Nicotinamide Adenine Dinucleotide (NAD) Boosters for Longevity (Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR))

Table of Contents

1. What Nicotinamide Adenine Dinucleotide Does and Why It Matters
2. Why Nicotinamide Adenine Dinucleotide Declines With Age
3. CD38 and the Nicotinamide Adenine Dinucleotide Consumers
4. The Precursor Cascade (Tryptophan to Nicotinamide Riboside to Nicotinamide Mononucleotide to Nicotinamide Adenine Dinucleotide)
5. Nicotinamide Mononucleotide vs Nicotinamide Riboside: The Sinclair-Brenner Debate
6. The Slc12a8 Transporter Controversy
7. Human Clinical Trials
8. Niacin and Nicotinamide as Cheaper Alternatives
9. Practical Protocol and Cautions
10. Key Research Papers
11. Connections
12. Featured Videos

What Nicotinamide Adenine Dinucleotide Does and Why It Matters

Nicotinamide adenine dinucleotide (oxidized nicotinamide adenine dinucleotide) is the most abundant non-protein redox molecule in living cells. It exists in two forms — oxidized nicotinamide adenine dinucleotide and reduced nicotinamide adenine dinucleotide (NADH) — and shuttles electrons between metabolic reactions. The nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide ratio is the central indicator of cellular energy state.

Beyond its role as a redox cofactor, nicotinamide adenine dinucleotide is consumed (not just recycled) by three families of enzymes that are central to aging:

1. Sirtuins (SIRT1–SIRT7): nicotinamide adenine dinucleotide-dependent deacylases that regulate gene expression, DNA repair, mitochondrial biogenesis, and metabolic flux. Discussed in depth on the Sirtuin Activators page. Sirtuin activity is rate-limited by nicotinamide adenine dinucleotide availability.
2. PARPs (Poly-ADP-Ribose Polymerases): respond to DNA strand breaks by transferring ADP-ribose units from nicotinamide adenine dinucleotide onto target proteins. PARP1 alone can consume up to 80% of cellular nicotinamide adenine dinucleotide in heavily damaged cells, depleting the pool available for sirtuins and energy metabolism.
3. CD38 and CD157: nicotinamide adenine dinucleotide glycohydrolases originally identified on lymphocyte surfaces but now known to be expressed on many cell types. CD38 activity rises with age and accelerates nicotinamide adenine dinucleotide decline.

Loss of nicotinamide adenine dinucleotide therefore simultaneously degrades energy metabolism, sirtuin signaling, and DNA repair — three of the hallmarks of aging at once. This is the mechanistic rationale for the nicotinamide adenine dinucleotide-precursor longevity hypothesis: if we can restore nicotinamide adenine dinucleotide, we can simultaneously restore mitochondrial function, sirtuin activity, and DNA repair capacity.

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Why Nicotinamide Adenine Dinucleotide Declines With Age

Multiple independent measurement methods (mass spectrometry of skin biopsies, NMR of muscle tissue, plasma assays) have converged on the conclusion that nicotinamide adenine dinucleotide declines with age. The precise magnitude varies by tissue and measurement method, but a roughly 50% decline in skeletal muscle and brain nicotinamide adenine dinucleotide between ages 40 and 60 is consistent across studies.

The decline is driven by three interacting processes:

1. Reduced synthesis: enzymes in the salvage pathway (NAMPT, NMNAT) decline with age in some tissues, reducing the rate at which nicotinamide is recycled back into nicotinamide adenine dinucleotide.
2. Increased consumption by CD38: CD38 expression on tissue-resident macrophages and other cells rises markedly with age, increasing nicotinamide adenine dinucleotide glycohydrolase activity in tissue.
3. Increased PARP activity: cumulative DNA damage with age drives chronic PARP1 activation, which consumes nicotinamide adenine dinucleotide.

The result is a chronic energy-and-signaling deficit that aligns with the broader pattern of age-related mitochondrial dysfunction. Restoring nicotinamide adenine dinucleotide pharmacologically — in mice — has been shown to restore mitochondrial function, improve insulin sensitivity, improve exercise capacity, and partially reverse age-related decline in muscle and brain function. Whether the same effects translate to humans at the doses and timeframes used in clinical trials remains the central open question.

