NAD/NAD+ Supplements (NR and NMN)

Comprehensive Evidence Review of popular "longevity supplement"

One of the earliest recorded accounts of a supposed cure for aging appears in The Epic of Gilgamesh, an ancient Mesopotamian text composed around 2100 BCE. In the story, the hero Gilgamesh obtains a special plant said to restore youth. However, his hope is dashed when the plant is stolen by a serpent, symbolising the elusive nature of immortality.¹ Elixir of Life in Ancient China was sought by several emperors, especially Qin Shi Huang (3rd century BCE). Mercury-based concoctions were at times employed, ironically causing harm instead of prolonging life.²

The Philosopher’s Stone in Western Alchemy was rumored to grant eternal life and perfect health. Alchemists spent centuries attempting to produce this legendary substance, but no verifiable results materialised.³ From the XIX century, in the United States, numerous patent medicines promised to slow or halt aging. These remedies commonly contained little beyond basic ingredients like mineral oil, alcohol, or spices. They were sold widely, yet lacked proven efficacy. ⁴

All those miraculous cures had one thing in common: they didn’t work, and made those who sold them rich.

Distinguishing genuine potential in so-called “longevity drugs” from mere speculation can be both difficult and disheartening, especially when enthusiasm becomes widespread.

A therapy that has attracted significant attention in recent years is nicotinamide adenine dinucleotide (NAD), a molecule central to numerous vital cellular functions. Reduced levels of NAD has been linked to age-related diseases and the aging process itself. As a result, various approaches to boosting NAD—either by directly supplementing it or through precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN)—have sparked interest for the potential benefits they may offer, including extended lifespan, enhanced metabolic health, improved physical performance, and other promises.

Does it work?

NAD is a molecule found in every cell, where it acts as a key coenzyme in numerous metabolic reactions and other cellular functions. The term “NAD” encompasses two versions of the same compound: NAD+ and NADH, reflecting how this molecule manages electron transfer between other molecules—a mechanism essential for both breaking down and building up substances, as well as for handling oxidative stress.

NAD+ (the oxidized form) can take electrons from other molecules, whereas NADH (the reduced form) can donate electrons in return (see Figure 1).

Figure 1: Chemical structures and interconversion between NAD+ (left) and NADH (right) – the oxidized and reduced forms of NAD, respectively.

NAD also plays a part in various processes related to DNA repair and gene regulation. Put simply, NAD holds a prominent position among essential biological molecules.

Although NAD is essential for cell survival and function, it didn’t really catch the eye as a factor in aging until the late 1990s and early 2000s. That’s when interest grew in a group of enzymes called sirtuins. Researchers realised these enzymes, which depend on NAD, might potentially help lengthen lifespan — but how?

The rise and fall of the sirtuin hypothesis

In mammals, there are seven sirtuin enzymes (labelled SIRT1 through SIRT7). Their job is to modify other proteins, which can affect different cell activities, including turning genes on or off. Around the early 2000s, these enzymes became a hot topic when scientists showed that increasing the amount of a yeast sirtuin gene (called SIR2) made yeast cells live longer. Later work demonstrated that raising sirtuin levels in roundworms and fruit flies also boosted lifespan, suggesting that what was seen in yeast could apply to more complex creatures as well.

Where does NAD fit into all this? Sirtuins depend on NAD to function. Normally, NAD shuttles back and forth between two forms (NAD+ and NADH), but sirtuin activity actually breaks NAD down into smaller parts (ADP ribose and nicotinamide). Because sirtuins need NAD, higher NAD levels can activate them. This discovery linked gene control (via sirtuins) with metabolism (NAD), leading some to propose that sirtuins might explain why cutting calories can extend lifespan. Enthusiasm around this idea grew further when researchers noticed that NAD levels decline with age in many tissues, sparking the hypothesis that raising NAD might help counter ageing.

The effects of increasing sirtuin levels on yeast lifespan have been consistently observed, though they may vary depending on the yeast strain. Importantly, these effects are separate from the lifespan extension seen with calorie restriction.

However, while findings in yeast are a good starting point, they’re only meaningful if they provide insight into the lifespan of more complex organisms, ideally mammals. Unfortunately, this doesn’t seem to be the case for sirtuins.

