Dietary Supplementation With NAD⁺-Boosting Compounds in Humans: Current Knowledge and Future Directions

Background and Rationale

NAD⁺ and Aging:
The article begins by noting that nicotinamide adenine dinucleotide (NAD⁺) is a vital coenzyme involved in energy metabolism, redox reactions, and as a co-substrate for various NAD⁺-dependent enzymes. Declines in NAD⁺ levels have been observed with advancing age and in several disease states (such as metabolic disorders, cardiovascular disease, and neurodegenerative conditions). These declines are thought to contribute to age-related functional impairments and increased susceptibility to chronic diseases.

NAD⁺ Boosting as a Therapeutic Strategy:
Preclinical studies using animal models have provided promising evidence that boosting NAD⁺ through precursor supplementation—using compounds such as nicotinamide riboside (NR), NR combined with pterostilbene, and nicotinamide mononucleotide (NMN)—can improve a range of physiological functions. These include enhanced mitochondrial function, improved insulin and glucose regulation, reduced inflammation, and better physical performance.

Objectives and Scope of the Review

Purpose:
The review aims to synthesize currently available clinical trial data regarding the chronic oral supplementation of NAD⁺ precursors in humans. It focuses on the effects of NR, NR plus pterostilbene, and NMN, while also highlighting areas where existing evidence remains inconclusive.

Target Populations:
The studies reviewed include trials performed in generally healthy individuals, midlife and older adults, populations with cardiometabolic risk factors (such as overweight or obesity), and patient groups (for instance, individuals with Parkinson’s disease, amyotrophic lateral sclerosis [ALS], or other chronic conditions).

Key Findings from Clinical Trials

1. Nicotinamide Riboside (NR) Trials:

Healthy Populations:
Initial open-label and randomized controlled trials in healthy young to older adults have shown that NR supplementation is safe and well tolerated. For example, one trial administered escalating doses (250 mg/day up to 2,000 mg/day) over an 8-day period in healthy adults, resulting in an approximate twofold increase in whole blood NAD⁺ levels.

Another trial with midlife and older subjects (age 55–79) using 500 mg twice per day for six weeks found a ~60% increase in NAD⁺ levels in peripheral blood mononuclear cells. Exploratory endpoints indicated reductions in resting systolic blood pressure and arterial stiffness in some participants, though these effects did not retain statistical significance after adjustment for multiple comparisons.

Overweight/Obese Populations:
Trials in overweight and obese individuals have had mixed outcomes. Some studies reported modest improvements in markers like insulin sensitivity and favorable shifts in body composition, while others did not detect significant changes in metabolic function, body weight, or exercise capacity.

Patient Populations:
In patient populations such as those with Parkinson’s disease, NR supplementation for 30 days led to increases in brain NAD⁺ levels (assessed via magnetic resonance spectroscopy) and modest improvements in motor function for a subset of participants. However, variability in response was noted.

2. NR Plus Pterostilbene Combination:

Healthy Adults:
Some trials evaluating the combination of NR with pterostilbene (a polyphenol posited to activate SIRT-1) in healthy older adults have shown dose-dependent increases in whole blood NAD⁺ levels. In one study, a low-dose regimen (250 mg NR + 50 mg pterostilbene) improved certain cardiovascular and liver function markers, whereas a higher dose improved mobility outcomes but was also associated with elevations in LDL cholesterol.

Patients with Chronic Conditions:
There is emerging data from clinical trials in patient groups—for instance, in individuals with nonalcoholic fatty liver disease and in those with ALS—indicating that the NR plus pterostilbene combination may offer modest improvements in functional outcomes such as muscle performance and lung function, alongside changes in biochemical markers. Nonetheless, sample sizes remain small and further research is needed.

3. Nicotinamide Mononucleotide (NMN) Trials:

Generally Healthy Populations:
NMN has been studied in a range of healthy individuals from young to older adults. Short-term trials (ranging from four weeks to several months) indicate that NMN is safe and can increase NAD⁺ abundance in serum or whole blood to varying extents. However, many studies did not observe significant changes in functional outcomes such as exercise capacity, insulin sensitivity, or cardiovascular function.

Overweight/Obese Populations and Patient Groups:
In overweight and obese cohorts, NMN supplementation has shown some promise in improving insulin sensitivity and modestly affecting body composition, although results are not uniformly positive across studies. In a trial involving patients with heart failure with reduced ejection fraction, NMN modestly doubled whole blood NAD⁺ levels and was associated with improvements in mitochondrial function and a reduction in markers of inflammation, despite no observed changes in exercise capacity or overall cardiac function.

Limitations Identified in the Literature

Small Sample Sizes & Heterogeneity:
Many of the clinical trials involve small sample sizes (often n ≤ 40) that limit statistical power. Additionally, there is wide heterogeneity in dosing regimens, treatment durations, and the populations studied.

Variability in Pharmacokinetics and Bioavailability:
The oral bioavailability and the metabolic fate of NAD⁺ precursors such as NR and NMN are complex and not fully understood. Interindividual differences in intestinal transport, metabolism, and the role of the gut microbiome may contribute to variability in trial results.

Assay Sensitivity and Methodological Considerations:
Differences in sample collection, processing, and analytical methods (e.g., mass spectrometry versus enzymatic assays) lead to variability in NAD⁺ quantification. Furthermore, most trials assess steady-state NAD⁺ levels without capturing dynamic metabolic fluxes.

Inconsistent Clinical Outcomes:
While numerous studies have documented increases in NAD⁺ or related metabolites, improvements in clinical outcomes such as insulin sensitivity, cardiovascular function, and physical performance are inconsistently observed.

Future Research Directions

Optimization of Dosing and Duration:
Larger, well-powered randomized controlled trials (RCTs) are needed to determine the optimal dose and treatment duration that yield clinically significant benefits.

Population-Specific Effects:
Future studies should include diverse populations (with adequate representation of both sexes and various age groups) and focus on patient populations with significant physiological dysfunction where NAD⁺ boosting may prove more effective.

Combination Therapies:
Research should explore the potential synergistic effects of NAD⁺ precursors in combination with lifestyle interventions such as aerobic exercise, diet modifications, or other therapeutic modalities.

Dynamic Metabolic Assessment:
Implementing isotope tracer studies and dynamic assays could provide a more complete understanding of the NAD⁺ metabolome and the actual flux of NAD⁺ synthesis and consumption following supplementation.

Standardization of Laboratory Methods:
There is a call for standardization in sample collection and NAD⁺ measurement techniques to reduce interlaboratory variability and enhance reproducibility across studies.

Source:

Freeberg, K. A., Udovich, C. C., Martens, C. R., Seals, D. R., & Craighead, D. H. (Year not specified). Dietary Supplementation With NAD⁺-Boosting Compounds in Humans: Current Knowledge and Future Directions. PubMed Central, PMC10692436. Retrieved from https://pmc.ncbi.nlm.nih.gov/articles/PMC10692436/