NMN vs NR: NovosLabs version (2023)
NAD+ is a very important molecule, having a myriad of effects in our cells, including enabling the proper functioning of sirtuins, enzymes that protect our DNA and regulate the epigenome, and helping PARPs to do their job, which is repairing damaged DNA.
The older we get, the more the NAD+ levels in our cells decline. Low levels of NAD+ are associated with (R,R):
- A decline in metabolism, leading to weight gain and an increased risk of type 2 diabetes, metabolic syndrome, fatty liver, and other metabolic disorders
- Fatigue
- Reduced blood vessel health
- Age-related muscle loss
- Aging-related cognitive decline
- Aging-related eyesight and hearing loss
- Shorter lifespan
Increasing NAD+ levels leads to many health benefits on various organs, such as the brain, cardiovascular system, and muscles (R):
Source: Therapeutic Potential of NAD+-Boosting Molecules: The In Vivo Evidence. Cell Metabolism. Luis Rajman, etc al.
Given that NR and NMN increase NAD+ levels, they are often called NAD boosters.Many studies show that NR and NMN can improve various aging hallmarks, like a dysregulated epigenome, DNA damage, protein accumulation, inflammaging (aging-related inflammation) and various other aging mechanisms.
But the big question of course is: which is best, NMN or NR?
Currently, there are no studies comparing NMN and NR head-on regarding health effects and lifespan effects. However, many aging specialists and researchers believe NMN is better than NR. They quote various reasons for this.
1. NMN is one step ahead
Compared to NR, NMN is already one step further down the pathway to produce NAD+.
The pathway that leads to NAD+ is as follows:
NR is converted into NMN, and then NMN is used to build NAD+, or:
NR => NMN => NAD+ => DNA repair and epigenetic maintenance
NMN is thus one step further down the NAD+ pathway. NR first needs to be phosphorylated to create NMN, which then is built into NAD+.
NAD+ is the molecule that enables sirtuins and PARP enzymes to work (e.g. repairing DNA damage and maintaining the epigenome).
2. NMN seems to demonstrate more impressive effects in studies
Source: Nicotinamide mononucleotide supplementation reserves vascular dysfunction and oxidative stress with aging in mice. Aging Cell, 2016
If you look at the whole of the studies done with NMN and NR, it seems that NMN enables stronger and more diverse effects than NR. The studies done with NMN just seem more impressive.
For example, 5-month old mice that received NMN for over a year showed improved insulin sensitivity and lipid metabolism, better vision, increased bone density, improved mitochondrial and metabolic functioning, better weight, and a stronger immune system (R).
Old mice that received NMN for 8 weeks improved vascular health considerably, demonstrated by for example decreased artery stiffness and less arterial oxidative stress (R).
NMN given to old mice could even restore their fertility again (R).
Such improvements for a wide array of aging-related symptoms and diseases seems more typical with NMN than with NR.3. NMN has effects that NR doesn’t have
For example, NMN has been shown to increase endurance and exercise capacity, up to 80 percent, something that NR couldn’t achieve. To the contrary, one study showed that NR actually reduced physical performance by 35%.
In a mitochondrial disease model, called Friedreich’s ataxia, NMN could successfully treat various symptoms of this serious metabolic disease (R), while NR could not achieve this (R).
In a mouse Alzheimer model, NMN reduced beta-amyloid accumulation (R), while NR could not reduce the formation of beta-amyloid (it could however improve cognitive function) (R). Accumulation of beta-amyloid proteins is one of the driving forces behind Alzheimer’s disease.
Professor David Sinclair from Harvard University, arguably one of the biggest experts in the world regarding NMN, NR and NAD+ metabolism, discusses in this interview some reasons why NMN could be better than NR.
4. Biotech companies focus on NMN, not NR
Various companies that are developing the next treatments for aging are focusing on NMN, not NR.For example, Life Biosciences’s subsidiary company Jumpstart Fertility focuses mainly on NMN and NNM analogues, not NR, to improve fertility in animals (R).