Attempts to replicate the lifespan-boosting effects of sirtuin activation in worms and flies have failed, and closer examination of the original studies revealed that the results were due to insufficient controls rather than any real impact on longevity. Most significantly, studies in mice have shown that altering sirtuin levels does not affect lifespan.

So this is all bullshit?

Essentially, yes.

The idea that sirtuins generally extend lifespan has been widely debunked.

This doesn’t rule out the possibility that NAD could affect ageing through other pathways unrelated to sirtuins. NAD plays a role in numerous cellular processes, so its age-related decline could influence ageing and health in many ways beyond just activating sirtuins. But there is no evidence to support this claim.

How does NAD change with age?

All hypotheses regarding the utility of NAD supplementation rely heavily on the observation that levels decline over time. Let’s take a closer look.

It is well-established that NAD levels decrease with age, but the extent of this decline varies across different tissues. A 2022 review highlighted that the most significant drop seems to occur in skin tissue, where NAD+ levels in young adults are, on average, about 68% lower than those in newborns.

By middle age, levels decline a further 60% compared to young adults, with no significant reduction observed beyond middle age. In contrast, studies have shown only a modest 10–20% decline in NAD+ levels in the brain between young adults and those aged 70 and older. Similarly, whole blood NAD+ levels show a decrease of about 10–20% from young adulthood to old age, though some research suggests this decline may not occur in women.

The reasons behind the decline in NAD+ levels with age remain unclear. It likely depends on the balance between how much NAD+ is produced and how much is used—this could involve increased consumption, reduced production, or a mix of both. However, we still don’t fully understand how ageing affects this balance or if different tissues experience it in unique ways.

One possible explanation for increased NAD+ consumption is that DNA damage becomes more frequent with age, activating PARP enzymes that use NAD+ to repair DNA. Additionally, the ageing process may lead to more senescent cells—cells that have stopped dividing due to stress or old age. These cells can increase the production of CD38, a protein found on many immune cells, which also depletes NAD+.

On the other hand, NAD+ levels might fall because the body produces less of it. This could happen if the enzymes responsible for creating or recycling NAD+ become less active as we age. Both increased consumption and reduced production could play a role in the overall decline.

Interestingly, some research suggests that the so-called "decline" in NAD levels with age might not be a true decrease, but rather a shift in the balance between the two forms of the molecule: NAD+ and NADH.

Many studies assessing NAD levels haven’t used methods that can clearly differentiate between these two states. However, in studies that employed advanced spectroscopic techniques, a drop in NAD+ levels with age was often accompanied by an increase in NADH. This shift toward the reduced form (NADH) has been observed in tissues such as the kidney, liver, heart, and lungs of rats, as well as in at least one study of human brain tissue.

Do the NAD/NADH/NMN supplements do anything?

Two key challenges limit the effectiveness of NAD supplementation: the natural regulation of NAD levels in cells and its poor bioavailability.

NAD is crucial for cellular function, so cells tightly regulate its levels to prevent harmful imbalances. Typically, NAD+ levels stay within a range of 200–500 μM, depending on the cell type and environmental factors. If levels drop too low, essential processes like glycolysis are disrupted, leading to cell death. On the flip side, excessively high NAD+ levels can lead to a buildup of nicotinamide (NAM), which inhibits enzymes like PARPs. Since PARPs are critical for DNA repair, their inactivation can cause genomic instability, eventually resulting in cell death. This raises the question: during ageing, do NAD levels decline enough to fall outside this regulated range and cause problems? It seems not to be the case.

Another challenge is NAD’s bioavailability. When taken orally, NAD is broken down in the digestive system rather than being absorbed into the body intact. Intravenous administration avoids this issue, bypassing the gut and liver, but even then, there’s no clear pathway for NAD to enter cells from the bloodstream.

This limits its effectiveness, even if maintaining or boosting NAD levels might be beneficial for ageing. To address this, researchers have turned to NAD precursors—compounds that the body can convert into NAD—to overcome these bioavailability issues.

What are NAD precursors?

