If you’ve researched anti-aging supplements on the internet, there’s a good chance you came across Nicotinamide Adenine Dinucleotide or NAD. In recent years, there has been substantial research on the various ways to replenish the NAD+ coenzyme to support healthy aging.
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WHAT IS NAD+?
NAD+ is a coenzyme (helps enzymes work) found in all living cells, that performs a crucial role in longevity and homeostasis – your body’s ability to maintain a stable internal environment despite the constant changes in our outer environment.
[1]
NAD+ is an important molecule in the human body that involved in over 500 enzymatic reactions including DNA repair, cellular metabolism, protein activity regulation and energy production. NAD+ also has potent regenerative effects as it may slow the physical and mental effects associated with aging, holding neuroprotective and anti-aging properties.
NAD+ works to help your cells extract energy from the food you eat. Mitochondria, the powerhouse of the cell which store and manufacture ATP, the cell’s energy currency, use the energy to keep your cells working properly.
Basically, without NAD+, you can’t utilize any of the nutrients from food. It also ensures the proteins are folded into the shape required for their specific functions (e.g. proteins which work as receptors for hormones demand certain shapes).
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NAD+ Precursors: NR vs NMN
Researchers have found that NAD+ levels slowly decline with age. Scientists have indicated a depletion of NAD+ may be linked to age-related health issues. Fortunately, there are several ways to boost the production of this vital molecule.
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While NAD+ is available in meat and dairy, it is not readily found in quantities that are high enough to meet the body’s declining levels. Moreover, the body can produce NAD+ by converting NAD+ precursors through various biosynthetic pathways – precursors are chemical compounds that take part in a chemical reaction that results in the formation of a new molecule.
Niacin (vitamin B3), nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN) or dietary tryptophan act as precursors or building blocks to NAD+. NA and NAM, often termed niacin or vitamin B3, are two of the least used pathways for obtaining NAD+ because they require too high levels to convert into NAD+ and come with side effects like inflamed skin.
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The most effective and recognized NAD+ booster vitamins are Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN). While both NR and NMN are great supplements for getting your NAD+ levels up, there are some noteworthy differences in how they function, as well as how their respective benefits and side effects vary.
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WHAT IS NR?
Nicotinamide Riboside (NR) is a precursor for NAD+ and a type of vitamin B3. NR is first converted to NMN then into NAD+. NR is naturally occurring in food sources such as milk and yeast products, however, the quantities found in food are insufficient to fulfill the body’s requirements for NAD+. Many turn to NR supplements as they are more effective at raising cellular levels of NAD+.
Several human randomized placebo trials on NR supplements have indicated that NR is highly effective at replenishing NAD+ and is readily absorbable. One pilot study found NR raised human blood NAD+ levels as much as 2.7-fold using a single dose of NR.
Another study on mice found NR elevated liver cell levels of NAD+ far superiorly than nicotinamide and nicotinic acid. The researchers found NR had better bioavailability and absorption than other NAD+ precursors nicotinamide and nicotinic acid.
[5]
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WHAT IS NMN?
Nicotinamide Mononucleotide (NMN) is a synthetically produced nucleotide that is the subject of many prominent studies for its powerful anti-aging effects. Similar to niacin and Nicotinamide Riboside (NR), NMN converts into NAD+, a coenzyme involved in many life-sustaining biological processes.
In mammalian cells, NMN can be synthesized either from nicotinamide (type of vitamin B3) or from Nicotinamide Riboside (NR) with the help of an essential enzyme called Nicotinamide Phosphoribosyltransferase (NAMPT).
NMN is naturally present in a variety of foods, with highest concentrations in broccoli, cucumber, edamame and cabbage. It can also be found in small amounts in raw beef, cow’s milk, avocado and tomatoes. Many prefer consuming NMN in dietary supplements as the levels found in foods are too low to meet our daily requirements of NAD+.
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Animal studies have indicated that NMN supplements effectively increase the NAD+ concentration in a variety of tissues such as the brain, with related health benefits such as steady circadian rhythms, healthier brain as well as supporting healthy aging.
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NR VS. NMN: Differences and Similarities
When comparing NR vs NMN, research has found the two compounds to be very similar in terms of their capacity to promote longevity and healthy aging. They do differ in some ways, however. So, which one should you choose?
