How do NAD+, NMN, and NR compare?

How do NAD+, NMN, and NR compare?
September 29, 2019 Nattha W
In Benefits

What is NAD+?

NAD+ stands for nicotinamide adenine dinucleotide. It is a cofactor that facilitates enzyme function. It is called the molecule of youth because it stimulates a family of anti-aging proteins called sirtuins1⁠.

In addition, NAD+ is an electron carrier in the process of burning carbohydrates, proteins, and fats into energy. Initial stages of these metabolic pathways (glycolysis and Kreb’s cycle) convert NAD+ into the high-energy NADH. Then, the mitochondria convert NADH into energy (ATP) and NAD+.

Having high NAD+ means that the mitochondria are functioning well and that there is no excess of calories2,3⁠. The high NAD+ levels activate Sirtuins, a family of enzymes that helps reduce oxidative stress, repair DNA, and reduce inflammation4⁠. Increased activity of Sirtuins, especially SIRT1 and SIRT2, increase the lifespan in yeasts, worms, and flies5⁠. In addition, high NAD+ activates DNA repair enzymes called poly ADP-ribose polymerases (PARPs)1⁠.

NAD+ levels decrease with age and poor health status. As a result, increasing NAD+ and activating Sirtuins have hit the anti-aging movement by the storm because they can be easily supplemented.

Lifestyle factors that increase NAD+

  • Maintaining a healthy circadian rhythm 6
  • Having balanced immune responses with no chronic low-grade inflammation 7
  • Fasting and caloric restriction 8
  • A Ketogenic diet 9
  • Exercise (in muscles) 10
  • Cold thermogenesis (in brown fat cells) 11

NAD+ and its precursors are also found in low levels in milk and unprocessed foods (meat and vegetables)12⁠.

Are you low in NAD+?

Unless you go to sleep soon after sunset and wake up with sunrise, restrict blue light at night, avoiding sitting for hours daily, and experience no inflammatory symptoms, your NAD+ levels are likely not optimal. The modern lifestyle is not conducive to optimal levels of NAD+, so most people will benefit from supplementation to increase NAD+. The best way to know if you are low in NAD+ is if you experience the benefits of supplementation.

Health Benefits of Increasing NAD+

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Image source: ref #13

Low NAD+ can result in:

  • Cognitive dysfunction (brain fog) and age-related cognitive decline14,15
  • Weight gain and poor metabolism16,17
  • Metabolic syndrome and type II diabetes4
  • Poor blood vessel health and cardiovascular disease progression18
  • Fatty liver18
  • Worsened prognosis and recovery from traumatic brain injury19
  • Fatigue4
  • Age-related muscle loss20
  • Age-related hearing and eyesight loss21,22
  • Shortened lifespan5
  • Poor circadian rhythm, such as becoming a night person6

Supplements that Increase NAD+

Image source: ref #23

NAD+ is created from vitamin B3 (niacin, NA and niacinamide, NAM). The conversion of niacinamide to nicotinamide mononucleotide (NMN) and subsequently NAD+ is dependent on the enzyme NAMPT, which is the bottleneck (rate-limiting) step in the generation of NAD+. NAMPT levels are highly dependent on a healthy circadian rhythm, cellular stress, inflammation, and nutrient status, which explains why an unhealthy lifestyle could deplete NAD+24⁠.

On the other hand, nicotinamide riboside (NR) and NMN could be converted into NAD+ without NAMPT function. Therefore, supplementation or administration with NR, NMN, or NAD+ rather than niacin or niacinamide is more likely to help mitigate low NAD+ due to lifestyle factors or poor health.

Different forms of NAD+ Supplements – NAD+, NMN, and NR

For a supplement to be effective, it has to be shelf-stable and has good oral bioavailability. Oral bioavailability refers to the amount of substance that reaches your target organ and produces the desired results if you ingest the substance.

Although NAD+ and its metabolites are found in your blood and every cell in your body, supplementation to increase NAD+ isn’t straightforward due to varying bioavailability. In this section, we will explain what studies say about the differences between these substances.

1) Nicotinamide Adenine Dinucleotide (NAD+)

NAD+ is a strong oxidizing agent, which means that it’s difficult to make a shelf-stable NAD+ product with high oral bioavailability. NAD+ is a delicate molecule that usually does not survive digestion if ingested – it gets broken down into 50% NAM and 50% NMN25⁠. Therefore, oral NAD+ could have the same effect as taking half the number of molecules as NMN.

However, direct administration of NAD+ onto the target cells or intravenously (injected into the blood or drip) has demonstrated some promising results. In rodents, intranasal NAD+ help mitigate brain injuries, reduce neuronal damage, and overall reduce the negative impact of traumatic brain injuries in the short-term 19⁠.

Although never officially published, many clinics have used intravenous NAD+ therapy to treat addictions and mental health under medical supervision. Sublingual NAD+ is also effective.