Mammals mainly rely on internal recycling systems, called "salvage pathways," to maintain NAD+ levels, but a small amount of dietary NAD precursors (around 20 mg of niacin or its equivalents for humans) is also needed. These precursors must be absorbable to some extent and able to contribute to the body’s NAD supply by converting into NAD+.

Tryptophan, nicotinic acid (NA/niacin), nicotinamide (NAM), nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) are all used to produce NAD+, but they differ in how they are absorbed and taken up by cells. For example, NMN seems to be converted to NR in the gut before absorption, and while NR can be absorbed, much of it is broken down into NAM during digestion.

Since NAD itself cannot be absorbed directly or transported into cells, supplementing with precursors is currently the most promising way to boost NAD+ levels. NR, for instance, can enter cells through specialised transporters called ENTs (equilibrative nucleoside transporters). Some believe NMN may have its own transporter, but the more widely accepted view is that NMN is first converted to NR and then taken up via ENTs. Other precursors like tryptophan and NA use different transport systems, while NAM can pass into cells freely without requiring active transport.

Do NAD precursors raise NAD+ levels in your cells?

NAD precursors can enter cells and trigger pathways that produce or recycle NAD+, boosting overall levels. Different precursors follow specific pathways; for example, NR converts to NMN, which then produces NAD+ through the salvage pathway. NMN is key for mitochondrial NAD+, while other precursors like NA and tryptophan raise NAD+ through their own routes.

However, how well tissues take up NAD precursors and produce NAD+ varies. For instance, the small intestine and spleen show the highest NAD turnover, while muscle, fat, and brain—often targeted by NAD supplements—have much lower turnover. Most tissues rely on the salvage pathway using NAM, while the liver and kidneys primarily use the de novo synthesis pathway.

Lab studies initially suggested NAD precursors like NR and NMN boost NAD+ levels, but these were mostly in vitro. More recent animal studies show promising results. In mice, NR supplementation over weeks significantly increased NAD+ in skeletal muscle, while NMN showed less effect on muscle but boosted NAD+ in tissues like fat, liver, and pancreas. Both NR and NMN have also been shown to raise NAD+ levels in the brain. These findings suggest that NAD precursors can enhance NAD+ in tissues important for metabolism, cognition, and health, though doses in animals were often higher than those that can be safely used in humans.

Do NR or NMN increase human lifespan?

No human trials have tested this, as such studies would be too lengthy and expensive. Instead, the most direct evidence comes from studies in rodents.

The Interventions Testing Program (ITP), known for its rigorous lifespan studies, tested NR in outbred mice. Starting at 8 months of age (comparable to humans in their early 30s), 136 female and 156 male mice were given NR in their diet for the rest of their lives, while 607 control mice had a standard diet. The results showed no impact on median or maximum lifespan for either sex. Although one testing site reported a slight increase in female lifespan with NR, this was offset by another site showing a slight decrease and a third reporting reduced lifespan in males.

For NMN, the ITP hasn’t conducted similar tests. However, a recent study led by Dr David Sinclair, a proponent of NAD and sirtuin research, reported that female mice given about 550 mg/kg/day of NMN (starting at 13 months, roughly mid-40s in humans) showed an 8.5% increase in median lifespan and a 7.9% increase in maximum lifespan compared to controls. However, these findings, which haven’t been peer-reviewed⁵, need caution. The treated females’ lifespan was similar to treated males and controls, suggesting the "extension" might simply reflect shorter-than-expected lifespans in the female controls rather than a benefit from NMN. Perhaps this is why David didn’t submit his work for peer review.

What about other possible health benefits?

Although there’s little evidence to suggest NAD precursors extend lifespan, their role in essential cellular functions has led to speculation that NAD+ depletion might contribute to age-related diseases.

As a result, NAD precursors have been studied for their potential to address major health concerns such as metabolic syndrome, neurodegenerative diseases, cancer, and cardiovascular disease.

Additionally, because NAD is crucial for mitochondrial function and energy production, researchers have examined whether these precursors could improve physical performance outside of disease contexts. Below, we review the current research, which has primarily focused on NR.