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CD38 and the Nicotinamide Adenine Dinucleotide Consumers

The discovery that CD38 is the dominant age-related nicotinamide adenine dinucleotide consumer (Camacho-Pereira et al., Cell Metab 2016) shifted the field. Mice lacking CD38 do not show the age-related nicotinamide adenine dinucleotide decline; conversely, CD38 overexpression accelerates nicotinamide adenine dinucleotide loss and aging phenotypes. This implies that a CD38 inhibitor could raise nicotinamide adenine dinucleotide as effectively as supplementing precursors.

The candidate CD38 inhibitor with the most attention is apigenin, a flavonoid found in parsley, chamomile, celery, and onions. Apigenin inhibits CD38 in vitro and raises nicotinamide adenine dinucleotide in mice. Apigenin supplements are now sold by some longevity-focused vendors. Whether apigenin reaches plasma concentrations sufficient to inhibit CD38 in vivo at supplement doses is uncertain. Quercetin is also a CD38 inhibitor at high concentrations. 78c is an experimental CD38 inhibitor with stronger in vitro activity but no human data.

The implication for protocol design is that a comprehensive nicotinamide adenine dinucleotide-restoration strategy might combine precursor supplementation (nicotinamide riboside or nicotinamide mononucleotide, to drive synthesis) with CD38 inhibition (apigenin/quercetin, to reduce consumption), although this combined approach has not been rigorously tested in humans.

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The Precursor Cascade (Tryptophan to Nicotinamide Riboside to Nicotinamide Mononucleotide to Nicotinamide Adenine Dinucleotide)

Cells make nicotinamide adenine dinucleotide through multiple parallel routes, all of which converge on the central molecule:

1. De novo from tryptophan: dietary tryptophan can be converted to nicotinamide adenine dinucleotide through an 8-step kynurenine pathway. This is the slowest and least efficient route, but it explains why severe niacin deficiency requires extreme dietary restriction.
2. From niacin (nicotinic acid): niacin is converted to nicotinamide adenine dinucleotide through the Preiss-Handler pathway. This is the route used by therapeutic high-dose niacin for dyslipidemia, and is highly efficient but causes the well-known flush.
3. From nicotinamide (NAM): NAM enters the salvage pathway via NAMPT (the rate-limiting enzyme) which converts it to nicotinamide mononucleotide, which NMNAT then converts to nicotinamide adenine dinucleotide. This is the dominant pathway in most tissues most of the time.
4. From nicotinamide riboside (NR): nicotinamide riboside enters cells through nucleoside transporters, gets phosphorylated by NRK1/NRK2 to nicotinamide mononucleotide, and then converted to nicotinamide adenine dinucleotide by NMNAT. This route bypasses NAMPT (which is the bottleneck in some tissues).
5. From nicotinamide mononucleotide (NMN): nicotinamide mononucleotide can be converted directly to nicotinamide adenine dinucleotide by NMNAT. But because nicotinamide mononucleotide is a charged phosphate, it generally cannot cross cell membranes directly — the Sinclair lab's claim that a specific nicotinamide mononucleotide transporter (Slc12a8) exists is the subject of the controversy discussed below.

The cascade matters because it determines which oral precursor actually delivers nicotinamide adenine dinucleotide to the inside of cells. Nicotinamide riboside is the most established — Trammell's seminal 2016 Nat Commun paper showed nicotinamide riboside is uniquely orally bioavailable. Nicotinamide mononucleotide is also orally bioavailable, but Brenner's lab and others have argued that orally administered nicotinamide mononucleotide is mostly converted back to nicotinamide riboside (or to nicotinamide) in the gut before entering cells, making it effectively nicotinamide riboside by the time it reaches the cell interior. The Sinclair lab's counterargument hinges on the Slc12a8 transporter.

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Nicotinamide Mononucleotide vs Nicotinamide Riboside: The Sinclair-Brenner Debate

The two leading nicotinamide adenine dinucleotide precursors on the market are nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). They are chemically nearly identical — nicotinamide mononucleotide is nicotinamide riboside with an added phosphate group. The longevity supplement market has become deeply tribal about which is better, and the debate maps fairly cleanly onto two academic camps led by two prominent investigators with declared commercial conflicts.

