NAD+ Is Not a Supplement. It's a Coenzyme. That Distinction Matters.
Nicotinamide adenine dinucleotide (NAD+) is one of the most important molecules in human biology. It participates in over 500 enzymatic reactions, is essential for mitochondrial energy production, DNA repair, gene expression regulation, and cellular stress responses. Every cell in your body uses NAD+ constantly. This is not disputed by anyone. NAD+ is as real as ATP.1
The aging connection is also well-established. NAD+ levels decline significantly with age in skin, blood, liver, muscle, and brain tissue. This decline correlates with reduced mitochondrial function, impaired DNA repair capacity, increased inflammation ("inflammaging"), and the onset of age-related metabolic diseases. The question is not whether NAD+ matters. The question is whether taking a pill can reverse the consequences of its decline.1,2
NMN (nicotinamide mononucleotide) is a direct precursor to NAD+ in the salvage pathway, the body's primary route for NAD+ production. NR (nicotinamide riboside) is another precursor, one step upstream from NMN. Both are converted to NAD+ inside cells. The supplement industry has turned both into consumer products, but NMN has attracted the most hype, the most regulatory drama, and the most prominent scientific champion.
In Mice, NMN Does Nearly Everything
Demonstrated benefits in mice: Extended lifespan in invertebrates by up to 30%. Restored NAD+ levels in aged tissues. Improved mitochondrial function, insulin sensitivity, and lipid metabolism. Enhanced muscle regeneration and stem cell activity. Protected against neurodegeneration, cardiovascular decline, kidney damage, and liver aging. Improved fertility in aged female mice. Rescued cerebromicrovascular function and cognitive performance.2,3
The caveat that changes everything: Mouse metabolism, lifespan, dosing kinetics, and NAD+ dynamics are fundamentally different from humans. Spectacular rodent data is the starting point of drug development, not the end. Most interventions that work in mice fail in human trials.
The mouse data is genuinely impressive and nobody disputes it. The problem is that the supplement industry treats mouse studies as product validation rather than what they actually are: preclinical evidence that justifies human trials. You cannot buy a mouse study at Whole Foods. You can, however, buy a supplement whose entire marketing narrative rests on one.
NAD+ Goes Up. Then What?
As of early 2026, there are roughly two dozen completed human trials of NMN supplementation. They consistently demonstrate two things: NMN is safe at doses up to 1,200 mg/day, and it reliably raises circulating NAD+ levels by approximately 130–150%. These findings are robust and reproducible. No serious adverse events have been reported across trials.4,5
What the trials have not consistently demonstrated is that raising NAD+ levels translates into the functional benefits seen in mice. This is the translation gap at the center of the NMN story.
Findings: NMN significantly increased blood NAD+ levels. Significant effects on gait speed (muscle function marker). Significant reduction in ALT (liver health marker). Improved insulin resistance (HOMA-IR) at lower doses. No significant effects on fasting glucose, total cholesterol, LDL, HDL, triglycerides, body weight, or BMI.6
Translation: Modest, selective benefits emerging from pooled data. The strongest signals are in muscle function and insulin sensitivity, consistent with earlier individual trials. But the headline metabolic benefits the market promises, like weight loss and cholesterol reduction, are absent.
Key conclusion: "While oral NR supplementation consistently increased NAD+ levels across participants of different ages and health conditions, it did not lead to measurable improvements in physiological functions, such as cardiovascular health. Similar outcomes have also been reported in clinical trials utilizing NMN supplementation."7
Study sizes remain small (typically n=14–62). Duration is short (4–12 weeks, rarely longer). Most trials lack sham controls or long-term follow-up. The signal-to-noise ratio is poor.
The honest summary: NAD+ goes up reliably. Functional outcomes are inconsistent, modest when positive, and absent for the most marketed claims. We don't yet know if raising NAD+ with supplements reverses aging in humans.
500+ enzymatic reactions. Decline with age proven. Central to metabolism, DNA repair, mitochondria.
Lifespan extension. Organ protection. Metabolic rescue. Cognitive improvement. Fertility restoration.
NMN reliably raises blood NAD+ 130–150% in humans. Safe at tested doses. Reproducible across trials.
Modest gains in muscle function, insulin sensitivity. No consistent cardiovascular, cognitive, or metabolic improvements. Small, short trials.
