Niagen – The Ultimate Guide to Benefits, Research & Dosing
The Fountain of Youth is a spring that purportedly restores youth and vitality to anyone fortunate enough to drink or bathe in its rejuvenating waters. The Fountain came to prominence in the 16th century thanks to Juan Ponce de Leon who searched high and low for it during his voyage to Florida in 1513.
Alas, the Fountain of Youth has yet to be discovered as originally thought; however, groundbreaking research in the field of sports supplements may have unlocked its own potential fountain of youth.
The research is still early, but initial feedback shows that Niagen® may be the golden ticket for reversing aging, boosting metabolism, improving memory, and increasing muscle endurance.
What is Niagen®?
Niagen®, also known as nicotinamide riboside (NR), is a naturally-occurring form of vitamin B3. NR was only recently discovered in 2004 vitamin precursor of Nicotinamide Adenine Dinucleotide (NAD+).  As a precursor, the body converts NR into NAD+, an essential molecule found in every living cell of the body.
Why is NAD+ So Important?
NAD+ is a coenzyme present in all living cells. It serves a vital role along with enzymes that drive a number of reduction-oxidation reactions, moving electrons from one reaction to another. Additionally, NAD+ enables cells to convert the food we consume into usable energy that we need. 
NAD+ is also heavily involved in cellular communication where it serves as the communication molecule between the nucleus and the mitochondria, the energy producing factories of the cell. If NAD+ levels are low, then communication may be impaired and mitochondrial dysfunction may ensue. FYI, mitochondrial dysfunction is a prominent characteristic of aging and age-associated diseases.  Keep this in mind going forward, as it’ll show up again!
Now that you’ve got a basic understanding of NAD+ now it’s time to dig a little deeper into the specific functions of this crucial coenzyme.
Competition for NAD+
Since NAD+ is involved in some many cellular processes, it should come as no surprise that there is considerable competition within the body for NAD+. In fact, there is a three-way fight for NAD+ stores between sirtuins, PARPs (Poly [ADP-ribose] polymerase), and NAD+ hydrolases.
Where things get even more complicated is when you realize that sirtuins and PARPs, along with NAD+ hydrolases, have diametrically opposing roles in the aging process. Basically, sirtuins act as mediators of increased life span, while PARPs and NAD+ hydrolases promote the exact opposite effect.
What’s even more interesting is the the antagonism between sirutins and PARPs extends even further when you realize that sirtuin-1 (SIRT1) also inhibits PARP1 through deacetylation and they exert opposing activities on cellular proteins. 
NAD+ and Aging
NAD+ concentrations depend on several variables, including the cellular redox state (NAD+/NADH ratio), as well as the rates of NAD+ production and consumption. Typically, NAD+ is much more plentiful than NADH, so it’s expected that variations in NAD+ concentration directly affect sirtuin functioning.
Also, it’s important to note that NAD+ concentrations can change depending of various conditions. For example, NAD+ concentrations increase when fasting or during exercise or calorie reduction , whereas NAD+ levels decrease during high-fat diets and during aging. 
The fact that NAD+ concentrations increase under life span-increasing conditions and decrease during aging or under certain conditions that decrease life span indicates that NAD+ levels contribute significantly to the aging process. This can be further extrapolated to the idea that NAD+ supplementation potentially combats the aging process; and, in fact, this has been successfully shown in yeast and worms. 
NAD+ and Obesity
Research has shown that SIRT1 and NAMPT (Nicotinamide Phosphoribosyltransferase – a protein coding gene) work together to regulate the body’s metabolism, including glucose-regulated insulin secretion at pancreatic β cells and circadian regulation of NAD+ generation.  Pancreatic β cells and neurons represent a “weak point” in NAD+ metabolism as these tissues display the lowest amount of NAMPT, the rate-limiting enzyme in the NAD+ “salvage pathway.” 
NAMPT exists in two forms, which appear to oppose each other — elevated eNAMPT is associated with obesity, type 2 diabetes, and nonalcoholic fatty liver disease , whereas iNAMPT appears to decrease greatly with age or the presence of the inflammatory cytokine tumor necrosis factor α. 
Research has demonstrated that supplementing with NMN (an NAD+ precursor) restores NAD+ levels in rats with diet–induced type 2 diabetes and improves glucose intolerance and lipid profiles.
NAD+ and Brain Health
It’s already been established that NAD+ levels decrease with age, and that low NAD+ levels are associated with metabolic dysfunction and disease. That’s not the end of the NAD+ story though.