Metro Biotech is looking into NMN and NMN analogues to improve NAD+ metabolism. In fact, if you look at the patent applications Metro Biotech filed, they patented NMN analogues (containing a phosphate group, as NMN does), not NR analogues (which do not contain a phosphate group):
Source: Google Patents
This seems to indicate that the phosphate group, or the NMN-like structure, is very important.
5. Esteemed experts take NMN supplements, not NR
Professor David Sinclair from Harvard University is one of the leading longevity researchers in the world who has spent decades researching NR, NMN and NAD+. He takes NMN himself, not NR.
Learn more about the supplements David Sinclair takes here.
6. The closer to NAD+, the stronger the effect?
NAM (nicotinamide) is converted into NR, which is converted into NMN, which then builds up NAD+.
NAM has been shown not to extend lifespan (it however could improve health span) (R). In contrast to NA, NR could improve lifespan according to one study (R).
Some scientists believe that the further down the NAD+ pathway you go, the more powerful the effects get. This is an educated guess of course. Ideally, we need head-to-head comparison studies between NR and NMN on lifespan. Until now, such studies have not been conducted.
7. NASA and US military prefer NMN, not NR
NASA is looking into NMN to see if it can prevent muscle atrophy (the dwindling away of muscles) in astronauts, and if NMN can protect their DNA against cosmic radiation (R,R,R).
This would be especially important for a mission to Mars, during which astronauts will be in zero-gravity conditions and exposed to DNA-damaging cosmic radiation for years while traveling to the red planet. It’s interesting to see that NASA is mainly looking into NMN, not NR.
The United States Special Forces are working on an “anti-aging pill” for their soldiers to improve their performance. This pill is based on NMN, not NR (R,R). In fact, it’s based on a crystalline form of NMN, like MIB-626.
Interestingly, this NMN-based compound is also being tested for Alzheimer’s disease (R), Friedreich’s ataxia, mitochondrial myopathy, Leber’s hereditary optic neuropathy (LHON), non-alcoholic steatohepatitis (NASH), and kidney injury.
8. NMN is more stable than NR
NR is very unstable in the bloodstream: it is quickly degraded into vitamin B3 (R,R). In contrast, NMN is very stable.
9. Almost all NR is broken down into nicotinamide (NAM) before it reaches tissues
Most NR, when taken orally, is already broken down in the gut into NAM (nicotinamide), a form of vitamin B3.The very little NR that is absorbed by the gut, first passes the liver and is also broken down into NAM (nicotinamide/vitamin B3).
So if you take NR, you in fact take expensive vitamin B3 (nicotinamide or NAM)!
Of course, many NR supplement sellers claim that NR increases NAD+ levels. And that’s true. Why?
NAM (nicotinamide/vitamin B3) is also a precursor to NAD+. If you take NAM (nicotinamide/vitamin B3) you indeed increase NAD+ levels. But this is not a great way to increase NAD+ levels. For example, NAM (nicotinamide/vitamin B3) inhibits sirtuins.
This makes sense, because in order to make sirtuins function well, NAD+ is converted into NAM (nicotinamide/vitamin B3). But if there is already too much NAM (nicotinamide/vitamin B3), this hinders the conversation of NAD+ into NAM, thus hindering the functioning of sirtuins, the important proteins that repair and maintain our DNA and epigenome.
This explains why when mice receive oral NR, levels of nicotinamide (NAM/vitamin B3) in the blood increase 16 times after 20 minutes and 40 times after 100 minutes (R). Other studies also show that oral NR mainly reaches the bloodstream and tissues in the form of nicotinamide (NAM/vitamin B3) (R).
According to the authors:
“Elegant tracer experiments demonstrated that after oral intake, NR was utilized as such by the liver, while it predominantly reached the peripheral tissues as its degradation product, NAM [nicotinamide or vitamin B3].”