Metabolic disease (no benefits)

NAD is essential for cellular metabolism. However, despite its theoretical links to metabolic health, clinical trials have repeatedly shown no benefits of NAD precursors for metabolic diseases.

One of the largest studies tested NR supplementation (2000 mg/day) in 40 obese but non-diabetic men over 12 weeks. The results showed no meaningful changes in body composition, energy use, insulin sensitivity, cholesterol levels, or liver function. There was a slight, non-significant trend toward reduced liver fat in the NR group, but the only notable difference was a modest increase in triglycerides—an undesired outcome, though levels stayed within normal ranges. Follow-up analyses from the same trial found no impact on pancreatic function, incretin hormone release (GLP-1 and GIP), or skeletal muscle mitochondrial function. In all cases, NR failed to show clear benefits for metabolic health.

Neurodegenerative disease (no benefits)

NAD+ depletion has been linked to neurodegenerative diseases like Alzheimer’s and Parkinson’s. While animal studies suggest that restoring NAD+ levels may improve cognitive function, human trials have produced mixed results.

Studies in rodents show that NAD precursors like NR and NMN can reduce neuroinflammation, combat oxidative stress, and improve memory and cognitive performance, such as in Alzheimer’s models.

In humans, findings have been less consistent. A 10-week trial with 20 individuals with mild cognitive impairment found that NR supplementation increased blood NAD+ levels but did not improve cognitive function. Similarly, a 24-week study of nicotinamide (NA) in Alzheimer’s patients showed no effect on cognition.

More positive outcomes have been observed in Parkinson’s trials. One study found that 30 days of NR supplementation raised brain NAD+ levels in some participants and was linked to small improvements in Parkinson’s symptoms. Human studies remain small and short-term, leaving questions about the broader impact of NAD precursors on cognitive decline unanswered. Ongoing trials may provide more clarity in the future.

Cancer (no benefits, and may make cancer grow faster)

The connection between NAD and cancer is complex.

While low NAD levels may contribute to cancer by impairing energy production, DNA repair, and genomic stability, increasing NAD could theoretically support cancer growth, as it is essential for cell division.

As a result, studies on NAD precursors and cancer have shown mixed results, influenced by the type of cancer and study design.

While evidence for cancer prevention is limited, NAD precursors show promise in reducing side effects from cancer treatments like chemotherapy. Research in mice and cell models has found that NR and NMN can lessen DNA damage and neurotoxicity caused by chemotherapy.

However, there is also concern that these precursors might accelerate cancer growth, a risk that warrants careful consideration and further study.

Cardiovascular disease (no benefits)

NAD’s role in energy production and managing oxidative stress has led to speculation that NAD precursors might protect against cardiovascular disease (CVD). The heart, which has some of the highest NAD levels in the body, may benefit from NAD’s effects, and lab studies suggest that treating cardiac muscle precursor cells with NAD precursors can improve their survival under low-oxygen conditions. However, few studies have directly examined whether NAD precursors can prevent or treat CVD, apart from research on niacin.

Niacin, studied since the 1950s, has shown effectiveness in reducing triglycerides and harmful lipoproteins that promote atherosclerosis. Early trials suggested it could slow CVD progression and lower the risk of cardiovascular events. However, larger studies have found its benefits modest compared to standard treatments like statins, and its side effects, especially flushing, are common and significant. As a result, niacin is rarely used today for CVD management.

For other NAD-boosting supplements like NR and NMN, evidence is limited. A few small trials have focused on arterial stiffness, but results have been inconclusive. A six-week crossover study with NR in 24 healthy participants showed a non-significant trend toward lower aortic stiffness. Similarly, a 12-week study of NMN in 17 participants showed a slight, non-significant reduction in arterial stiffness compared to placebo.

No studies have demonstrated clear cardiovascular benefits or examined major cardiovascular events, leaving no reason to believe these supplements improve heart health.

Exercise performance (no benefits)

NAD is essential for energy production and mitochondrial function, both critical for physical performance. This has led to the idea that boosting NAD+ levels might improve exercise capacity. However, clinical trials investigating NAD precursors for this purpose have shown little effect.