As it turns out, NAD+ reserves are also linked to brain health. When NAD+ levels decline, there is a subsequent reduction in SIRT-1 and SIRT-3 enzymes which have been linked to neurodegeneration.  Basically, if NAD+ levels decline too much you brain’s ability to function at high level is seriously impaired, not a good thing if you want to stay sharp in your golden years!
Problems with Declining NAD+
We’ve gone through A LOT of science above, and it can get pretty dizzying, but if we had to distill it to a list of what can go wrong when NAD+ is deficient, this is what can happen:
- Cognitive dysfunction 
- Inflammation of vascular systems leading to hypertension, heart attack and stroke 
- Increased fat storage in the liver 
- Increased visceral fat storage (i.e. belly fat) 
- Increased blood sugar levels, Insulin resistance, and metabolic syndrome 
- Increased fatigue and loss of muscle strength 
Based on all of these preceding reasons, you can see why it’s vitally important to maintain healthy levels of NAD+. Boosting NAD+ levels encourages optimal cellular metabolism, mitochondrial function, and energy production.
The problem comes with how to elevate those levels via supplementation…
The Answer is… Niagen®.
You might be thinking after reading all of this, why do I need Niagen®, can’t I just supplement with free form NAD+?
In most organisms NAD+ can be synthesized from compounds present in the body, or from certain amino acids like tryptophan or aspartic acid. It can also be produced from more complex components such as nicotinamide or niacin. However, you simply can’t supplement with free from NAD+.
Well, you could in theory, it just would not be very effective as NAD+ is broken down in the stomach before it can ever make its way to the intestines for absorption into the bloodstream.
However, Niagen is a patented form of Nicotinamide Riboside (NR) that acts as a precursor to NAD+ and has been clinically proven to elevate levels of the critical coenzyme. Niagen is manufactured by Chromadex, and although you may see a variety of products using Niagen, it is all sourced from this manufacturer.
Now, let’s take a peek at some of the latest research using this age-reversing ingredient!
A recent study conducted at Harvard University, by Dr. David Sinclair, found that increasing NAD+ levels was critical to slowing down the aging process by reversing certain markers of aging in our cells, making it a proverbial “fountain of youth”! 
The results suggest that many of the the normal age-related conditions affecting people is due in part to reduced mitochondrial functioning, and that increasing NAD+ levels could potentially restore mitochondrial functioning and therefore “turn back the hands of time.”
Dr. Charles Brenner authored the first human study investigating the effect of different doses of NR on NAD+ levels in humans.  One of the fellow researchers on the team, Samuel A.J. Trammel, extensively documented the findings in his Phd dissertation titled Novel NAD+ metabolomic technologies and their applications to Nicotinamide Riboside interventions. 
In this study 6 female and 6 male subjects (ages of 30 to 55) were randomized to receive 100, 300, or 1,000mg of Nicotinamide Riboside. Blood levels of NAD+ were measured at 1, 2, 4, 8 and 24 hours following NR supplementation. The test was repeated two more times, with 7 days between testing.
Researchers found that the 300mg dose was slower to reach peak NAD+ levels in the blood, but approximately equal to the 1,000mg dose at 24 hours. Additionally, the study also that repeated doses of NR do not elevate NAD+ levels beyond the maximum level attained with the first dose — meaning there is a limit or “ceiling” to how high NAD+ levels can be elevated via NR supplementation.
These results indicate a “ceiling” to how high supplementation with NR can raise NAD+ levels.
Another clinical trial using the Elysium Health BASIS™ brand of Nicotinamide Riboside was recently completed, but the findings have not been published as of the writing of this article. Elysium Health did issue a press release though that detailed the objectives as well as the results. 
This trial was much larger than the initial human study, as it involved 120 elderly subjects (60-80 years old) tested bi-weekly over 8 weeks. The subjects were divided into 3 groups receiving either placebo, one, or two capsules of BASIS™ (250 mg of Chromadex NIAGEN), along with 50 mg of Chromadex Pterostilbene.
Results detailed in the press release state that the single 250mg dose of Niagen increased blood NAD+ levels by 40% and that those elevated levels were maintained throughout the 8 weeks of the trial!
The group receiving the 500 mg dose (2 capsules) exhibited an increase that was “significantly higher” than the 250 mg dose, and reached 90% at 4 weeks into the trial. Researchers noted that NAD+ levels plateaued at the 4 week mark, and declined afterwards, indicating that a higher dose of NR would not necessarily equate to higher NAD+ levels.
This is in line with the findings from the first study that the “sweet spot” for Niagen supplementation is between 250-500 mg per day.