– Carles Canto et al, Molecular Metabolism, 2019
A panel of European scientists who looked at all available studies regarding NR metabolism concluded:
“Altogether, the Panel notes that NR is likely to be absorbed mainly as NAM [nicotinamide or vitamin B3] following hydrolysis in the gut. In case a fraction of the NR would be absorbed intact, it is expected to be rapidly metabolised to NAM [nicotinamide or vitamin B3] in the blood. NAM [nicotinamide or vitamin B3] acts as a precursor of NAD+ in cells and is primarily metabolised in the liver to 1‐MN through methylation and subsequently to 2‐PY, and 4‐PY, following oxidation.
– H.K Knutsen et al. EFSA Journal, 2019
But it is even worse. Despite that NR increases NAD+ levels in a less desirable way (by inhibiting sirtuins, among others), it increases NAD+ levels mainly in the whole blood, and not in the muscle and other important tissues!
Scientists conclude (R):
“Moreover, although an increase in NAD+ levels in whole blood has been detected upon NR administration in humans (R,R), supplementation with this precursor has failed to increase NAD+ in other tissues, such as muscle biopsies, even after 1 g administration during 6 weeks (R). This inefficacy in raising NAD+ might explain why NR has no apparent effect on total energy expenditure, blood glucose or insulin sensitivity in humans (R).”
– R. H. Houtkooper. The Journal of the Federation of American Sciences for Experimental Biology, 2021
In contrast to NR, NMN is much more stable in the gut, liver, and blood. Mice that are given NMN in drinking water exhibit an increase of NMN in the bloodstream, and increased NAD+ levels (R). As you can see in the graph below, the red curve shows an increase of NMN in the bloodstream (plasma) when given NMN orally:
According to Professors Yasumasa Bessho and Yasukazu Nakahata from the Nara Institute of Science and Technology and Nagasaki University in Japan:
“In mice, plasma NMN level has been shown to increase as early as 2.5 min after oral NMN administration as these NAD+ precursors make their way through the gut lining en route to the liver. Plasma NMN level stayed elevated for around 15 min before dropping to normal level, and this was followed by a gradual increase of hepatic NAD+ levels 15 to 30 min after administration. A slight NAD+ increase was also observed in skeletal muscle and the cortex of the brain 60 min after NMN administration. This demonstrated that supplemented NAD+ precursor can immediately perfuse through tissue barriers and rapidly metabolize into NAD+ in different major organs.”
Nicotinamide Phosphoribosyltransferase as a Key Molecule of the Aging/Senescence Process. International Journal of Molecular Sciences, 2021
10. NMN can activate SIRT3
NMN activates SIRT3 (R), while NR seems not to be able to activate SIRT3 (R).
There exist 7 different sirtuins, and they have various different effects in the cell. Some sirtuins are active only in the cell nucleus, others in the mitochondria, while others are active in the cytoplasm.
The more a substance can activate different sirtuins, the better.
11. Nicotinamide riboside (NR) does not extend lifespan in mice
Just like nicotinamide (R), nicotinamide riboside (NR) does not extend lifespan in mice, and this according to well-conducted studies (R).
So despite many websites and manufacturers touting nicotinamide riboside (NR) for “anti-aging” purposes and to extend lifespan, NR does not seem to be able to extend lifespan.
We should not be surprised by this, given most NR gets already broken down into nicotinamide (vitamin B3) in the gut before it’s absorbed. Given that studies have shown that nicotinamide does not not extend lifespan it’s not surprising that NR also does not extend lifespan.
Furthermore, too much nicotinamide can actually inhibit sirtuins and PARPs, which are important DNA repairing enzymes (R).
12. Opinions are overly skewed towards NR supplements, not always for the best reasons
Many websites and people promote NR supplements, not NMN supplements. There is a lot of hype around NR.
But why is this, especially given scientific studies seem to suggest, and various experts believe, that NMN is better than NR?
First of all, and most importantly, the production process of NR is patented.
This means that only very few companies can make NR. Companies that own patents and licenses on NR can make a lot of money.
This is one reason why some companies still strongly promote NR as an anti-aging supplement (despite studies showing NR does not extend lifespan (R)). Given the monetary vested interests, many companies tout NR, while downplaying NMN.