Charles Brenner (City of Hope) discovered nicotinamide riboside's role as a vitamin B3 precursor and patents related to it that became the basis for ChromaDex's Niagen product. Brenner's position: nicotinamide riboside is the only oral nicotinamide adenine dinucleotide precursor with rigorously characterized pharmacokinetics, nicotinamide mononucleotide is mostly degraded to nicotinamide riboside or nicotinamide before absorption, the claimed Slc12a8 nicotinamide mononucleotide transporter findings are flawed, and nicotinamide mononucleotide's marketing premium over nicotinamide riboside is not scientifically justified.

David Sinclair (Harvard) is the most prominent academic advocate for nicotinamide mononucleotide and has a financial interest in companies marketing nicotinamide mononucleotide-based products including Tally Health and various supplement brands. Sinclair's position: nicotinamide mononucleotide is endogenously synthesized just before nicotinamide adenine dinucleotide, is one step closer in the salvage pathway, and the Slc12a8 transporter allows nicotinamide mononucleotide to enter cells directly. Sinclair's 2019 Nature Metabolism paper (Grozio et al.) reported identification of Slc12a8 as the nicotinamide mononucleotide transporter.

What the data actually show, fairly read:

• Both nicotinamide riboside and nicotinamide mononucleotide raise blood nicotinamide adenine dinucleotide in humans by 1.5× to 2× at gram doses. Magnitudes are comparable.
• Nicotinamide riboside has substantially more rigorous human pharmacokinetic data because it has been studied for longer with academic and industry funding (Conze et al., Sci Rep 2019, multi-dose 8-week study).
• Nicotinamide mononucleotide human data exist (Yoshino et al., Science 2021, in prediabetic postmenopausal women) showing increased muscle insulin sensitivity, but the dose was lower and the trial smaller.
• The Slc12a8 finding has been disputed by other labs (Schmidt-Pennington, Nat Metab 2021) which were unable to replicate the nicotinamide mononucleotide-transporter activity.
• U.S. Food and Drug Administration (FDA) actions: in 2022 the U.S. Food and Drug Administration reclassified nicotinamide mononucleotide as a "new drug" under investigation, banning its sale as a dietary supplement in the US (a regulatory, not safety, decision). Nicotinamide riboside remains classified as a supplement.

The honest summary: at the level of evidence currently available, both nicotinamide riboside and nicotinamide mononucleotide raise human blood nicotinamide adenine dinucleotide by similar amounts. Nicotinamide riboside has more mature pharmacokinetic and safety data. Nicotinamide mononucleotide has clearer regulatory uncertainty. Neither has been shown in any rigorous trial to extend human lifespan or even to slow biological aging on validated clocks. The choice between them is closer to a tossup than the partisan marketing on both sides suggests.

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The Slc12a8 Transporter Controversy

The Slc12a8 paper (Grozio et al., Nat Metab 2019) reported that mouse small intestine expresses a sodium-dependent nicotinamide mononucleotide transporter encoded by the Slc12a8 gene. The paper claimed that knockdown of Slc12a8 dramatically reduced nicotinamide mononucleotide uptake, and that the transporter was upregulated in conditions of nicotinamide adenine dinucleotide deficiency. The result was hailed by nicotinamide mononucleotide advocates as proof that nicotinamide mononucleotide reaches cells intact.

In 2021, a multi-author rebuttal in Nature Metabolism (which led to an editorial correction) argued that the Grozio data could not be replicated. Independent groups using purified Slc12a8 protein in liposomes failed to detect nicotinamide mononucleotide transport activity. The original Slc12a8 paper was the subject of an extensive Author Correction but was not formally retracted.

The current consensus position among biochemists is that Slc12a8 may or may not transport nicotinamide mononucleotide, but if it does, the activity is not as dramatic as the original paper claimed. Oral nicotinamide mononucleotide reaching cells likely does so primarily through degradation to nicotinamide riboside (which uses nucleoside transporters) or to nicotinamide (which crosses membranes freely), with at most a minor direct-NMN component.

What this means in practice: if nicotinamide mononucleotide works as a nicotinamide adenine dinucleotide precursor in humans (and the human blood-NAD evidence suggests it does), the mechanism is probably indirect through conversion to nicotinamide riboside or NAM in the gut. The therapeutic effect should therefore be similar to nicotinamide riboside at equivalent molar doses.

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Human Clinical Trials

Human trial evidence on nicotinamide adenine dinucleotide precursors falls into three categories.

