Editor, Science of NAD
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Debates at the Frontiers of NAD Science
Which Is Better, NMN or NR?
Scientists have long known that NMN must be broken down into NR or NAM before it can enter the cell and replenish intracellular NAD:
Our results indicate that mammalian cells require conversion of extracellular NMN to NR for cellular uptake and NAD+ synthesis, explaining the overlapping metabolic effects observed with the two compounds.
We also showed that extracellular cleavage of NAD+ and NMN to NR is a prerequisite for using these nucleotides to maintain intracellular NAD contents….The degradation of NAD+ and NMN to NR or Nam is essential for these nucleotides to act as extracellular precursors of intracellular NAD...
That's why NMN only makes sense as a supplement if you do not have access to NR.
However, it has been suggested that an NMN transporter molecule, Slc12a8, might allow NMN to directly enter the cells, which could give NMN an advantage:
Opposing views exist to Grozio et al.'s determination for Slc12a8 being an NMN transporter, Schmidt and Brenner point out that levels of NAD are 500 times higher than NMN in normal liver samples, and Grozio et al. (2019) had failed to examine background/control levels, which undermines any result Grozio et al. (2019) delivered. The debate remains open and no robust conclusion in this regard can be made.
But Slc12a8 isn't well-expressed in all human cells, or even most human cells. So even if the transporter exists, NR would still be the better option for people trying to replenish NAD in their heart, nerves, muscles, eyes, and most or all other places.
How Can NAD Help Fight COVID?
NAD levels are critically important to your body's immune response. But many viruses, including COVID, knock down your NAD levels. With less NAD, your immune system has a harder time fighting back. Indeed, lower NAD levels correspond with worse COVID outcomes.
That's why replenishing NAD before and during a viral attack can support your immune system and allow it to fight back.
Studies of coronaviruses generally, including COVID-19 in particular, reveal an immune system drama. When a COVID infection is detected, the cell's innate immune system attaches a large piece of an NAD molecule to the virus in order to interfere with the virus's ability to reproduce.
The problem is that coronaviruses have a counterattack, which is an enzyme that removes the piece of NAD. That process of attachment and removal burns up the cell's NAD and impairs immune response:
Infected cells expend NAD+ in antiviral ADP-ribosylating activities while the virus attempts to reverse these modifications. Indeed, coronavirus infection strikingly depletes cellular NAD+ level
By the virtue of its high capacity to actively reverse antiviral ADP-ribosylation, this virus accentuated pre-existing states of NAD+ deficiency
It is speculated that SARS-CoV-2 depletes cellular NAD+ levels by overexpressing a set of PARPs, all of which compete for the same NAD+ pool....which ultimately reduces NAD+ levels
Why not just take NAD directly?
NAD is a big molecule that cannot enter cells directly:
Increasing evidence indicates that NAD+ cannot enter cells directly through the plasma membrane and that it must be converted into smaller, less charged molecules to enter cells
NAD+ cannot be taken up directly by the cell, but its precursors can.
Perhaps the only study to examine NAD supplementation by IV therapy found that the NAD was largely excreted, although some was degraded to precursors and generated NAM:
"The continuous IV infusion of NAD+ at a rate of 3 μmoles/min resulted in a significant (538%) increase in the urine NAD+ excretion rate…The urine excretion rate of the NAM metabolite meNAM was significantly increased (403%) at the 6h time point..."
The reason NAD supplements work at all is because a number of extracellular enzymes are able to degrade NAD into smaller pieces that can enter cells:
Extracellular NAD is degraded by three main classes of ectoenzymes [which can] lead to the formation of [adenosine, NMN, NAM, and NR].
Therefore, putting NAD directly into your blood stream will likely have a positive effect to the extent that (1) it gets broken down into NAM and your salvage pathway is not down-regulated, or (2) it gets broken down into NR and is absorbed as NR.
But it is less expensive, more efficient, and more convenient to just take the NR directly as an oral supplement, than to inject NAD. Anyone telling you that oral supplements do not get absorbed should instead be telling you that NAD doesn't get absorbed.
What Is The Difference Between the Precursors?