Also, the fact that NR is patented, is why a lot of research into NR has been funded by these companies. After all, if you have patent protection, it pays off to conduct studies because your ingredient is protected. Unpatented substances are often less researched because little money can be made of them.
In contrast to NR, NMN is not patented. Everyone can make it. Luckily, given NMN is such an interesting molecule, it is also a very widely researched one, and often by independent scientists because the molecule cannot be patented.
Secondly, NR is much cheaper and easier to manufacture than NMN. That is why most experiments in the past have been done with NR and not with NMN. Only recently has NMN been able to be produced more economically, but it is still very expensive. So most studies have been done with NR, and that is why NR has become more famous than NMN.
As Dr. Imtias Mehedi summarizes it:
“The high manufacturing cost of NMN causes an increase in the ultimate price that creates a burden from the patients’ perspective. Despite having these drawbacks, NMN could still be a potential chemical entity, to be used as a therapeutic agent in Alzheimer’s, diabetes, cardiovascular diseases. Some capsule formulations of NMN is already available in the market. With advanced clinical studies along with the exploration of newer pharmacological applications, NMN could be an ‘all-in-one’ intervention strategy, transpiring a new era of therapeutic approach in medical science.”
Additionally, some scientists might not openly want to say that NMN could be better than NR, because they previously have done research on NR, and don’t want to discredit their findings, or their patents on NR.
13. NMN taken orally is also absorbed
Don’t believe the still widespread claims that NMN cannot be orally absorbed, or that it is far less well absorbed than NR, or that you have to take NMN sublingually.
Often, these outdated claims are made by sellers of NR, who want to push their NR products. Or, by NMN sublingual tablet manufacturers who are looking for an edge with a distinct product, but not basing their claims on solid, NMN-specific studies.
NMN studies have clearly demonstrated that NMN can be readily absorbed when taken by mouth.
A specific protein, SLC12A8, has been found in mice that can transport NMN across cell membranes (R). Genetic analysis showed that this transporter is also present in humans (R).
That there exists a specialised NMN transporter shouldn’t be surprising, because studies have shown that orally administered NMN is very bioavailable and increases NAD+ in different tissues (R,R).
Also, studies in mice in which NMN is given orally demonstrate that NMN can improve many aging and health biomarkers (R,R,R). This clearly shows that NMN is absorbed and exerts effects in mammals.
A study in which NMN was administered orally to humans showed that NMN is absorbed, given various metabolites of NMN were found in the blood, showing that NMN was absorbed and metabolized (R).
Various companies that develop treatments for aging administer NMN orally in their trials.
A brief word about cellular uptake of NMN. Until recently the general idea was that NMN could not be directly taken up by cells. NMN first needed to be converted into NR in order to be taken up by the cells. Recent research however shows that NMN can be taken up directly by cells, crossing the cell membrane via a specific mechanism (R).
And if you are still not convinced, David Sinclair, a leading NR, NMN and NAD+ researcher from Harvard University takes his NMN powder (not NR) every morning with his yoghurt. He doesn’t inject, nor does he take it sublingually.
14. NMN supplements improve insulin resistance in humans, while NR doesn’t
Scientific studies indicate that NMN can improve insulin resistance in humans (R), while we don’t see this effect for NR in humans (R).
In fact, high doses of NR can even increase the risk of insulin resistance, as we see in animal experiments (R). According to the authors:
“Mice fed with high NR [nicotinamide riboside] showed a reduced metabolic flexibility, a lower glucose clearance rate and aggravated systemic insulin resistance. This was consistent with molecular and morphological changes in eWAT [white adipose tissue], including sirtuin 1 (SIRT1)-mediated PPARγ (proliferator-activated receptor γ) repression.”
– Professor Jaap Keijer, University of Utrecht, Netherlands
That too much NR can suppress sirtuin 1 is not surprising because when NR is taken orally, almost all is broken down quickly into nicotinamide (NAM) in the gut and liver. Too much NAM can actually hinder expression of sirtuins, as we discussed earlier in this article.