The trial using BASIS™ also measured much more than just NAD+ levels. Researchers tracked several “secondary” endpoints including:
- Body weight
- Treadmill performance
- Chair standing
- Activity performance standards
Once the results of this study are made public, we’ll have a better idea as to the truth behind many of the purported benefits of Niagen.
The latest study kicked off March 2016 and will run through December 2016. A total of 140 adult subjects (ages 40 – 60) will participate in the randomized, double-blind, placebo controlled parallel study.
Primary objectives of the study will be to observe change in levels of Urinary Methylnicotinamide (a Niagen Metabolite) as well as any change in levels of blood, muscle, and urine Nicotinamide Riboside Metabolites. Other outcome measures include any impact (increases or decreases) supplemental Niagen may exert on subjects’ Resting Metabolic Rate (RMR). 
Furthermore, several other clinical studies are being conducted where researchers are studying Niagen’s effects on a wide range of attributes including:
- Athletic performance
- Weight loss
- Neuroprotection (in regards to concussions sustained by college football players)
Benefits of Increased NAD+
A 2012 study showed that giving mice supplements of NR is effective in raising NAD+ levels and improved the numbers and function of mitochondria. 
The mice receiving NR demonstrated increased energy and improved insulin sensitivity, while also protecting the animals from symptoms of metabolic syndrome. Furthermore, researchers also documented increased endurance — mice receiving NR ran 33% farther on treadmill testing vs control mice.
Other benefits that have been found in mice receiving NR supplementation include:
- Reversed markers of aging in muscles
- Improved cardiovascular health
- Increased energy
- Better sleep
- Reduced muscle soreness
- Improved memory
- Clearer hearing and vision
As you can see from above, there has not been a wide range of human studies completed, as of yet. Plus, just because a supplement works wonders in mice does not always mean it will perform the same in humans.
However, clinical trials are underway and once the findings of those studies are published, the science and supplement community will have a greater understanding of the power of Niagen.
The human trials that have been completed have shown that Niagen successfully:
- Increases NAD+ levels
- Protects against hearing damage
So, we know some preliminary benefits of Niagen supplementation and have an idea of what it may do in humans.
Taking what we’ve learned about the role of NAD+ in the body and from the preliminary indications of all the completed human and animal research studies, we can come up with a list of benefits to using NR:
- Greater cognition
- Improved athletic performance
- Better memory
- Faster metabolic rate
- Increased ATP production and availability
- Reduced fat storage
- Greater insulin sensitivity and nutrient partitioning
- Improved heart health
- Increased vitality
There are potentially even more benefits, and as Niagen research continues to expand, so will the understanding of its effects.
Human trials so far have used doses ranging from 100mg to 1,000mg. The general consensus from the research indicates that a dose between 250 – 500mg per day is sufficient for adequately elevating NAD+ levels.
Niagen Side Effects
A recent safety assessment looked at all current studies using Nicotinamide Riboside and noted no significant or adverse side effects at dosages up to 3,000 mg per day. 
What’s more noteworthy, is that one of the hallmark features of NR is that it doesn’t cause the unpleasant (and often irritating ) “flushing” that often occurs when taking high doses of Niacin.
Now, bear in mind that Niagen is still a very new supplement that doesn’t have a long history of use or a plethora of research behind it, so always keep an eye out for the latest findings on the ingredient.
Another recent 2016 clinical trial just concluded this time using 120 elderly folks and once the results study of 120 elderly volunteers should be very helpful in determining best therapeutical and maximum recommended dosages. 
Where Can I Find Niagen?
You can find Niagen in a number of supplements as well as varying doses (different suppliers will include a certain amount based on their product and what other ingredients are included). Here at Tiger Fitness, you can find Niagen in the following product:
- HPN NR™ — 125mg Niagen per capsule
Niagen is a powerful new ingredient that can boost levels of the vitally important coenzyme NAD+. Animal and human research has shown that Niagen successfully elevates NAD+ levels and documented a number of benefits including improved neurological function, resisting the effects of aging, and increased metabolic rate..
Numerous products over the years have promised these same benefits, but ultimately failed to live up to the hype. Niagen, on the other hand, has the research showing it is not a scam ingredient.
However, until more research is published, we won’t be able to fully understand the power of this revolutionary ingredient.