- Unlike Nicotinamide Riboside (NR), Nicotinamide Mononucleotide (NMN) is not a form of vitamin B3 (niacin). This is because NMN contains a phosphate in its molecular structure, which hinders its ability to enter cells.
- The assimilation of NR and NMN into NAD+ is different. NR must first be broken down and then reassembled back into NMN through a process called phosphorylation of NR carried out by nicotinamide riboside kinases (NKR1/2). The resulting product NMN is subsequently converted into NAD+. In contrast, NMN does not need to be broken down into its constituent parts as it is directly converted into NAD+. Because of its ability to be easily assimilated by the digestive tract, NMN is absorbed faster in the gut. [7]
- One thing to note when considering NMN vs. NR is that more studies have been completed on NR than NMN. The only NMN clinical trials published thus far are on animals, whereas NR is the focus of numerous human studies. However, with the promising results obtained in animal studies, some NMN human trials are under way.
- NR research shows NR can raise circulating NAD+ levels in humans by 60% in older adults, through oral supplementation. There isn’t available data showing exactly how much NAD levels are increased from NMN supplementation. [8]
- Several human studies have confirmed NR’s ability to increase circulating NAD+, which was found to improve mitochondrial function in muscle, liver and brown adipose tissue. Animal studies found NMN plays an important role in the regulation of metabolism and circadian rhythms as a result of its impact on NAD+ and through its activation of sirtuins – sirtuins play a key regulatory role in many critical biological processes. [9]
NR VS NMN: Benefits
| NR |
NMN |
| NR is efficiently converted into NAD+ which greatly facilitates the variety of healthful and anti-aging benefits that are powered by NAD+.[10]
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NMN is assimilated and directly transformed into NAD+ in certain parts of the body, particularly in the gut.[11]
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| NR aids the conversion of food into usable energy by the body, and has been shown to repair damaged DNA and strengthen cells as well as improve learning.[12]
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NMN promotes healthy cellular energy levels and hold powerful regenerative properties which ensures healthy aging.
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| NR has also been found to support healthy sleep patterns and induce restful sleep by regulating the body's circadian rhythm.[13]
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NMN has been found to balance blood glucose levels and mediate the body's production of insulin through its impact on NAD+ levels in the body. [14]
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| NR has shown to improve mitochondrial function in muscle, liver and brown adipose tissue and is being used for its weight-loss benefits. [15]
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NMN helps to sharpen cognitive function through directly increasing NAD+ production in the brain and activating sirtuins. [16]
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| When it comes to side effects, both NR and NMN are exceptions as they have fewer recorded side effects in comparison to other NAD+ precursors (e.g. NA and niacin exhibit skin flushing).
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NR vs NMN: Side Effects and Dosage
Both Nicotinamide Riboside and Nicotinamide Mononucleotide supplements are generally well tolerated considered safe in recommended doses with no flushing.
A mice study in which scientists administered NR in doses of 300 mg/kg of bodyweight daily for a period of 3 months reported no adverse effects.
[17] Safety of NMN was tested in multiple rodent studies. Researchers found doses of 500 mg of NMN were safe and effective without causing any serious side effects.
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Human studies suggest NR supplements are safe and effective, even in high doses of 2000-mg taken once a day over a period of 12 week to 24 weeks. Some have experienced rare and mild side effects in including itchiness, digestive upset, and fatigue.
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Before taking any supplement or medication, be sure to consult your doctor. It is not recommended to use this supplement if you are taking any medication. This supplement may not be safe for pregnant or breastfeeding women as there is currently insufficient research to support its use.
Conclusion
As we gathered above, both NMN and NR offer similar benefits as they both increase NAD+ levels, which has been shown to encourage healthy aging, mediate energy metabolism, as well as strengthen cardiovascular and brain health. Where they differ is how they are assimilated in the body. The conversion of NR into NAD is more complex whereas NMN’s transformation into NAD is straightforward.
As a potent antioxidant, NR is studied for its abilities to hinder the negative signs of aging, protecting the brain and body from age-related conditions. It is widely consumed supplement because of its powerful antioxidant and anti-inflammatory effects which have found to prevent DNA damage and support healthy mitochondrial function.
