Dr. Peter Attia: NMN vs NR - Latest Research Review

Feb 05, 2025

NAD Precursors NR and NMN Discussion

The debate around NAD precursors NR and NMN continues to evolve, but the cellular mechanisms and effectiveness of these compounds are becoming clearer. The data shows that NR can easily cross cell membranes directly, while NMN faces barriers due to its additional phosphate group. When ingested orally, NMN must first have its phosphate group cleaved in the gut, making it a less efficient precursor to NAD compared to NR.

The practical implications are significant. While some argue that taking higher doses of NMN can compensate for its lower efficiency, this approach quickly becomes cost-prohibitive. At mouse-equivalent doses, the daily cost would approach $300, making it unrealistic for most people. The same cost barrier exists for NAD infusions, which can range from $300 to $1,000 per treatment.

Attia points to the Interventions Testing Program (ITP) as the most rigorous tool available for testing longevity molecules. The ITP conducts trials in non-inbred mice across three institutions, providing the closest approximation to human studies we can achieve. Notably, NR failed to show any life extension benefits in ITP testing, even at robust doses of 500-1,000 mg/kg.

In contrast, several other compounds have demonstrated success in ITP trials. Rapamycin showed effectiveness even when administered to elderly mice. Canagliflozin (an SGLT2 inhibitor) and acarbose (a glucose absorption inhibitor) both extended lifespan without requiring weight loss, suggesting that glycemic control independent of body weight may be crucial for longevity.

These findings raise important questions about the real-world benefits of NAD precursors. While many people invest significant money in NR, NMN, or NAD infusions, the concrete benefits remain unclear. The acute increase in NAD levels may not translate to meaningful improvements in lifespan or healthspan, particularly given the lack of positive results in rigorous ITP testing.

The science suggests that NR is likely the more efficient NAD precursor compared to oral NMN, particularly at standard dosages of 300-600mg versus 1500mg. However, the sublingual administration of NMN may offer a cost-effective alternative, though its benefits may be confounded by secondary effects such as its laxative properties.

What’s notably missing is a direct comparison study measuring blood NAD levels between 600mg oral NR and 1g sublingual NMN. Such data would provide valuable insights into the relative effectiveness of these two popular supplementation strategies.

NMN and NR Studies on Liver Fat and Glucose

Recent studies exploring NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide) supplementation have produced intriguing yet modest results in human trials. A notable study examined NR combined with pterostilbene, a sirtuin activator similar to resveratrol, in approximately 100 participants with fatty liver disease.

The three-arm study measured hepatic fat through MRI scans, with fatty liver disease diagnosed at levels exceeding 5%. Participants received either a placebo, standard dose, or double dose of the NR-pterostilbene combination. Initially, the results appeared disappointing – no significant differences emerged in hepatic fat, body weight, inflammatory markers, glycemic markers, or liver function tests.

However, a sub-analysis revealed one statistically significant finding: participants with hepatic fat below 27% who received the standard dose showed a reduction from 20% to 15%. While statistically significant, this reduction still left participants well above the 5% threshold for fatty liver disease, questioning its clinical relevance.

Attia emphasizes a crucial distinction in medical research: statistical significance doesn’t equate to clinical significance. A blood pressure reduction from 160/100 to 157/97 might be statistically significant but offers minimal real-world benefit to patients.

A second noteworthy study from Washington University examined NMN’s effects on glucose disposal. The research compared placebo and NMN groups, measuring glucose disposal with and without insulin infusion. While the NMN group showed statistically significant improvement in insulin-mediated glucose disposal, the clinical impact was minimal.

To contextualize these results, Attia compared them to studies using red light therapy on participants’ backs during oral glucose tolerance tests, which reduced postprandial glucose by 8% – another example of statistical significance without meaningful clinical impact.

The need for complex statistical analysis to reveal these modest effects suggests limited practical application. As Attia notes, when researchers must resort to intricate statistical manipulations to demonstrate results, the underlying effect is likely insignificant.

These findings underscore the importance of evaluating both statistical and clinical significance in supplement research. While NR and NMN show promise in laboratory settings, their real-world impact on human health markers remains subtle at best.

NMN NR and Skin Cancer Research

The debate around NMN versus NR supplementation appears to be more commercial than scientific. Both compounds serve as precursors to NAD+, with the main structural difference being a phosphate group. While NR currently holds FDA “generally recognized as safe” (GRAS) status, NMN’s regulatory status remains contentious.

Most studies examining these compounds’ benefits reveal statistically significant but clinically insignificant results. Changes in metrics like LDL cholesterol, HDL, triglycerides, and exercise performance tests show minimal real-world impact, particularly in younger populations.

However, one compelling finding emerges from research into skin cancer prevention. Studies indicate a 60-80% reduction in basal cell and squamous cell carcinomas with NAD+ precursor supplementation. While this doesn’t affect melanoma rates—the deadliest form of skin cancer—the potential protection against these common, sun-exposure-related cancers deserves attention.

Attia notes that skin tissue shows the most dramatic reduction in NAD+ levels compared to other body tissues. This correlation might explain why the strongest evidence for NR/NMN supplementation benefits appears in skin cancer prevention. For individuals with increased risk factors—whether due to skin type, occupation, or lifestyle—this protective effect could prove significant.

For most people, especially those with darker skin or limited sun exposure, the benefits may not justify the cost. Yet for high-risk populations, the potential 60-80% reduction in non-melanoma skin cancer risk presents a compelling case for supplementation.

Huberman questions whether continuing NMN supplementation is worthwhile, while Attia suggests the choice between NR and NMN is less important than understanding their specific applications. The evidence points to targeted use based on individual risk factors rather than broad-spectrum supplementation for general health or longevity.

The landscape of NAD+ precursor supplementation illustrates a crucial principle in health optimization: interventions should be tailored to specific risk factors and supported by meaningful clinical outcomes rather than statistical significance alone.

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