1) Bieganowski, P; Brenner, C (2004). “Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans”. Cell. 117 (4): 495–502. doi:10.1016/S0092-8674(04)00416-7. PMID 15137942
2) Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science (80- ). 2015;350(6265):1208 LP-1213. http://science.sciencemag.org/content/350/6265/1208.full
3) D. C. Wallace, A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005).10.1146/annurev.genet.39.110304.095751pmid:16285865doi:10.1146/annurev.genet.39.110304.095751
4) U. Kolthur-Seetharam, F. Dantzer, M. W. McBurney, G. de Murcia, P. Sassone-Corsi, Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage. Cell Cycle 5, 873–877 (2006). 10.4161/cc.5.8.2690pmid:16628003 doi:10.4161/cc.5.8.2690
5) S. B. Rajamohan, et al. SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1. Mol. Cell. Biol. 29, 4116–4129 (2009). 10.1128/MCB.00121-09pmid:19470756 doi:10.1128/MCB.00121-09
6) Y. Nakahata, et al. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324, 654–657 (2009).10.1126/science.1170803pmid:19286518 doi:10.1126/science.1170803
7) C. Cantó, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature458, 1056–1060 (2009). 10.1038/nature07813pmid:19262508 doi:10.1038/nature07813
8) J. T. Rodgers, et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).10.1038/nature03354pmid:15744310 doi:10.1038/nature03354
9) N. Braidy, et al. Age related changes in NAD+metabolism oxidative stress and Sirt1 activity in wistar rats. PLOS ONE 6, e19194 (2011).10.1371/journal.pone.0019194pmid:21541336 doi:10.1371/journal.pone.0019194
10) J. Yoshino, et al. Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011).10.1016/j.cmet.2011.08.014pmid:21982712 doi:10.1016/j.cmet.2011.08.014
11) H. Massudi, et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLOS ONE 7, e42357 (2012).10.1371/journal.pone.0042357pmid:22848760 doi:10.1371/journal.pone.0042357
12) P. Belenky, K. L. Bogan, C. Brenner, NAD+ metabolism in health and disease. Trends Biochem. Sci. 32,12–19 (2007). 10.1016/j.tibs.2006.11.006pmid:17161604 doi:10.1016/j.tibs.2006.11.006.
13) L. Mouchiroud, et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).10.1016/j.cell.2013.06.016pmid:23870130 doi:10.1016/j.cell.2013.06.016.
14) Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P. Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science. 2009;324:654–657.
15) Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, Takahashi JS, Imai S, Bass J. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science. 2009;324:651–654.
16) S. Imai, et al. The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing. Diabetes Obes. Metab. 15 (suppl. 3), 26–33 (2013). 10.1111/dom.12171pmid:24003918doi:10.1111/dom.12171
17) A. Garten, et al. Nampt: Linking NAD biology, metabolism and cancer. Trends Endocrinol. Metab. 20, 130–138 (2009). 10.1016/j.tem.2008.10.004pmid:19109034doi:10.1016/j.tem.2008.10.004
18) A. Garten, et al. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat. Rev. Endocrinol. 11, 535–546(2015).26215259pmid:26215259
19) H. Massudi, et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLOS ONE 7, e42357 (2012).10.1371/journal.pone.0042357pmid:22848760 doi:10.1371/journal.pone.0042357
20) Imai SI, Guarente L. NAD and sirtuins in aging and disease. Trends Cell Biol. 2014 Aug;24(8):464-71.
21) Sebastián C , Satterstrom FK,Haigis MC, Mostoslavsky R. From sirtuin biology to human diseases: an update. J Biol Chem. 2012 Dec 14;287(51):42444-52.
22) Min SW, Sohn PD, Cho SH, Swanson RA, Gan L. Sirtuins in neurodegenerative diseases: an update on potential mechanisms. Front Aging Neurosci. 2013 Sep 25;5:53.
23) Imai S, Guarente L. NAD+ and Sirtuins in Aging and Disease. Trends in cell biology. 2014;24(8):464-471. doi:10.1016/j.tcb.2014.04.002.
24) Sebastián C, Satterstrom FK, Haigis MC, Mostoslavsky R. From Sirtuin Biology to Human Diseases: An Update. The Journal of Biological Chemistry. 2012;287(51):42444-42452. doi:10.1074/jbc.R112.402768.
25) Min S-W, Sohn PD, Cho S-H, Swanson RA, Gan L. Sirtuins in neurodegenerative diseases: an update on potential mechanisms. Frontiers in Aging Neuroscience. 2013;5:53. doi:10.3389/fnagi.2013.00053.
26) Sebastián C, Satterstrom FK, Haigis MC, Mostoslavsky R. From Sirtuin Biology to Human Diseases: An Update. The Journal of Biological Chemistry. 2012;287(51):42444-42452. doi:10.1074/jbc.R112.402768.
27) Oellerich MF, Potente M. FOXOs and Sirtuins in Vascular Growth, Maintenance, and Aging. Sinclair Brian DN, ed. Circ Res. 2012;110(9):1238 LP-1251. http://circres.ahajournals.org/content/110/9/1238.abstract.
