NAD Wars: NMN vs NR in the Aging Battle

In this episode of Daily Value, we look inside the NAD+ wars - breaking down the science, the hype, and the controversy surrounding Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN). These two molecules have been promoted as keys to longevity, but the story is far more complex. We’ll look at the biochemistry of NAD+ metabolism, compare what the research really says about NR and NMN, and dig into the regulatory drama that’s shaped their (NMN’s) availability. Most importantly, we’'ll look at a bigger-picture strategy for restoring NAD+, one that goes beyond precursors alone.

00:00 the NAD Wars

01:02 Understanding NAD+ and Its Importance

01:52 The Role of NR and NMN in NAD+ Replenishment

02:29 Biochemical Pathways of NAD+ Production

04:14 Challenges and Regulatory Issues with NMN and NR

05:44 Clinical Research and Safety Profiles

07:13 Complexities in Boosting NAD+ Levels

09:04 Multi-Targeted Strategies for NAD+ Restoration

13:25 Conclusion: Embracing Complexity in Aging

PMID: 35134387

PMID: 39026037

doi:10.1002/fft2.511

Chapters

• 0:00 The Molecular Battle of Aging
• 0:42 NAD+ Fundamentals and Age-Related Decline
• 2:15 NMN vs NR: Metabolic Pathways Explained
• 4:24 Regulatory Challenges and Clinical Safety
• 7:25 Beyond Precursors: NAD+ Restoration Complexity
• 9:06 Multi-Target Strategy for NAD+ Optimization
• 11:40 Practical Recommendations and Conclusion

Transcript

Speaker 1: 0:00

There's a molecular battle raging at the heart of aging, fought between two molecules that promise to restore youth from the inside out. That's nicotinamide riboside, also called NR, and nicotinamide mononucleotide, also called NMN. While NR boasts clinical trials and regulatory stability, nmn faces scrutiny from scientists and regulators alike. But, as recent research highlights, replenishing NAD plus is far more complex than choosing sides. Today we're going to dig deep into the biochemical realities, clinical data and regulatory drama behind the NAD wars and ask if either molecule alone is truly enough to combat aging. Hello everyone, welcome back to Daily Value. I'm William Wallace, and today we're taking a look at a molecule whose depletion has profound effects on our health nicotinamide adenine dinucleotide, nad+. As many of us know it. It's not an exaggeration to say that NAD+ is fundamental to life itself. It serves as an essential coenzyme for hundreds of enzymatic reactions that regulate metabolism, maintain mitochondrial function and facilitate DNA repair. But here's the issue Our NAD plus levels are not stable throughout our lives. Research consistently shows that NAD plus concentrations decline sharply as we age, starting notably around middle age and into later years. This decline does not just correlate with aging. It may actively drive many aspects of the aging process. Lower NAD plus levels compromise cellular energy production, reduce the efficiency of DNA repair mechanisms and weaken cellular resilience against inflammation. This is where our molecular contenders, nicotinamide riboside, nr, and nicotinamide mononucleotide, nmn, enter the picture. Both have surged into the spotlight because of their ability to replenish cellular NAD plus levels. However, as recent research reviews emphasize, boosting NAD plus levels isn't as simple as just taking a precursor. It's a complex biochemical dance influenced by multiple enzymes, transporters and pathways. To truly understand how NR and NMN stack up against each other, we need to briefly understand how NAD plus metabolism works and why restoring NAD plus is both promising and challenging.

