⚠️ New Product Alert ⚠️ Nicotinamide Mononucleotide Enteric Coated Tablets | 125mg

Okay, so you have opened up a whole complex can of worms. Like many things, it's VERY complex. I will attempt to make it slightly less complex for everyone.

Here is the full study: https://sci-hub.tw/10.1038/cdd.2014.164

So what are we looking at with this study? Well they set out to look at what happens to mice when they are subjected to axonal nerve damage. The reason they did this is that they discovered a type of mouse referred to as Wallerian degeneration slow (Wld^S) mice, where transected axons survive 10 times longer than in wild types (WTs) mice. The Wld^S mice show less axon degeneration in some existing disease models. Essentially they found a type of mouse who's axons survive longer than normal mice. Because of this, they set out to study why that might be.

So what is a Wld^S mouse? Well in mammals there are 3 isoforms of the nicotinamide mononucleotide adenylyltransferase enzyme: nuclear NMNAT1, cytoplasmic NMNAT2, and mitochondrial NMNAT3. These NMNAT enzymes catalyze the conversion of NMN to NAD+. Essentially, these NMNAT enzymes are responsible for the rate-limiting conversion of NMN to the thing we really want in cells: nicotinamide adenine dinucleotide (NAD+). The Wld^S mutation results in a modified NMNAT1 enzyme, by partially relocating NMNAT1 from nuclei to axons, which results in enhanced activity. Remember above I called it nuclear NMNAT1, but NMNAT2 was cytoplasmic? Well this Wld^S mutation results in a partial relocation of the NMNAT1 enzyme from the nuclei into the axons. So whereas normal mice rely on NMNAT2 in the axons, Wld^S type mice can rely on both NMNAT1 and NMNAT2. This is important for the findings of the study. Wld^S also partially colocalizes with the mitochondria, which results in improved CA^2+ buffering capacity. What is the primary cause of excitotoxicity? Excess CA^2+ in cells.

If you want to read more on the specifics surrounding Wld^S, here are some studies. Be forewarned, they are very complex.

https://sci-hub.tw/10.1523/jneurosci.3814-08.2009

https://sci-hub.tw/10.1523/JNEUROSCI.4304-08.2009

So what happens when mice are subjected to nerve injury? Well it appears that after nerve damage NMNAT activity is diminished. Specifically, NMNAT2 being depleted leads to the buildup of NMN in the axons, later resulting in axonal degeneration. One could posit that it is merely a result of NAD+ levels falling, since NMNAT2 is catalyzing the conversion of NMN to NAD+ in the axons. However, they tested this by inhibiting nicotinamide phosphoribosyltransferase (NAMPT) with the drug FK866, which is the rate-limiting enzyme preceding NMNAT. Inhibiting NAMPT both leads to decreases in NAD+ and protection from axonal damage. So it simply being a result of decreased NAD+ in axons is unlikely to be the main mechanism. So the nerve damage seems to result in a depletion of NMNAT2, which results in a buildup of NMN in axons, as the NMN cannot convert to NAD+. Inhibiting the production of NMN by blocking NAMPT both protects from the type of Wallerian degeneration observed in the study, while also lowering NAD+ in axons. So the buildup of NMN after the depletion of NMNAT2 is key to the degeneration. So let's circle back to the Wld^S mice. Why do they show less degradation? Well remember they have partial relocation of NMNAT1 into axons. So while after nerve injury their NMNAT2 levels also deplete, their partial relocation of NMNAT1 into axons helps to prevent the buildup of NMN. Pretty interesting!

So WTF is going on here? It's pretty clear that nerve damage results in the depletion of NMNAT2 in axons, which results in the buildup of NMN there, with a reduction in NAD+, and a delayed degeneration of the axons themselves. Wld^S type mice have a mutation that partially collocates their NMNAT1 enzyme in axons, which helps them protect themselves from the buildup of NMN after depletion of NMNAT2. Pre-administering the drug FK866, which is a selective NAMPT inhibitor protect from the axonal degeneration by preventing the production of NMN in the first place. So the buildup of NMN in axons with no way to convert to NAD+ is clearly an issue. So why is that? The study cannot prove the exact mechanism yet. There is a delay between the buildup of NMN in axons and axonal degeneration, though. So it is likely not NMN itself, but some sort of imbalance caused by the inability of the NMN in axons to convert to NAD+ after nerve damage, due to a depletion of the NMNAT2 enzyme. The study says this: " We cannot completely exclude a role for a related, potentially even unknown, endogenous metabolite of NMN, but there is no detectable rise in NR." So it is not a rise in nicotinamide riboside in axons leading to it, nor a decrease in NAD+. There could be an unknown metabolite of NMN that happens in axons that we just have not discovered yet, and preventing the conversion of NMN to NAD+ by depleting NMNAT2 triggers that. That would make sense for the delay in the degeneration after NMN buildup, but more work would need to be done to prove that. One thing is for certain: it's the depletion of NMNAT2 in neurons resulting in the Wallerian axonal degeneration. That happens after nerve injury. So it could be a compensatory mechanism like apoptosis.

Other studies have shown that NMN protects from cytotoxicity.

Nicotinamide Phosphoribosyltransferase Protects Against Ischemic Stroke Through SIRT1-dependent Adenosine Monophosphate-Activated Kinase Pathway

Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice

Furthermore, other studies show exogenous NMN helps with brain mitochondrial function, blood brain barrier integrity, and cerebral ischemia. So NMN is mostly protective.

Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model

NAD Replenishment With Nicotinamide Mononucleotide Protects Blood-Brain Barrier Integrity and Attenuates Delayed Tissue Plasminogen Activator-Induced Haemorrhagic Transformation After Cerebral Ischaemia

Nicotinamide mononucleotide \(NMN\) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice

Nicotinamide Mononucleotide: A Promising Molecule for Therapy of Diverse Diseases by Targeting NAD+ Metabolism

So exogenous NMN supplementation, like what you would be doing with our NMN tablets, shows tons of benefits and no observed risks. Yes, there is a mechanism in axons after nerve injury that can lead to degeneration because of a buildup of NMN in those axons. However, that will happen with exogenous NMN supplementation or not. Your NAMPT enzyme in your brain will be creating NMN there regardless. The axonal degeneration is more a result of a depletion of NMNAT2. Furthermore, long-term studies of NMN in healthy mice show benefits and slowing of cognitive decline. If NMN was resulting in axonal degeneration, obviously we would not see this.

Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice

So while that study is interesting, and further studies should elucidate what is happening in axons after nerve injury, it does not appear to me to be a risk for exogenous NMN supplementation.