Insulin resistance is an important driver of aging and aging-related diseases. The more resistant our tissues are to insulin, the faster they age. Increased insulin resistance is a precursor to type 2 diabetes, but also increases the risk of heart disease, Alzheimer’s disease and many other aging-related diseases.
We highlighted tips to prevent and revert insulin resistance here.
15. Anecdotal evidence
Many people who took both NR and NMN supplements claim that NMN supplements have considerably stronger effects than NR supplements.
This can aslo be corroborated by one of the founders of NOVOS, who tried both NR and NMN, and felt more energized with NMN, in fact so much that he had to stop taking NMN in the evening because it left him too energized to fall asleep.
On Amazon, you can find many testimonies from people who tried both NMN and NR supplements, claiming that an NMN supplement works better for them:
And what about taking NAD+?
Given that the whole goal of taking NR and NMN supplements is to increase NAD+ levels, why not take NAD+ itself?The problem is that NAD+ is a large molecule. If you take it orally, it gets broken down in the gut.
Also, even if NAD+ were not broken down by the digestive enzymes, it would be too big to be taken up by the gut cells.
NAD+ can however be delivered intravenously, skipping the digestive tract. Some clinics offer NAD+ delivered via an intravenous (IV) injection.
However, intravenous NAD+ causes sudden very high peaks of NAD+ in the blood. Too much NAD+ can perhaps also not be a good thing, for example causing too much reductive stress (R).
It also remains to be seen if the NAD+ in the blood can actually enter the cells. It could be that the NAD+ is broken down in the bloodstream into specific constituents, of which the effects can cascade down into the cells. For example, NAD+ in the blood is partly broken down into adenosine, which can enter the cells and then increase ATP levels, among other things.
Nonetheless, getting once in a while an NAD+ infusion is very irregular. Ideally, NAD+ levels are increased almost continuously, like every day. This can be achieved by taking a daily NMN supplement, which also increases NAD+ levels more gently.
And what about vitamin B3, such as nicotinamide (niacinamide) and niacin (nicotinic acid)?
Niacin (also known as nicotinic acid) and nicotinamide (NAM, also known as niacinamide) are all different forms of vitamin B3.
Taking nicotinamide (NAM) is not advised. Firstly, NAM is too early in the pathway that converts NAM into NAD+. The pathway is as follows:
NAM => NMN => NAD+
So NAM needs first to be converted into NMN which then builds NAD+. It’s better to take NMN, which is a direct precursor to NAD+.
Secondly, nicotinamide could actually inhibit sirtuins, the important enzymes that help to protect the DNA and the epigenome.
This is because NAD+ is converted into NAM in order to “activate” the sirtuins. If there is too much NAM present, this will hinder this conversion of NAD+ into NAM, and thus proper sirtuin functioning (R).
Niacin, another B3 vitamin, is also a less ideal way to increase NAD+ levels.
Contrary to NMN, niacin is far earlier in the pathway to create NAD+. Given niacin is so early in this pathway, and given its involvement in many other pathways, niacin can lead to more side effects.
For example, niacin supplements have been associated with side effects such as flushing (which is quite uncomfortable) and increased glucose levels, which could perhaps increase the risk of type 2 diabetes in the long term (R,R).
Conclusion
Additionally, studies show impressive results of NMN on many aging mechanisms, more so than NR.
Various biotech companies look into NMN to treat aging and aging-related diseases. Well-known experts on NAD+ metabolism take NMN, not NR, which might hint at something.
Additionally, many people claim that NMN supplements work better for them than NR supplements, especially to improve energy.
NR supplements are often advised and touted on the internet, mainly by people who sell NR supplements. One reason for this is that NMN is a relatively new molecule, which cannot be patented and was very expensive and difficult to manufacture until very recently.
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| Source: NovosLabs.com |
Reposted from: https://novoslabs.com/nmn-vs-nr-is-nmn-better-than-nr/
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