- Sensory System Protection: Long-term NR administration delayed age-related hearing loss (especially for high-frequency hearing) in mice; NMN improved retinal health in aged mice; NAM (nicotinamide) reduced glaucoma-related neurodegeneration.
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Viral Infections: Viruses like Zika (ZIKV), SARS-CoV-2, and COVID-19 damage health by disrupting NAD+ metabolism. In mouse models:
- NR reduced cell death and improved survival rates in ZIKV-infected mice.
- NAD+ supplementation lowered mortality in SARS-CoV-2-infected mice.
- Studies on NAD+ for post-acute COVID-19 syndrome are ongoing.
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Organ-Specific Benefits:
- Lungs: Increased TCA cycle activity, reduced inflammation and lung pathology.
- Kidneys: Mitigated sequelae of renal ischemia.
- Liver: Improved liver function, reduced steatosis, inflammation, and fibrosis.
- Muscles: Enhanced motor function, physical activity, and muscle bioenergetics.
- Cardiovascular System: Reprogrammed metabolism, reduced vascular dysfunction.
- Immune System: Lowered inflammation and macrophage infiltration.
- Reproductive System: Reduced fetal malformation risk, increased maternal and fetal NAD+ levels.
- Digestive System: Improved fat absorption and cellular energy, regulated gut microbiota.
- Nervous System: Enhanced spatial memory and neuronal metabolism, reduced neurodegeneration.
2.2 Cellular Studies
- Senescent Cells & NAD+ Depletion: Senescent cells (which drive chronic inflammation) induce CD38 expression in neighboring macrophages and endothelial cells via the senescence-associated secretory phenotype (SASP). CD38 directly consumes NAD+ and NMN (reducing NAD+ synthesis raw materials), exacerbating NAD+ depletion.
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Key Cellular Effects of NAD+:
- Mitophagy: Increased expression of NIX and PINK1, enhanced mitochondrial unfolded protein response (UPRmt).
- Autophagy: Increased deacetylation of ATG1 and ATG8.
- Metabolism: Improved cellular metabolism and energy production.
- Stem Cells: Enhanced regenerative capacity.
- Anti-Senescence: Reduced cellular senescence and oxidative stress (increased ROS resistance, upregulated UCP2).
- DNA Repair: Reduced telomere dysfunction, enhanced DNA repair pathways (BER, NHEJ, HR, NER).
3. Safety & Technical Challenges
3.1 Safety “Red Lines”
- Dosage Risks: NA’s side effects (flushing, itching) reduce patient compliance, and its cardiovascular risks (ischemic stroke) serve as a warning. While NR and NMN have not reported major adverse effects in clinical trials, the 3g/day safety limit for NR (from the NR-SAFE trial) should not be exceeded.
- Unresolved Questions: Clear risk warnings, specific dosage ranges, and large-scale, long-term trials are still needed.
3.2 Technical Advances & Limitations
- Production Technology: Microbial fermentation has improved NR purity; enzymatic synthesis has boosted NMN production and reduced costs—laying the groundwork for clinical popularization.
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Administration Routes:
- Oral NR: Bioavailability is affected by gut microbiota.
- Intravenous injection: Bypasses first-pass metabolism but is costly.
- Nanocarriers: Egg albumin-fucoidan encapsulated NMN improved bioavailability in mice, but long-term safety data is lacking.
- Personalized Needs: Women are more sensitive to NMN’s glucose metabolism benefits; AD patients may require NAD+ precursors that cross the blood-brain barrier.
4. The Future of NAD+ Research
NAD+ research has a 100-year history—starting in fermentation tanks, gaining fame through four Nobel Prizes, and now taking center stage in the era of healthy aging. With advances in AI-assisted protein design and precision therapies targeting NAD+ metabolism, could the next groundbreaking NAD+ discovery win another Nobel Prize?
The answer lies not in capsules, but in time, data, and rational anticipation.
References
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