28) Haigis MC, Sinclair DA. Mammalian Sirtuins: Biological Insights and Disease Relevance. Annual review of pathology. 2010;5:253-295. doi:10.1146/annurev.pathol.4.110807.092250.
29) Kemper JK, Choi S, Kim DH. Sirtuin 1 Deacetylase: A Key Regulator of Hepatic Lipid Metabolism. Vitamins and hormones. 2013;91:385-404. doi:10.1016/B978-0-12-407766-9.00016-X.
30) Tao R, Wei D, Gao H, Liu Y, DePinho RA, Dong XC. Hepatic FoxOs Regulate Lipid Metabolism via Modulation of Expression of the Nicotinamide Phosphoribosyltransferase Gene. The Journal of Biological Chemistry. 2011;286(16):14681-14690. doi:10.1074/jbc.M110.201061.
31) Schug TT, Li X. Sirtuin 1 in lipid metabolism and obesity. Annals of medicine. 2011;43(3):198-211. doi:10.3109/07853890.2010.547211.
32) Ahn J, Lee H, Jung CH, Jeon TI, Ha TY. MicroRNA-146b promotes adipogenesis by suppressing the SIRT1-FOXO1 cascade. EMBO Molecular Medicine. 2013;5(10):1602-1612. doi:10.1002/emmm.201302647.
33) Yang X, Yin L, Li T, Chen Z. Green tea extracts reduce adipogenesis by decreasing expression of transcription factors C/EBPα and PPARγ. International Journal of Clinical and Experimental Medicine. 2014;7(12):4906-4914.
34) Haigis MC, Sinclair DA. Mammalian Sirtuins: Biological Insights and Disease Relevance. Annual review of pathology. 2010;5:253-295. doi:10.1146/annurev.pathol.4.110807.092250.
35) Maiese K, Chong ZZ, Shang YC, Wang S. Novel Directions for Diabetes Mellitus Drug Discovery. Expert opinion on drug discovery. 2013;8(1):35-48. doi:10.1517/17460441.2013.736485.
36) Sasaki T, Hye-Jin K, et al. Induction of Hypothalamic Sirt1 Leads to Cessation of Feeding via Agouti-Related Peptide. Endocrinology 2010 151:6, 2556-2566.
37) Feige, Jérôme N. et al. Specific SIRT1 Activation Mimics Low Energy Levels and Protects against Diet-Induced Metabolic Disorders by Enhancing Fat Oxidation. Cell Metabolism , Volume 8 , Issue 5 , 347 – 358.
38) Green MF, Hirschey MD. SIRT3 weighs heavily in the metabolic balance: a new role for SIRT3 in metabolic syndrome. J Gerontol A Biol Sci Med Sci. 2013;68(2):105-107. doi:10.1093/gerona/gls132.
39) Gomes AP, Price NL, Ling AJY, et al. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell. 2013;155(7):1624-1638. doi:10.1016/j.cell.2013.11.037.
40) Trammell SAJ, Schmidt MS, Weidemann BJ, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nature Communications. 2016;7:12948. doi:10.1038/ncomms12948.
41) Trammell, Samuel A.J.. “Novel NAD+ metabolomic technologies and their applications to Nicotinamide Riboside interventions.” PhD (Doctor of Philosophy) thesis, University of Iowa, 2016. http://ir.uiowa.edu/etd/3203.
42) “Elysium Health | Optimize Your Health.” Elysium Health | Optimize Your Health, www.elysiumhealth.com/clinical-trial-press-release.
43) “A Study Investigating the Effects of Niagen™ in Healthy Adults. – Full Text View – ClinicalTrials.gov.” Home – ClinicalTrials.gov, clinicaltrials.gov/ct2/show/NCT02712593.
44) Cantó C, Houtkooper RH, Pirinen E, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity. Cell metabolism. 2012;15(6):838-847. doi:10.1016/j.cmet.2012.04.022
45) “Safety Assessment of Nicotinamide Riboside, a Form of Vitamin B3. – PubMed – NCBI.” National Center for Biotechnology Information, www.ncbi.nlm.nih.gov/pubmed/26791540.
46) Cantó C, Houtkooper RH, Pirinen E, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity. Cell metabolism. 2012;15(6):838-847. doi:10.1016/j.cmet.2012.04.022.
47) “A Study to Evaluate Safety and Health Benefits of Basis™ Among Elderly Subjects. – Full Text View – ClinicalTrials.gov.” Home – ClinicalTrials.gov, clinicaltrials.gov/ct2/show/study/NCT02678611.