Pharmacokinetic and safety trials are well-established. Conze et al. (Sci Rep 2019) gave healthy adults 1g/day of Niagen nicotinamide riboside for 8 weeks, showed approximately doubled blood nicotinamide adenine dinucleotide, and reported good safety. Martens et al. (Nat Commun 2018) ran a similar 6-week nicotinamide riboside study in healthy middle-aged adults with similar nicotinamide adenine dinucleotide elevation. Both established that nicotinamide riboside is safe at gram doses and reliably raises blood nicotinamide adenine dinucleotide.

Clinical biomarker trials are mixed. Martens et al. found that nicotinamide riboside lowered systolic blood pressure by 8 mmHg in adults with prehypertension (a clinically meaningful effect). Dollerup et al. (Am J Clin Nutr 2018) gave 2g/day nicotinamide riboside to obese insulin-resistant men for 12 weeks and found NO improvement in insulin sensitivity, NO improvement in mitochondrial function, and NO change in body composition — despite confirmed nicotinamide adenine dinucleotide elevation. This was one of the most consequential null results in the field. Yoshino et al. (Science 2021) gave 250 mg/day nicotinamide mononucleotide to prediabetic postmenopausal women for 10 weeks and found improved muscle insulin sensitivity but no change in body composition or systemic insulin sensitivity.

Endpoint trials — trials of nicotinamide riboside or nicotinamide mononucleotide with clinical disease endpoints or aging biomarkers — are essentially absent. The longest published trial is approximately 6 months. No trial has reported epigenetic clock changes from nicotinamide riboside or nicotinamide mononucleotide. No trial has demonstrated reduced mortality, cardiovascular events, or cognitive decline.

The fair summary: nicotinamide adenine dinucleotide precursors are safe at the gram-dose range, reliably raise blood nicotinamide adenine dinucleotide, may modestly improve specific markers in specific populations (blood pressure in middle-aged adults on nicotinamide riboside, muscle insulin sensitivity in prediabetic women on nicotinamide mononucleotide), but have not been shown to deliver the broader healthspan or lifespan effects that the marketing implies. The biological hypothesis is strong; the clinical evidence is thin.

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Niacin and Nicotinamide as Cheaper Alternatives

An underappreciated point is that niacin (nicotinic acid) and nicotinamide (NAM) are also nicotinamide adenine dinucleotide precursors — they cost a fraction of nicotinamide riboside or nicotinamide mononucleotide and are widely available as Vitamin B3. The reason the field has nonetheless focused on nicotinamide riboside and nicotinamide mononucleotide deserves examination.

Niacin causes the well-known prostaglandin-mediated "niacin flush" at doses above 100 mg, which limits chronic use. It is dramatically effective at raising nicotinamide adenine dinucleotide in tissue. The Coenzyme Q10 + niacin + ALCAR combination (the Saraswathy "mitochondrial cocktail") has shown benefits in mitochondrial disease patients. High-dose niacin (1–3 g/day) was historically used for dyslipidemia but fell out of favor when statins took over.

Nicotinamide (NAM) does not cause flushing and is cheap. The concern is that high-dose NAM directly inhibits sirtuins (as a product-inhibition effect of the sirtuin reaction). For this reason, NAM at gram doses may paradoxically reduce sirtuin activity even while raising nicotinamide adenine dinucleotide. Nicotinamide riboside avoids this because it enters the salvage pathway downstream of the inhibition point.

The honest cost-benefit analysis: 500 mg/day of immediate-release nicotinic acid, taken at bedtime with an aspirin pre-medication to mute the flush, raises nicotinamide adenine dinucleotide comparably to gram-dose nicotinamide riboside at perhaps 1/20th the cost. The newer precursors have a marketing premium that is not fully matched by mechanistic advantage.

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Practical Protocol and Cautions

If choosing to supplement a nicotinamide adenine dinucleotide precursor:

• Nicotinamide riboside (NR): 300–1000 mg/day with breakfast. Most established human safety data. Niagen brand has the most clinical trial support.
• Nicotinamide mononucleotide (NMN): 250–1000 mg/day. Regulatory status in the US uncertain (no longer marketable as a dietary supplement as of 2022). Some users prefer sublingual delivery, though stability and absorption claims for sublingual nicotinamide mononucleotide are largely unvalidated.
• Cycling: some practitioners recommend 5 days on, 2 days off, or 8 weeks on, 2 weeks off, to avoid potential downregulation of synthesis. No clinical evidence supports or refutes cycling.
• Combine with CD38 inhibition: 25–100 mg/day apigenin or 250–500 mg/day quercetin to reduce nicotinamide adenine dinucleotide consumption.
• Combine with sirtuin substrate (or activator): see the Sirtuin Activators page for resveratrol and pterostilbene rationale. If sirtuin substrate (nicotinamide adenine dinucleotide) is restored but the enzymes themselves are not active, the benefit may be limited.