In studies on short-term supplementation, a trial with 12 young men (average age 22.9) and 12 older men (average age 71.5) found that taking 500 mg of NR two hours before exercise did not affect VO2 max in either group. However, older participants showed a slight improvement in resistance to fatigue.

Among trials on repeated supplementation, the most encouraging results come from a six-week study in amateur runners. Those taking NMN (600–1200 mg/day) showed improvements in oxygen uptake and power output at the first ventilatory threshold (where breathing rate starts to increase during exercise). However, there were no significant changes in VO2 max, peak power, or heart rate.

Another six-week crossover study in older adults (average age 65) using 1000 mg of NR daily found no effect on VO2 max, treadmill endurance, muscle fatigue, grip strength, or measures of mobility.

Overall, the evidence does not support a benefit of NAD precursors for enhancing physical performance.

So there are no benefits. What about harms?

NAD precursors are considered safe in short-term studies, but two potential risks warrant attention.

The most common side effect is flushing, though this is mainly associated with niacin and intravenous NAD, not with NR or NMN. Flushing, caused by prostaglandin release from immune cells in the skin, leads to redness, warmth, or itching. While some view this as evidence of treatment effectiveness, it has no known link to any health or longevity benefits of NAD.

Another concern is the potential for NAD precursors to accelerate the growth of existing cancers. In mice injected with breast cancer cells, those treated with NR showed faster tumour growth and more brain metastases than controls. This aligns with earlier findings that tumours rely heavily on NAD for glycolysis to sustain rapid growth. Some preclinical studies suggest that reducing NAD biosynthesis could slow tumour progression. However, it’s important to note that these findings indicate NAD precursors might fuel existing cancers, not that they cause cancer to develop.

So, should I take it?

At Solutions Makers we do NOT routinely recommend NMN/NAD supplements.

Despite significant interest and investment, the evidence supporting NAD precursors as anti-ageing treatments remains limited. While these compounds are essential for cellular function, their role in extending healthy lifespan is still poorly understood, even at a basic level. The connection between NAD precursors, intracellular NAD levels, and ageing processes is far from clear.

That said, NAD-based therapies shouldn’t be dismissed entirely. While there’s no evidence to back the anti-ageing claims often made about these supplements, some preclinical studies and a few clinical trials suggest potential disease-specific benefits, particularly for conditions like Parkinson’s. However, these findings are preliminary, and more rigorous research is needed to confirm their value.

For now, while it’s worth keeping an eye on emerging research, relying on NAD precursors to promote a longer, healthier life seems premature. Instead, the best approach remains focusing on proven strategies such as regular exercise, balanced nutrition, quality sleep, and emotional well-being.

These methods are more reliable and effective for maintaining health while we wait for clearer evidence on NAD therapies.

References

1. Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999;13(19):2570-2580. doi:10.1101/gad.13.19.2570

2. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403(6771):795-800. doi:10.1038/35001622

3. Villalba JM, Alcaín FJ. Sirtuin activators and inhibitors. Biofactors. 2012;38(5):349-359. doi:10.1002/biof.1032

4. Kaeberlein M, Kirkland KT, Fields S, Kennedy BK. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol. 2004;2(9):E296. doi:10.1371/journal.pbio.0020296

5. Brenner C. Sirtuins are Not Conserved Longevity Genes. Life Metab. 2022;1(2):122-133. doi:10.1093/lifemeta/loac025

6. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschöp MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci U S A. 2008;105(28):9793-9798. doi:10.1073/pnas.0802917105

7. Banks AS, Kon N, Knight C, et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 2008;8(4):333-341. doi:10.1016/j.cmet.2008.08.014

8. Bordone L, Cohen D, Robinson A, et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell. 2007;6(6):759-767. doi:10.1111/j.1474-9726.2007.00335.x

9. Kincaid JW, Berger NA. NAD metabolism in aging and cancer. Exp Biol Med (Maywood). 2020;245(17):1594-1614. doi:10.1177/1535370220929287

10. Zhang J, Hong Y, Cao W, Shi H, Ying W. SIRT2, ERK and Nrf2 mediate NAD+ treatment-induced increase in the antioxidant capacity of differentiated PC12 cells under basal conditions. bioRxiv. Published online December 15, 2018:497404. doi:10.1101/497404