Raising NAD+ is not the same as reversing aging. The gap between "NAD+ levels increased" and "you aged slower" has not been bridged by human clinical evidence.
Although NMN is proposed as a calorie-restriction and exercise mimetic, it should not be taken as an excuse for gluttony and a substitute for physical activity.
NMN meta-analysis, Critical Reviews in Food Science and Nutrition, 2024The Evangelist Has a Company
No discussion of NMN is complete without addressing David Sinclair. The Harvard genetics professor is the field's most prominent advocate, author of the bestselling book Lifespan, and a prolific media presence whose claims about NAD+ and aging have driven much of the consumer market. His research group has produced foundational work on sirtuins, NAD+ metabolism, and epigenetic reprogramming. He is a serious scientist with serious credentials.3
He is also the co-founder of MetroBiotech, the company that developed MIB-626, a proprietary crystalline form of NMN that was investigated as a pharmaceutical drug. It was MetroBiotech's IND (Investigational New Drug) authorization that triggered the FDA's 2022 exclusion of NMN from dietary supplements. Sinclair's company's drug application was the direct cause of the regulatory crisis that threatened the NMN supplement market. MIB-626 trials showed improved lipid profiles and blood pressure, but the fact that these results came from the company co-founded by the field's most vocal public advocate is a conflict that the longevity community has been remarkably uninterested in scrutinizing.8,9
Scientific role: Harvard professor, principal investigator on foundational NAD+/sirtuin research, co-author of the 2024 Cell Metabolism review summarizing anti-aging clinical trials. Public evangelist for NAD+ supplementation.3
Commercial role: Co-founder of MetroBiotech (MIB-626, NMN drug candidate). Co-founder of multiple longevity-related companies. His public advocacy directly benefits the market for products related to his commercial interests.
Note: Conflicts of interest do not invalidate research. But when the most prominent public voice for a supplement category also has financial interests in that category's commercial success, consumers should factor that into their evaluation of his claims.
The Regulatory Drama Was Never About Safety
In November 2022, the FDA determined that NMN could not be marketed as a dietary supplement because MetroBiotech had received IND authorization to investigate it as a drug before NMN was established as a lawful supplement. This was a regulatory interpretation of the drug preclusion clause in DSHEA, not a safety determination. The FDA never said NMN was dangerous. It said NMN couldn't be sold as a supplement while under drug investigation.8
The Natural Products Association filed a citizen petition in March 2023 and a lawsuit in August 2024. A federal court stayed FDA enforcement in October 2024. In September 2025, the FDA reversed its position entirely, confirming that NMN is lawful for use in dietary supplements. The agency concluded that NMN had been marketed as a supplement in the U.S. as early as 2017, before the drug investigation, satisfying the "race to market" provision.9,10
Throughout this entire saga, NMN remained available for purchase. The FDA never enforced its exclusion. Most retailers continued selling it. Amazon briefly pulled NMN products, then they came back. The regulatory drama generated enormous free marketing for NMN as a supplement, precisely because consumers interpreted "the FDA tried to ban it" as evidence of pharmaceutical conspiracy rather than bureaucratic interpretation of supplement law.
Safety Profile
NMN appears safe in all completed human trials at doses up to 1,200 mg/day for up to 12 weeks. No serious adverse events reported. Long-term safety (years of daily use) has not been studied. The FDA's regulatory action was never based on safety concerns.4,5
Quality Control
Many NMN products fail independent testing for purity and dosage accuracy. Products are often underdosed or mislabeled. NMN requires proper storage, as it degrades at room temperature. The supplement market has no pre-market testing requirement. Third-party tested products from verified manufacturers are essential.9
Exercise Does This for Free
Aerobic and resistance training upregulate NAMPT, the rate-limiting enzyme in NAD+ recycling, raising skeletal muscle NAD+ levels by 25–30%. Exercise also provides mitochondrial biogenesis, cardiovascular protection, cognitive benefits, and metabolic improvement through mechanisms NMN has not demonstrated in humans.7
The Cancer Question
Some researchers have raised concerns that boosting NAD+ could theoretically fuel cancer cell metabolism, as tumors are highly metabolically active and may benefit from increased NAD+ availability. This has not been demonstrated in human NMN studies, but long-term cancer surveillance data from NMN supplementation does not exist.2
Good Biology, Preliminary Medicine
NAD+ biology is one of the most important areas of aging research. The molecule's role in cellular metabolism, DNA repair, and mitochondrial function is established science. The decline of NAD+ with age is real and measurable. The animal data demonstrating that restoring NAD+ can reverse age-related pathology is genuinely compelling. None of this is hype.