2) Nicotinamide Riboside (NR)

Charles Brenner’s group has conducted several human studies to test the safety and effectiveness of NR. NR is readily absorbed in the gut and taken up by cells throughout the body, possibly because NR is smaller than NMN and NAD+. In humans, obese men and healthy subjects tolerated 2000 mg of NR well in a 12-week trial 26⁠. NR has no mutagenic or toxic activity 27

3) Nicotinamide Mononucleotide (NMN)

Biochemically, NMN is more similar to NAD+ than NR. Some of the NMN consumed needs to be converted into NR, before getting absorbed into cells and converted into NMN, and subsequently NAD+. Most studies of the effectiveness of NMN so far have been done in mice, although there are many registered clinical trials for NMN, such as NCT03151239, UMIN000021309, UMIN000030609, and UMIN000025739.

How do NMN and NR compare?

Although both NMN and NR are precursors of NAD+ with good oral bioavailability and safety profile, there are some nuanced differences between NMN and NR supplementation.

Inside the cells, NRK enzymes help convert NR into NMN. NR molecules are generally absorbed into cells through a type of protein called Equilibrative Nucleoside Transporters (ENTs). Whereas, NMN molecules may be converted into NR by an enzyme called CD73 before the NR is absorbed through ENT. Some types of cells have the protein Slc12a8 on the outside (denoted as a question mark), which act as an exclusive access door for NMN to enter cells28. Image source: ref #2

Pharmacokinetics

NR – In an n=1 study, a 52-year-old healthy man consumed 1,000 mg of NR for 1 week, and donated his blood and urine samples. NMN and NAD+ started to become detectable in blood cells (PBMC) at around 4.1 hours after the first dose. Similarly, in mice fed with NR, liver NMN detectably increased at approximately 3 – 4 hours after administration29⁠. At 7.7 hour, NAD+ increased by 2.7-fold above baseline concentration in these blood cells.

Similarly, another open-label human study showed that NR levels in whole blood peaked at around 3 hours after a 1000 mg dose of NR 30⁠. Therefore, it is possible that NR may take 2 – 3 hours to get absorbed through the gut, or that some NR is degraded into nicotinamide before getting converted into NMN and subsequently absorbed.

NMNIn mice, NMN is absorbed through the gut and was detectable in the blood within 2 – 3 minutes. Within 15 minutes, NMN was completely absorbed into tissues and subsequently converted into NAD+ for further use. Mice administered with NMN had elevated NAD+ for about 30 minutes 31,32⁠. However, after six months of NMN administration, only liver and brown fat, but not muscle and white fat, have elevated NAD+ 32⁠.

Cellular Uptake and Usage

Because NR is smaller, it may enter the cells more readily than NMN. Some NMN may be broken down into NR outside the cells, and subsequently converted into NMN again once it’s transported into the cells 33.⁠⁠

Because NR supplementation has shown benefits in brain, fat, liver, pancreatic, and muscle cells, it suffices to say that NR can enter these cells. Once NR enters the cells, the NRK enzyme converts it into NMN, before another enzyme converts it into NAD+. Note that NRKs are considered the bottleneck enzymes in the process of utilizing NR, so tissues that lack NRK may have trouble utilizing NR 33⁠.

Whereas, for NMN, specific transporters are necessary to uptake it directly into cells. Slc12a8 was identified as the key protein that can rapidly absorb NMN through the gut and into specific tissues, such as the pancreas, and the liver 28⁠. For tissues that do not have Slc12a8, NMN may need to be converted into NR before entering these cells.

However, in rodents, NMN also effectively enhanced NAD+ synthesis in the heart, kidney, testes, eyes, blood vessel (aorta), hippocampus, and hypothalamus 34⁠.

Detected Slc12a8 protein levels by tissue from the Human Protein Atlas. Note that this data should be considered preliminary.

Detected NRK1 protein levels by tissue from the Human Protein Atlas. Note that this data should be considered preliminary.

Bioavailability Conclusion: It appears that NMN is absorbed through the gut in minutes, whereas NR may take around 3 hours. However, there is more evidence for NR being directly absorbed into cells than NMN, except for cells that produce Slc8a12 proteins. Besides, cells that produce NRK enzymes can more readily use NR, whereas cells that do not produce NRK enzymes will more readily use NMN if they can uptake NMN.

Effects on NAD+ Increase

Few studies have directly compared NR and NMN side by side in a controlled experiment. In one study that did so, NR increased NAD+ marginally (insignificantly) better than NMN in liver cells of mice33⁠. NRK1 enzyme was necessary for the liver cells to utilize both NR and NMN. However, the effects of NR and NMN on NAD+ levels in other cell types are likely to vary and remain to be studied.

Differences in Biochemical Activities and Potential Clinical Efficacy

In most cases, NMN and NR benefit health by increasing NAD+. Both have almost identical health benefits, with a few exceptions, including:

  1. Friedreich’s Ataxia (FRDA) – In rodent models of this rare congenital heart disease, NMN successfully treated FRDA, whereas NR treatment failed35,36⁠.
  2. In mouse models of Alzheimer’s, subcutaneous (under the skin) administration of NMN reduced beta-amyloid plaque production. Although NR reduced neuroinflammation, reduced hippocampal cell death, and improved cognitive function, it did not reduce amyloid plaque production15⁠.

Ready to increase your NAD+? Choose the right NAD+ supplement for yourself here.

References

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