NAD cannot enter cells directly. Also, you already get plenty of NAD in your diet. The challenge is not getting NAD into your body, but getting it into your cells. That's why you need a precursor, which is a smaller piece of NAD than can enter the cell and help build intracellular NAD.
Niacin (NA) only gets turned into NAD if an enzyme called NAPRT is present. NAPRT is abundant in some cell-types, but it is poorly expressed in others, so NA won't replenish NAD very well in nerve or muscle cells, for example, or under conditions where NAPRT is depressed, like viral infection. Niacin also causes problems at higher doses.
Nicotinamide (NAM) can be used by every cell, but only gets turned into NAD if an enzyme called NAMPT is present. NAMPT is present in every cell, but there isn't enough of it under some circumstances, including old age and some types of metabolic stress. So NAM may not work well sometimes. NAM may also inhibit sirtuins. Finally, high doses of NAM can have toxic side effects.
Nicotinamide Riboside (NR) is available to every cell, and bypasses rate-limiting steps that can prevent NA and NAM from creating NAD. NR has no known significant negative side effects, even at doses as high as 2,000 mg/day.
Nicotinamide Mononucleotide (NMN), like NAD cannot enter cells directly -- at least not most cells -- and must be broken down into other precursors like NR and NAM before replenishing intracellular NAD. Therefore, it is more efficient, and often less expensive, to supplement with NR directly than to use NMN.
Are NAD Precursors Just for Old People?
No, NAD precursors are not just for when you get old.
For sure, aging is one condition that drives down NAD levels, in animals and humans alike. And when it comes to reproductive health, the effects of aging begin earlier than it might appear. But aging is not the only thing that drives down NAD levels.
NAD levels can be reduced episodically and temporarily, too, by a wide variety of common metabolic stresses, such as overeating, obesity, alcohol consumption, vigorous exercise, sun exposure, time zone disruption, postpartum, viral infection, reactive oxygen, DNA damage, bright light, even loud noises:
NAD+ consumption is not constant. Under some circumstances, such as...upon DNA damage, NAD+ is consumed at a higher rate and, therefore, NAD+ synthesis rates also need to increase to maintain NAD+ levels..." ---
That's because your body initiates repair processes in response to various metabolic insults, and those repair processes consume NAD, leaving you, at least temporarily, with less.
This study found that when NR was not available to muscle cells that had been injured -- not due to old age -- repair time was delayed:
During regeneration, muscle stem cells (MuSCs) from [mice with both NRK1 and NRK2 knocked out] hyper-proliferate but fail to differentiate. Double NRK Knockout also alters the recovery of NAD+ during muscle regeneration as well as mitochondrial adaptations and ECM remodeling required for tissue repair. These metabolic perturbations result in a transient delay of muscle regeneration which normalizes during myofiber maturation at late stages of regeneration via over-compensation of anabolic IGF1-Akt signaling.
If NAD IV therapy and injections are no good, why are there so many clinics offering it?
Good question. NAD IVs have been around for decades, and have been used to treat addiction. NAD IV therapy might have been the best available technology for that, before the discovery of NAD precursors that could get past the rate-limiting steps that can sometimes prevent NAD biosynthesis from Niacin (NA) and Nicotinamide (NAM).
For several decades, IV NAD+ has been used as a holistic ‘underground’ approach for the treatment of various forms of addiction...NAD+ precursors provide ‘newer’ alternatives for raising NAD+ levels...
The reason that NAD IV therapy has an effect is because NAD can be broken down in circulation into NMN, and NMN to NR, which can then enter cells and work in ways that NA and NAM cannot. So the holistic, underground approach to NAD replenishment could have generated unique results and thrived.
But if that's right, then NR and NMN would represent new technologies that could deliver the same molecules to cells with much less trouble and expense.
That, in turn, would mean that IV therapy for NAD might just be an obsolete technology. IV NAD drips can cost 10x more than oral supplements, and no study shows injecting NAD into your veins is 10x better than simply taking orally the same precursors that your body might be generating in circulation.
Does NR reach my cells, or does it get degraded first?