What is hype, or at least premature, is the consumer market's conclusion. Taking an NMN supplement reliably raises your blood NAD+ levels. That is well-demonstrated. But "raised NAD+ levels" is a biomarker change, not a clinical outcome. The human trials have not consistently demonstrated that this biomarker change translates into the functional improvements, like reduced cardiovascular risk, improved cognition, slowed aging, or extended healthspan, that the animal data suggests and that the marketing promises.
The trials are small (n=14–62 typically), short (4–12 weeks), and many lack proper controls. A 2024 meta-analysis found modest signals in muscle function and insulin sensitivity, which is encouraging. But the absence of cardiovascular, cognitive, and metabolic benefits in a pooled analysis of over 400 participants is not nothing. It is data.
If you're going to take NMN: Choose third-party tested products from verified manufacturers. Store properly (stability matters). Don't exceed 500 mg/day until longer-term safety data exists. Don't treat it as a substitute for exercise, diet, or sleep, all of which have stronger evidence for every outcome NMN is marketed for.
If you're deciding whether to start: Ask yourself what outcome you're hoping for. If the answer is "I want to raise my NAD+ levels," NMN does that. If the answer is "I want to age slower," no human clinical evidence supports that claim yet. The trials are coming. The science may eventually get there. But you're paying for a hypothesis, not a result.
NAD+ is genuinely critical to cellular health and declines with age. NMN reliably raises NAD+ levels in humans and appears safe in short-term studies. But "NAD+ went up" is a lab value, not a health outcome. The spectacular mouse data has not been replicated in human functional endpoints. The field's most prominent advocate co-founded the company whose drug application triggered a regulatory crisis. Exercise raises muscle NAD+ by 25–30% for free. NMN supplementation is a scientifically reasonable bet on a hypothesis that has not yet been proven in humans. Bet accordingly.
Sources
- Wang E, et al. Biological properties, synthetic pathways and anti-aging mechanisms of NMN. Biogerontology. 2025. Multi-target mechanisms, NAD+ biosynthesis pathways.
- Yang Y, et al. The safety and antiaging effects of NMN in human clinical trials: an update. Adv Nutr. 2023. Review of NAD+ biology, aging mechanisms, clinical trial progress.
- Guarente L, Sinclair DA, Kroemer G. Human trials exploring anti-aging medicines. Cell Metabolism. 2024. Comprehensive review of 8 geroprotective drug categories including NAD+/sirtuins.
- Renue By Science. A current list of completed NMN human trials. Updated Feb 2025. Catalog of ~24 completed trials spanning 2016–2025.
- Pencina KM, et al. MIB-626, an oral formulation of NMN, increases circulating NAD+ in middle-aged and older adults. J Gerontol A. 2022;78(1):90–96.
- NMN meta-analysis. Efficacy of oral NMN supplementation on glucose and lipid metabolism. Crit Rev Food Sci Nutr. 2024. 9 RCTs, n=412. Significant: gait speed, ALT, HOMA-IR. Non-significant: glucose, cholesterol, weight, BMI.
- Healthspan review. Do NAD+ boosters work? NR and NMN for aging, cognition & muscle. 2025. "Supplementation consistently elevated NAD+ but did not lead to measurable improvements in physiological functions."
- FDA. NMN exclusion letter. November 2022. Drug preclusion clause determination. Not a safety finding.
- FDA. Response to NPA/ANH citizen petition. September 29, 2025. NMN declared lawful in dietary supplements. Reversal of 2022 position.
- NutraIngredients. FDA reinstates NDI status of NMN. December 2025. Letters issued to SyncoZymes and Inner Mongolia Kingdomway.
- Sinclair Lab publications. Harvard Medical School. NMN rescue of cerebromicrovascular function, cognitive function, fertility, metabolic impairment in mice.