11. Brenmoehl J, Hoeflich A. Dual control of mitochondrial biogenesis by sirtuin 1 and sirtuin 3. Mitochondrion. 2013;13(6):755-761. doi:10.1016/j.mito.2013.04.002

12. Peluso A, Damgaard MV, Mori MAS, Treebak JT. Age-dependent decline of NAD+-universal truth or confounded consensus? Nutrients. 2021;14(1):101. doi:10.3390/nu14010101

13. Bagga P, Hariharan H, Wilson NE, et al. Single-Voxel 1 H MR spectroscopy of cerebral nicotinamide adenine dinucleotide (NAD+ ) in humans at 7T using a 32-channel volume coil. Magn Reson Med. 2020;83(3):806-814. doi:10.1002/mrm.27971

14. Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc Natl Acad Sci U S A. 2015;112(9):2876-2881. doi:10.1073/pnas.1417921112

15. Yang F, Deng X, Yu Y, et al. Association of human whole blood NAD+ contents with aging. Front Endocrinol (Lausanne). 2022;13:829658. doi:10.3389/fendo.2022.829658

16. McReynolds MR, Chellappa K, Baur JA. Age-related NAD+ decline. Exp Gerontol. 2020;134(110888):110888. doi:10.1016/j.exger.2020.110888

17. Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Poljak A, Grant R. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS One. 2011;6(4):e19194. doi:10.1371/journal.pone.0019194

18. Williams PA, Harder JM, John SWM. Glaucoma as a metabolic optic neuropathy: Making the case for nicotinamide treatment in glaucoma. J Glaucoma. 2017;26(12):1161-1168. doi:10.1097/IJG.0000000000000767

19. Canto C. NAD+ precursors: A questionable redundancy. Metabolites. 2022;12(7):630. doi:10.3390/metabo12070630

20. Nikiforov A, Dölle C, Niere M, Ziegler M. Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation. J Biol Chem. 2011;286(24):21767-21778. doi:10.1074/jbc.M110.213298

21. Poljšak B, Kovač V, Milisav I. Current uncertainties and future challenges regarding NAD+ boosting strategies. Antioxidants (Basel). 2022;11(9):1637. doi:10.3390/antiox11091637

22. Liu L, Su X, Quinn WJ 3rd, et al. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab. 2018;27(5):1067-1080.e5. doi:10.1016/j.cmet.2018.03.018

23. Crisol BM, Veiga CB, Braga RR, et al. NAD+ precursor increases aerobic performance in mice. Eur J Nutr. 2020;59(6):2427-2437. doi:10.1007/s00394-019-02089-z

24. Seldeen KL, Shahini A, Thiyagarajan R, et al. Short-term nicotinamide riboside treatment improves muscle quality and function in mice and increases cellular energetics and differentiating capacity of myogenic progenitors. Nutrition. 2021;87-88(111189):111189. doi:10.1016/j.nut.2021.111189

25. Sauve AA, Wang Q, Zhang N, Kang S, Rathmann A, Yang Y. Triple-isotope tracing for pathway discernment of NMN-induced NAD+ biosynthesis in whole mice. Int J Mol Sci. 2023;24(13). doi:10.3390/ijms241311114

26. Roboon J, Hattori T, Ishii H, et al. Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide-induced microglial and astrocytic neuroinflammation by increasing NAD. J Neurochem. 2021;158(2):311-327. doi:10.1111/jnc.15367

27. Ramanathan C, Lackie T, Williams DH, Simone PS, Zhang Y, Bloomer RJ. Oral administration of nicotinamide mononucleotide increases nicotinamide adenine dinucleotide level in an animal brain. Nutrients. 2022;14(2):300. doi:10.3390/nu14020300

28. Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm. 2016;7(2):27-31. doi:10.4103/0976-0105.177703

29. Harrison DE, Strong R, Reifsnyder P, et al. 17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex. Aging Cell. 2021;20(5):e13328. doi:10.1111/acel.13328

30. Kane AE, Chellappa K, Schultz MB, et al. Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner. bioRxivorg. Published online June 27, 2024. doi:10.1101/2024.06.21.599604