Speaker 1: 2:30

Nad plus production predominantly occurs through the salvage pathway, which accounts for roughly 85% of total NAD plus biosynthesis. This pathway efficiently recycles nicotinamide back into NAD+, highlighting the critical importance of precursor molecules like NMN and NR. Nmn, a vitamin B3 derivative, occurs naturally within the human body as well as in various fruits and vegetables. Importantly, nmn exists in two forms, a-type and B-type, but only the B-type has demonstrated actual biological activity. Its primary physiological role is serving as an intermediary in NAD plus production. Specifically, nicotinamide phosphoribosyltransferase, or NAMPT, a rate-limiting enzyme, converts nicotinamide to NMN, which is subsequently transformed into NAD plus by NMN adenyl transferases or NMNAT. Nr, another NAD+ precursor, has a simpler biochemical pathway, discovered as a direct contributor to NAD+ metabolism in 2004. Nr bypasses the NAMPT-dependent step, converting directly into NMN via enzymes called nicotinamide riboside kinases. This makes NR uniquely efficient as it does not rely on the rate-limiting enzyme NAMPT. Both NMN and NR can be obtained from dietary sources, either in their free forms or as metabolites produced during NAD plus catabolism. Precursors such as tryptophan, nicotinamide and niacin also contribute to NAD plus synthesis but face limitations like side effects at higher doses, making NMN and NR particularly appealing as supplements to many.

Speaker 1: 4:14

While NMN and NR have gained attention for their potential health benefits, significant debate and regulatory uncertainty have emerged, particularly around NMN. Critics argue that NMN faces significant challenges regarding its cellular entry and bioavailability. Specifically, they note that NMN's structure as a nucleotide carrying an additional phosphate group limits its ability to freely cross cellular membranes. This characteristic may necessitate specific transporters, potentially limiting its effectiveness across various tissues. Adding to that complexity, nmn has recently been subject to regulatory scrutiny. Initially marketed as a dietary supplement, nmn faced regulatory action due to its prior investigation as a pharmaceutical drug, triggering the FDA's drug preclusion cause. This led to the temporary exclusion of NMN from the dietary supplement market in the United States. However, recent legal actions have resulted in a temporary stay, complicating its current status and leaving its market position uncertain as of right now. In contrast, nr maintains its generally recognized as safe also called grass status without regulatory interruption, supported by a more established body of actual human clinical data. These regulatory and structural considerations show important distinctions between NMN and NR, which seems to be influencing consumer perceptions as well as market dynamics.

Speaker 1: 5:44

Clinical research has provided evidence supporting the safety of both NMN and NR. In humans. Studies have shown NMN to be safe at oral doses ranging from 100 to 1,250 milligrams per day. For instance, clinical trials have demonstrated that a single doses of 100, 250, and 500 milligrams of NMN produced no notable clinical changes in body temperature, heart rate, blood pressure or oxygen saturation. Moreover, prolonged dosing of NMN at 1,250 milligrams daily for four weeks was also found to be safe and well-tolerated, further confirming NMN's safety profile, at least short-term. Nr has been extensively studied in human clinical trials. Safe daily doses of up to 2,000 mg have been established, with studies consistently demonstrating dose-dependent increases in blood NAD plus levels following administration. Specifically, clinical trials report increases in whole blood NAD plus levels by 22, 51, and 142% after daily NR doses of 100, 300, and 1,000 milligrams respectively, sustained over multiple weeks. Further benefits associated with NR supplementation include reduced fatty liver, decreased oxidative damage indicators and enhanced neuronal NAD plus levels when taking 1,000 milligrams of NAD. These clinical outcomes provide some support for the safety of NR and NMN supplements.

Speaker 1: 7:14

However, boosting NAD plus levels is not as simple and straightforward as simply increasing precursor intake, due to several interconnected biochemical bottlenecks and regulatory factors. Firstly, the NAD plus consuming enzymes like CD38, parps, also known as polyADP, ribose polymerases and sirtuins, become increasingly active with age and inflammation significantly elevating NAD plus turnover. This heightened consumption can rapidly offset any potential gains made through supplementation with precursors. Secondly, the efficiency of NAD plus recycling via the salvage pathway decreases with age. The enzyme NAMPT, necessary for recycling nicotinamide back into NAD plus, declines significantly over time, making the process less effective and limiting NAD plus replenishment. Additionally, the body responds to excessive nicotinamide accumulation by activating nicotinamide and methyl transferase NNMT. This enzyme methylates and excretes excess nicotinamide, further depleting available NAD plus precursors and leading to methyl donor depletion. Available NAD plus precursors and leading to methyl donor depletion, which can negatively impact all kinds of functions. These interconnected factors heightened NAD plus consumption, diminished recycling capacity and active removal of precursor molecules create a challenging biochemical environment.