Either way, whichever you chose, NMN and NR both good options as they elevate NAD+ levels, which decline with age. In doing so, they both offer powerful health benefits including improved circadian rhythms, better cardiac and cognitive function as well as strengthening homeostasis. While NMN has specifically been linked to improving blood glucose levels, balanced circadian rhythms and improved learning and supporting longevity, NR promotes weight-loss, improves memory and supports healthy aging.
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References:
[1] Cantó, C., Menzies, K. J., & Auwerx, J. (2015). NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus.
Cell metabolism,
22(1), 31–53. https://doi.org/10.1016/j.cmet.2015.05.023
[2] Bogan, K. L., & Brenner, C. (2008). Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD+ Precursor Vitamins in Human Nutrition
. Annual Review of Nutrition, 28(1), 11130. doi:10.1146/annurev.nutr.28.061807.155443
[3] Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, LiZ, Abel ED, Migaud ME, Brenner C.(2016) Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.
Nat Commun. 2016 Oct 10;7:12948.
[4] Bogan, K. L., & Brenner, C. (2008)., op. cit. 2
[5] Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, Li Z, Abel ED, Migaud ME, Brenner C.op., cit. 3
[6]Revollo JR, Grimm AA, Imai S.(2004)
The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem. 2004 Dec 3;279(49):50754-63. Epub 2004 Sep 20. PubMed PMID:15381699.
[7] Cantó, C., Menzies, K. J., & Auwerx, J. (2015), op., cit., 1
[8] Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. (2018)
Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286. doi: 10.1038/s41467-018-03421-7. PubMed PMID:29599478; PubMed Central PMCID: PMC5876407.
[9] Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O'Brien KD.
An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One. 2017 Dec 6;12(12):e0186459. doi: 10.1371/journal.pone.0186459. eCollection 2017. PubMed PMID: 29211728; PubMed Central PMCID: PMC5718430.
[10] Rajman, L., Chwalek, K., & Sinclair, D. A. (2018). Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence.
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27(3), 529–547. https://doi.org/10.1016/j.cmet.2018.02.011
[11] Ibid.
[12] Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y,Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J. (2012)
The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012 Jun 6;15(6):838-47. doi:10.1016/j.cmet.2012.04.022.PubMed PMID: 22682224; PubMed Central PMCID: PMC3616313.
[13] Nakahata Y, Bessho Y (2016)
The Circadian NAD(+) Metabolism: Impact on Chromatin Remodeling and Aging. Biomed Res Int. 2016;2016:3208429. doi:10.1155/2016/3208429. Epub 2016 Dec 5. Review. PubMed PMID: 28050554; PubMedCentral PMCID: PMC5165141
[14] Poddar, S. K., Sifat, A. E., Haque, S., Nahid, N. A., Chowdhury, S., & Mehedi, I. (2019).
Nicotinamide Mononucleotide: Exploration of Diverse Therapeutic Applications of a Potential Molecule. Biomolecules, 9(1), 34. https://doi.org/10.3390/biom9010034
[15] Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O'Brien KD., op. cit., 9
[16] Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, Tian R, Shen DD, O'Brien KD op. cit., 9
[17] Conze DB, Crespo-Barreto J, Kruger CL.(2016)
Safety assessment of nicotinamide riboside, a form of vitamin B(3). Hum Exp Toxicol. 2016 Nov;35(11):1149-1160.doi: 10.1177/0960327115626254. Epub 2016 Jul 11. Erratum in: Hum Exp Toxicol.2018 Apr;37(4):448. PubMed PMID: 26791540.
[18] Irie J, Inagaki E, Fujita M, Nakaya H, Mitsuishi M, Yamaguchi S, Yamashita K, Shigaki S, Ono T, Yukioka H, Okano H, Nabeshima YI, Imai SI, Yasui M, Tsubota K, Itoh H.
Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J. 2019 Nov 2. doi: 10.1507/endocrj.EJ19-0313. [Epub ahead of print] PubMed PMID:31685720.
[19] Martens CR et al.(2018)
Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+)in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286. doi: 10.1038/s41467-018-03421-7. PubMed PMID:29599478; PubMed Central PMCID: PMC5876407.
[20] Gong B et al (2013),
Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging. Jun;34(6):1581 doi:10.1016/j.neurobiolaging.2012.12.005. Epub 2013 Jan 9. PubMed PMID: 23312803;PubMed Central PMCID: PMC3632303.