Cautions:

1. Cancer concern: nicotinamide adenine dinucleotide supports both sirtuin-mediated tumor suppression AND cellular energy that fuels cancer proliferation. Several animal studies have shown that nicotinamide riboside can accelerate growth of established tumors in some models. Anyone with an active cancer diagnosis or recent cancer history should consult oncology before starting nicotinamide adenine dinucleotide precursors.
2. Liver enzyme elevation: rare, dose-dependent, reversible. Check alanine aminotransferase (ALT)/aspartate aminotransferase (AST) at baseline and 3 months on gram-dose precursors.
3. Methylation burden: nicotinamide adenine dinucleotide precursors are ultimately disposed of through methylation (to N-methylnicotinamide), which consumes S-adenosylmethionine. Some practitioners suggest co-supplementing TMG (trimethylglycine, 500–1000 mg) on high-dose nicotinamide adenine dinucleotide precursor protocols, particularly in methylenetetrahydrofolate reductase-variant individuals.
4. Drug interactions: high-dose niacin interacts with statins and blood-pressure drugs. Nicotinamide riboside and nicotinamide mononucleotide have fewer reported interactions but data are limited.

The fair statement to a patient considering nicotinamide adenine dinucleotide precursors: the biological hypothesis is strong, the human evidence is suggestive in specific subgroups (prehypertension, prediabetes), the cost is meaningful ($30–$60/month for nicotinamide riboside; more for nicotinamide mononucleotide), and no rigorous trial has yet demonstrated lifespan or healthspan extension. Reasonable people may choose to supplement on the strength of mechanism; equally reasonable people may wait for endpoint data.

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Key Research Papers

1. Bieganowski P, Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell 2004; 117:495–502. — PubMed PMID: 15137942
2. Trammell SAJ et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 2016; 7:12948. — PubMed PMID: 27721479
3. Yoshino J et al. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab 2011; 14:528–536. — PubMed PMID: 21982712
4. Mills KF et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 2016; 24:795–806. — PubMed PMID: 28068222
5. Camacho-Pereira J et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction. Cell Metab 2016; 23:1127–1139. — PubMed PMID: 27304511
6. Martens CR et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun 2018; 9:1286. — PubMed PMID: 29599478
7. Dollerup OL et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men. Am J Clin Nutr 2018; 108:343–353 (the null result) — PubMed PMID: 32320006
8. Grozio A et al. Slc12a8 is a nicotinamide mononucleotide transporter. Nat Metab 2019; 1:47–57 (with subsequent Author Correction) — PubMed PMID: 32694650
9. Yoshino M et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 2021; 372:1224–1229. — PubMed PMID: 33888596
10. Conze D et al. Safety and metabolism of long-term administration of NIAGEN (nicotinamide riboside chloride) in a randomized, double-blind, placebo-controlled clinical trial of healthy overweight adults. Sci Rep 2019; 9:9772. — Search PubMed
11. Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol 2014; 24:464–471. — PubMed PMID: 24786309
12. Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science 2015; 350:1208–1213. — PubMed PMID: 26785480
13. Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab 2018; 27:529–547. — PubMed PMID: 29514064
14. Massudi H et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One 2012; 7:e42357. — PubMed PMID: 22848760
15. Covarrubias AJ et al. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 2021; 22:119–141. — PubMed PMID: 33353981

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Connections

• All Remedies
• Benefits Deep Dive (Hub)
• Caloric Restriction and Mimetics
• Sirtuin Activators
• Sinclair Stack and Critique
• Longevity Protocols (Main)
• Nicotinamide Mononucleotide
• Nicotinamide Riboside
• Resveratrol
• Vitamin B3 (Niacin)
• Quercetin
• Apigenin
• Coenzyme Q10
• TMG (Trimethylglycine)
• Type 2 Diabetes
• Alzheimer's Disease

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