31. Dollerup OL, Christensen B, Svart M, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. Am J Clin Nutr. 2018;108(2):343-353. doi:10.1093/ajcn/nqy132

32. Dollerup OL, Trammell SAJ, Hartmann B, et al. Effects of nicotinamide riboside on endocrine pancreatic function and incretin hormones in nondiabetic men with obesity. J Clin Endocrinol Metab. 2019;104(11):5703-5714. doi:10.1210/jc.2019-01081

33. Dollerup OL, Chubanava S, Agerholm M, et al. Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin-resistant men. J Physiol. 2020;598(4):731-754. doi:10.1113/JP278752

34. Hou Y, Wei Y, Lautrup S, et al. NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer’s disease via cGAS-STING. Proc Natl Acad Sci U S A. 2021;118(37):e2011226118. doi:10.1073/pnas.2011226118

35. Wang X, Hu X, Yang Y, Takata T, Sakurai T. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 2016;1643:1-9. doi:10.1016/j.brainres.2016.04.060

36. Campbell JM. Supplementation with NAD+ and its precursors to prevent cognitive decline across disease contexts. Nutrients. 2022;14(15):3231. doi:10.3390/nu14153231

37. Turconi G, Alam F, SenGupta T, et al. Nicotinamide riboside first alleviates symptoms but later downregulates dopamine metabolism in proteasome inhibition mouse model of Parkinson’s disease. Heliyon. 2024;10(14):e34355. doi:10.1016/j.heliyon.2024.e34355

38. Orr ME, Kotkowski E, Ramirez P, et al. A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. GeroScience. 2024;46(1):665-682. doi:10.1007/s11357-023-00999-9

39. Phelan MJ. Phase II clinical trial of nicotinamide for the treatment of mild to moderate Alzheimer’s disease. J Geriatr Med Gerontol. 2017;3(1). doi:10.23937/2469-5858/1510021

40. Brakedal B, Dölle C, Riemer F, et al. The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell Metab. 2022;34(3):396-407.e6. doi:10.1016/j.cmet.2022.02.001

41. Berven H, Kverneng S, Sheard E, et al. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease. Nat Commun. 2023;14(1):7793. doi:10.1038/s41467-023-43514-6

42. Tummala KS, Gomes AL, Yilmaz M, et al. Inhibition of de novo NAD(+) synthesis by oncogenic URI causes liver tumorigenesis through DNA damage. Cancer Cell. 2014;26(6):826-839. doi:10.1016/j.ccell.2014.10.002

43. Allen NC, Martin AJ, Snaidr VA, et al. Nicotinamide for skin-cancer chemoprevention in transplant recipients. N Engl J Med. 2023;388(9):804-812. doi:10.1056/NEJMoa2203086

44. Chen AC, Martin AJ, Choy B, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373(17):1618-1626. doi:10.1056/NEJMoa1506197

45. Pan F, Kang S, Zhao Y, et al. Effect of β-nicotinamide mononucleotide on tumor formation and growth in a lung cancer mouse model. Mater Chem Front. 2021;5(2):995-1002. doi:10.1039/d0qm00897d

46. Qiu S, Shao S, Zhang Y, et al. Comparison of protective effects of nicotinamide mononucleotide and nicotinamide riboside on DNA damage induced by cisplatin in HeLa cells. Biochem Biophys Rep. 2024;37(101655):101655. doi:10.1016/j.bbrep.2024.101655

47. Yoo KH, Tang JJ, Rashid MA, et al. Nicotinamide mononucleotide prevents cisplatin-induced cognitive impairments. Cancer Res. 2021;81(13):3727-3737. doi:10.1158/0008-5472.CAN-20-3290

48. Acklin S, Sadhukhan R, Du W, Patra M, Cholia R, Xia F. Nicotinamide riboside alleviates cisplatin-induced peripheral neuropathy via SIRT2 activation. Neurooncol Adv. 2022;4(1):vdac101. doi:10.1093/noajnl/vdac101