One study says its data "exclude the possibility that oral NR is used exclusively as Nam."
Another study reports the opposite, that first pass metabolism of NR to NAM in the liver makes NR "similar to or indistinguishable from oral NAM."
A third study reports that its data "conclusively demonstrate that NR contributes to NAD mainly via NA" in the gut.
A fourth study says that there are two phases to oral NR absorption -- first it gets distributed as NR, next it gets broken down to NA in the gut and NAM in the liver.
They can't all be right.
And there are LOTS of studies that show NR working differently from either NA and NAM.
It's much more likely that all of the studies have a piece of the truth: some NR gets through as NR, some gets degraded to NA in the gut, and some gets turned into NAM in the liver, and therefore the overall effect of oral NR is to light up all the NAD biosynthetic pathways at once.
Collectively, that's what the data says.
And it's also what one of the earliest studies concluded: "NR produced or tended to produce dose-dependent elevation of the entire NAD+ metabolome."
You can read a summary of all these studies here. Read together, they make far more sense than when you read their apparently conflicting conclusions in isolation:
Why do you recommend NR?
There is no doubt that NAD levels decline under a many circumstances including chronic conditions like aging and inflammation, as well as episodic metabolic disturbances, like overeating, alcohol consumption, sun exposure, sleep disruption, viral infection, postpartum, and more.
There is also no doubt that your cells need adequate NAD levels in order to manage their affairs, including mission-critical functions like DNA repair.
Would it be okay if your cells were inadequately powered for just an hour or a day or a week? It's hard to say. You can't go without oxygen even for four minutes. And the accumulation of problems at the cellular level may be the very definition of aging, even if one particular episode doesn't kill you, or even cause noticeable harm. So NR is the only supplement for which I do not miss a day (I am roughly 60 years old.)
Whether humans will benefit as much as mice do remains to be seen, but the human studies are certainly showing effect.
Right now, NR seems to be the best NAD precursor, because it is available to every cell type of cell, it has the best safety profile, and it works even when other NAD precursors are blocked.
In the future, improved pharmaceutical-grade NAD precursors will likely become available, such as NRH. But for right now, NR is state of the art.
The studies agree. Here is what one study said:
NR is the main precursor of NAD+ in the central nervous system and the preferred precursor in mitochondria...NR is also the preferred precursor for supplementing NAD+ levels in animal models of heart failure and was shown to reduce cholesterol in obese mice. It has also been shown to exert a certain ameliorating effect on alcohol-induced liver disease and depressive behaviour and improve diabetic lesions and hepatic steatosis in mice with high-fat diet-induced obesity. NR can also ameliorate angiotensin Ⅱ-induced cerebral small vessel disease in mice and prevent noise-induced hearing loss. Similar to NMN, NR can also improve female fertility. NR is the only precursor that can prevent axon degeneration as well as the oxidative stress and organ damage caused by sepsis. Moreover, NR has been shown to exert a certain degree of therapeutic effect in the pathological progress of neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, aging, cerebral apoplexy, and hypertension and cardiovascular diseases. Numerous studies have shown that NR can increase the lifespan of all species tested so far, including mice...
Clinical studies on the short-term and long-term administration of NR have demonstrated the superior bioavailability and safety of NR. It is considered safe even when administered at a dose of 2000 mg a day for 12 weeks, and no adverse symptoms, such as nausea and vomiting, or undesirable skin flushing have been reported. Supplementation of NR neither inhibits NAD+-dependent enzymes nor causes side effects such as liver damage. A study indicated that with an increase in the NR level in tissues following NR administration, the activity of the enzyme sirtuin is significantly increased compared with NAM administration. Compared with other precursors, NR is gradually becoming a preferred candidate precursor because of its high bioavailability, safety, and ability to increase NAD+ levels. It offers many potential health benefits in diseases such as cardiovascular diseases, neurodegenerative diseases, and metabolic diseases. In summary, NR is a more effective precursor for synthesising NAD+ and increasing the activity of NAD+-dependent enzymes than NA and NAM... (emphasis added)
READ MORE: What Is NAD and Why Should You Care?