Thread by @CharlesMBrenner

There is so much disinformation going around about NMN, it's time for a tweetorial /1

Before you dismiss me as biased because I developed the NR patents @Dartmouth, consider that I've been working on nucleosides and nucleotides since 1993 when I began my postdoc @BrandeisU -- I've continued on the forefront of nucleoside/nucleotide research to this day /2

My primary motivation is for people not to be harmed. I also think it is horrible for people to be fooled or hoodwinked /3

We don't how many people have been harmed by taking NMN because we don't know what's in the bottles produced by so many suppliers. It is certain that everyone buying the NMN story is being hoodwinked. If they are buying NMN, their cells are getting either NR or nicotinamide /4

I will explain all, starting with the basic chemistry /5

What are nucleosides and nucleotides? Let's start with examples and then I will teach you the general principles. NR and adenosine are nucleosides. NMN, NAD and ATP are nucleotides. Nucleosides don't have phosphates. Nucleotides have one or more phosphates /6

Nucleosides are molecules with a base linked to a sugar. When the base is adenine (abbreviated A) and the sugar is ribose, you have adenosine. When the base is nicotinamide and the sugar is ribose, you have NR /7

Nucleosides circulate in the body and are taken up by cells through nucleoside transporters. Inside cells, nucleoside kinases add a phosphate to turn nucleosides into nucleotides. Adenosine kinase converts adenosine into AMP, which can then be converted to ADP and ATP /8

NR also circulates, though it is difficult to detect. When we draw blood, an enzyme that is normally inside cells spills out and breaks the NR into nicotinamide plus ribose. We know NR circulates because every cell has NR kinase (some cells have NR kinase 1 and 2) /9

Moreover, cells with NAD problems, such as those in a failing heart, turn up expression of their NR kinases so that when NR becomes available, NR kinases convert the NR to NMN. In a healthy cell, the NMN is then converted to NAD+, NADH, NADP+ and NADPH. That's how NR works /10

What NMN advocates are saying is that NMN is closer to NAD+ than NR is. They are saying that NR has to be converted to NMN and then to NAD+ and this makes NMN more powerful than NR because it is already has one of the phosphates on it toward rebuilding cellular NAD+ /11

If NMN were to get into cells, this would be true but NMN does not get into cells. In fact, no nucleotide has ever been shown to get into cells. NAD+ can be exported from cells through Cx43 and NMN was proposed to enter cells through Slc12a8 but NMN does not enter cells /12

If NMN entered cells as NMN, then it would not need NR kinase to elevate NAD+. We knocked out NR kinase. As expected, NR could not be used by cells from these mice to make NAD+. We and others showed that NMN loses its phosphate outside cells, becoming NR /13

The NMN proponents predicted that NMN would still work as NMN in cells that don't have NR kinase but we and others showed that when NR kinase is knocked out, NMN can only raise NAD+ by acting as nicotinamide. That's because NMN works by conversion to NR and needs NR kinase /14

NMN proponents further claimed that sodium channel Slc12a8 is an NMN transporter. Their data did not show this. Their data showed that there is no cellular increase in NMN after extensive incubation with NMN. Remarkably, their false paper has been cited more than 20 times /15

The fact that NMN is not transported and that NMN and NAD+ have to be made inside cells is not surprising. The 1988 Nobel Prize to Elion, Hitchings and Black for work done since the 1960s showed that you can't deliver nucleotides to cells, only bases or nucleosides /16

@davidasinclair also knows this. That's why his company modified the phosphate on NMN to make it cellularly available. Everything in this thread is supported by public data /17

But guess what happens when the NMN phosphate is modified so that you can load cells up with NMN? doi.org/10.1016/j.isci… Eternal life? /18

No. SARM1 protein is turned on by NMN to produce cADPribose that leads to cell death. Remember when I said that in a healthy cell, NMN is converted to NAD+, NADH, NADP+ and NADPH? In a damaged neuron, NMN cannot be converted to NAD+ and is a death signal /19

Modified NMN will not be a drug for health or longevity. Mark my words. It will be unethical to test it in people because it will produce SARM1-dependent damage in animals /20

Is this why I think that NMN is potentially dangerous as a supplement? No /21

Pure NMN can only deliver NR or nicotinamide to cells (just as NR can only deliver NR or nicotinamide to cells). So NMN itself cannot load up any damaged cell with hazardous levels of NMN /22

The problem is you literally have no idea what you are getting when you buy NMN. I would bet that there's caffeine in most NMN supplements. There is likely a large amount of nicotinamide and residual solvents. There's been no NDI on any NMN source. There are no safety data /23

With NR, if you buy from the company holding the patents, you know you are getting material that has been safety reviewed. There's public information about another seller of NR showing acetamide and toluene in their material /24

What keeps me up at night is the idea that someone will be hurt by taking NR. Safety first. People taking NMN are not been safe. And they've also been hoodwinked by the people asserting that it's closer to NAD+ than NR /end