49. Mori V, Amici A, Mazzola F, et al. Metabolic profiling of alternative NAD biosynthetic routes in mouse tissues. PLoS One. 2014;9(11):e113939. doi:10.1371/journal.pone.0113939

50. Liu L, Wang P, Liu X, He D, Liang C, Yu Y. Exogenous NAD(+) supplementation protects H9c2 cardiac myoblasts against hypoxia/reoxygenation injury via Sirt1-p53 pathway. Fundam Clin Pharmacol. 2014;28(2):180-189. doi:10.1111/fcp.12016

51. Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem Biophys. 1955;54(2):558-559. doi:10.1016/0003-9861(55)90070-9

52. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand. 1988;223(5):405-418. doi:10.1111/j.0954-6820.1988.tb15891.x

53. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8(6):1245-1255. doi:10.1016/s0735-1097(86)80293-5

54. Cashin-Hemphill L. Beneficial effects of colestipol-niacin on coronary atherosclerosis. JAMA. 1990;264(23):3013. doi:10.1001/jama.1990.03450230049028

55. Brown G, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323(19):1289-1298. doi:10.1056/NEJM199011083231901

56. Guyton JR, Slee AE, Anderson T, et al. Relationship of lipoproteins to cardiovascular events: The AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013;62(17):1580-1584. doi:10.1016/j.jacc.2013.07.023

57. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34(17):1279-1291. doi:10.1093/eurheartj/eht055

58. Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018;9(1):1286. doi:10.1038/s41467-018-03421-7

59. Katayoshi T, Uehata S, Nakashima N, et al. Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial. Sci Rep. 2023;13(1):2786. doi:10.1038/s41598-023-29787-3

60. Dolopikou CF, Kourtzidis IA, Margaritelis NV, et al. Acute nicotinamide riboside supplementation improves redox homeostasis and exercise performance in old individuals: a double-blind cross-over study. Eur J Nutr. 2020;59(2):505-515. doi:10.1007/s00394-019-01919-4

61. Liao B, Zhao Y, Wang D, Zhang X, Hao X, Hu M. Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study. J Int Soc Sports Nutr. 2021;18(1):54. doi:10.1186/s12970-021-00442-4

62. Hawkins J, Idoine R, Kwon J, et al. Randomized, placebo-controlled, pilot clinical study evaluating acute Niagen®+ IV and NAD+ IV in healthy adults. medRxiv. Published online June 10, 2024:2024.06.06.24308565. doi:10.1101/2024.06.06.24308565

63. Poljsak B, Milisav I. Vitamin B3 forms as precursors to NAD+: Are they safe? Trends Food Sci Technol. 2018;79:198-203. doi:10.1016/j.tifs.2018.07.020

64. Kamanna VS, Ganji SH, Kashyap ML. The mechanism and mitigation of niacin-induced flushing. Int J Clin Pract. 2009;63(9):1369-1377. doi:10.1111/j.1742-1241.2009.02099.x

65. Maric T, Bazhin A, Khodakivskyi P, et al. A bioluminescent-based probe for in vivo non-invasive monitoring of nicotinamide riboside uptake reveals a link between metastasis and NAD+ metabolism. Biosens Bioelectron. 2023;220(114826):114826. doi:10.1016/j.bios.2022.114826

66. Wei Y, Xiang H, Zhang W. Review of various NAMPT inhibitors for the treatment of cancer. Front Pharmacol. 2022;13:970553. doi:10.3389/fphar.2022.970553

67. Ghanem MS, Caffa I, Monacelli F, Nencioni A. Inhibitors of NAD+ production in cancer treatment: State of the art and perspectives. Int J Mol Sci. 2024;25(4):2092. doi:10.3390/ijms25042092

1. George, A. R. (1999). The Epic of Gilgamesh: A New Translation. Penguin Classics.

2. Sima Qian. (1993). Records of the Grand Historian (B. Watson, Trans.). Columbia University Press.

3. Forshaw, P. J. (2006). The early alchemical reception of John Dee’s Monas Hieroglyphica. Ambix, 53(2), 43–69.

4. Young, J. H. (1961). The Toadstool Millionaires: A Social History of Patent Medicines in America before Federal Regulation. Princeton University Press

5. They are not scientifically valid!!!