Speaker 1: 8:40

Effective strategies for NAD plus restoration thus require a multi-targeted approach that simultaneously addresses these underlying issues, rather than relying solely on precursor supplementation. Given the complexities and multiple bottlenecks outlined, effective NAD plus restoration requires interventions that targets various pathways simultaneously rather than relying solely on precursor supplementation simultaneously rather than relying solely on precursor supplementation. Firstly, addressing excessive NAD plus consumption by inhibiting the activity of major NAD plus consumers is critical. Natural compounds such as the flavonoid apigenin commonly found in parsley and chamomile have demonstrated the ability to inhibit CD38, leading to notable increases in NAD plus levels in some models. Another promising natural compound, quercetin, widely available as a dietary supplement, has also shown potential in preclinical studies for CD38 inhibition. Similarly, targeting the PARP enzymes, particularly PARP1, can significantly preserve NAD plus levels, at least it has in preclinical models. Luteolin, a flavonoid found in broccoli, and EGCG, found in green tea, exhibit natural PARP-inhibiting properties, potentially contributing to the preservation of NAD+.

Speaker 1: 9:55

Enhancing NAD+ recycling through activation of NAMPT is another viable strategy. Lifestyle interventions such as calorie restriction, occasional intermittent fasting and regular exercise significantly boost NAMPT activity, enhancing NAD synthesis naturally. Additionally, certain dietary compounds such as curcumin found in turmeric, have been suggested to support NAMPT activity indirectly through anti-inflammatory pathways. Lastly, activity indirectly through anti-inflammatory pathways. Lastly, inhibiting niacinamide and methyltransferase to prevent nicotinamide methylation and subsequent precursor loss can also be targeted. Naturally Dietary methyl donors such as trimethylglycine that's, betaine and choline supplementation, can support methylation processes, helping maintain balanced methyl donor pools while potentially reducing excessive nicotinamide excretion. A combined strategy incorporating precursor supplementation, for instance NR or NMN, dietary and lifestyle modifications to target CD38 and PARP activity, like consuming apigenin, quercetin, luteolin, enhancing recycling pathways via things like calorie restriction and exercise, and supporting methylation, presents a more holistic and synergistic approach to raising NAD plus levels and sustaining that A multi-pathway strategy may be what's needed to counteract NAD decline with age.

Speaker 1: 11:21

Nr, supported by substantial clinical evidence and a clear regulatory status, emerges as a reliable and reasonably well-studied NAD plus precursor. Clinical studies suggest doses ranging from 300 milligrams to 100 milligrams daily effectively elevate NAD plus levels, with doses up to 2,000 milligrams daily shown to be safe. But again, it's important to note that most studies done in humans with NR have not resulted in the same clinical outcomes that we see in preclinical models. At least that's not the case in people that are semi-healthy or already healthy, but there does seem to be some benefit in models like those of Parkinson's. Conversely, nmn offers promising preclinical data and reasonably robust safety profiles from early clinical studies, with oral doses ranging from 250 mg to 1,250 mg daily demonstrating good tolerability and significant NAD plus increases. However, nmn faces significant regulatory uncertainty and bioavailability challenges due to its molecular structure, potentially limiting widespread use, as well as effectiveness pathways involved in NAD plus decline.

Speaker 1: 12:48

True efficacy in NAD plus restoration likely demands a multi-targeted approach combining precursor supplementation and strategic dietary and lifestyle interventions. Compounds like apigenin dosed at 50 to 100 milligrams daily, quercetin at 250 to 500 milligrams daily, luteolin at 100-200 mg daily and curcumin at 500-1500 mg daily, coupled with supportive lifestyle practices like exercise and calorie restriction, offer a synergistic method for enhancing NAD plus synthesis, reducing excessive NAD plus consumption and improving precursor recycling and the NAD Plus wars. The real winner is not found in a single molecule, it's found in synergy. Remember aging isn't a battle we win molecule by molecule. It's a war won by embracing complexity. So arm yourself wisely, choose comprehensively and thrive at every age. Thank you for joining me today on Daily Value. Until next time, stay healthy.