In a video podcast interview last week, City of Hope’s Dr. Charles Brenner — who discovered Nicotinamide Riboside “NR” (FAQs) (Reviews) as an NAD boosting vitamin — fielded a host of questions from a New Zealand trained MD. While there’s lots of science here, there’s also lots of accessible information. The following are 4 key takeaways (video interview embedded below).

Key Takeaway #1 — NMN Makes No Sense

“NMN is Nicotinamide Riboside (NR) with a phosphate on it.

It’s not a vitamin.

It’s not something that can go into cells….

So anybody that is buying NMN is basically buying something where a chemist has put a phosphate on and then in their digestion the phosphate is coming off and then what is becoming available is Nicotinamide Riboside (NR), Nicotinamide, or Nicotinic Acid.

Compounds with phosphates don’t go into cells.

That’s settled science.

That’s been known for 25 or 30 years.”

…NMN to me makes no sense because with NMN the phosphate has to come off to be NR in order to be used through the NR kinase pathway.”

Key Takeaway #2 — Boosting NAD is Preventative Medicine

“…boosting NAD has potential activity that’s antiviral, almost certainly has activity in promoting resistance to DNA damage and better DNA repair, better resistance to damage from the sun and reactive oxygen species, things that occur in mouse models of obesity like reactive oxygen stress, things that occur in models of neurodegeneration.

So, it’s basically preventative, it’s preventative medicine.

Certainly it’s preventative medicine in rodents and the use case in humans would be in building resiliency.”

Key Takeaway #3 — Nicotinamide Riboside (NR) is the Best of the NAD Boosters

“NR (Nicotinamide Riboside) is one of 3 vitamin precursors of NAD.

All of them are great.

But, high-dose Nicotinic Acid causes flushing and high dose Nicotinamide inhibits some of the enzymes that we’re trying to stimulate.

For sure, it inhibits Sirtuins.

The advantage of NR is that NR doesn’t cause flushing, NR doesn’t inhibit PARPs or Sirtuins, and NR can be utilized as an NAD precursor in all of the cells and tissues in the body and in particular in those that are undergoing conditions of metabolic stress.”

Key Takeaway #4 — Nicotinamide Riboside (NR) is Orally Available:

…We have work that we’ve not yet published in which we have labeled Nicotinamide Riboside (NR) and we have tracked it in I think 5 or 6 different tissues. Work is not published yet.

There are things that we’ve done in my mouse model of heart failure in which oral Nicotinamide Riboside (NR) was addressing a problem in the failing heart where NAMPT expression is going down and Nicotinamide Riboside kinase pathway is going up.

There’s always work in preparation.

But Nicotinamide Riboside is orally available and analytical methods are always getting better.”

—-THE FULL PODCAST—-

(Key Quotes in Chronological Order, Video Below):

On How Dr Brenner Views Himself:

“I’m a 59 year old scientist.

I like to be at the top of my game.

I want to maximize my health and performance and mental and physical activity.

…I don’t agree that aging can be reversed and i don’t believe that we’re gonna live forever.”

Explaining N.A.D.

“N.A.D. is the central regulator of metabolism.

It’s actually one of four related coenzymes that mediate the key metabolic transformations that occur in all of our cells.

So, not only the conversion of everything that we eat into ATP biological energy but they mediate the conversion of everything that we eat into everything that we are.

So we make all of the molecules in our bodies.

We make our own cell membranes.

We make our own muscle.

We make our own RNA and DNA.

We make our own testosterone and estrogen…

We make our molecules in our cells by eating food.

And food goes through a bunch of very complicated steps called metabolism.

Some of that food gets converted into biological energy that runs our mechanical systems, some of it is used to repair our mechanical systems, some of it is used to store fat, and some of it is used to make molecules.

So NAD coenzymes are the mediators of all those transformations.”

Nicotinamide Riboside (NR) Raises N.A.D. Levels

“Nicotinamide Riboside (NR) is one of the three vitamin precursors of NAD.

It’s the one that that we discovered to be a precursor of NAD in 2004.

The other two, Nicotinamide and Nicotinic Acid (Niacin) were discovered to be NAD precursors essentially in 1938.

And there are differences between NR and those two other precursors…

On NMN:

“NMN is Nicotinamide Riboside (NR) with a phosphate on it.

It’s not a vitamin.

It’s not something that can go into cells….

The four NAD coenzymes are NAD+, NADH, NADP+ and NADPH.

Those molecules have two or three phosphate groups on them.

NMN has one phosphate group on it.

Compounds with phosphates don’t go into cells.

So anybody that is buying NMN is basically buying something where a chemist has put a phosphate on and then in their digestion the phosphate is coming off and then what is becoming available is Nicotinamide Riboside, Nicotinamide, or Nicotinic Acid.

Compounds with phosphates don’t go into cells.

That’s settled science.

That’s been known for 25 or 30 years.”

What about the Scientific Paper Discussing an NMN Transporter that Carries NMN over the Cell Membrane?

“It’s not an NMN transporter.

I would be delighted if there were such a thing.

But there’s no evidence in that paper for the transport of NMN.

It gets into technical details — but if you basically have 100 micromolar of NMN which is a high concentration on the outside of cells for an hour and you don’t see an increase in NMN inside the cells other than in the one minute the first time point which they said they couldn’t properly mix and then when you look at the actual data the error bar on it and it’s just…

There are assays in that paper that simply don’t make sense with a very simple phrase in science and technology and engineering called garbage in and garbage out.

So if you have poor analytical assays and you can’t measure something and you can’t do those time points and you don’t have the methods to detect something then you can’t say that you detected it.

And the fact of the matter is that the molecule that was reported to be an NMN transporter is in a family of enzymes that transports sodium and potassium.

Sodium and Potassium have no resemblance to any nucleoside or nucleotide. It’s not the class of proteins that would transport a nucleoside or nucleotide.

It would be profoundly amazing if it were true.

But there’s no evidence that it is true.

And, in fact, when you do the experiment which we and many other groups have done where you have NMN on the outside of cells and you use valid analytical methods that can separate NMN to NR you see that NMN is converted quantitatively — that means fully — to NR outside of the cell. Then NMN goes into the cell, phosphate gets put on it, and now it’s NMN inside the cell and then it gets converted into NAD.

By the way, NR and NMN are very low abundance metabolites. NAD is a very high abundance metabolite.

You know how you make NAD in your own body when you’re out in the woods — as a bear or as a frog or as a mouse — you eat food.

You eat food that has NAD coenzymes in it.

And you break down the NAD coenzymes into the vitamin precursors and you build those vitamin precursors back up into NAD coenzymes OR you eat food that has protein in it and some of the tryptophan gets converted into NAD very inefficiently.

So NMN can effectively function as an NAD precursor by breaking down into NR — but, so basically can everything in food.

You might as well eat NAD itself.

No one seriously thinks that NAD goes into cells.

But when you eat Thanksgiving dinner which most Americans had too much of yesterday — we had many many NAD inputs in our dinner the meat the vegetables the fish…

Now, the more refined things were, the more unlikely they were to have intact NAD in it.

But, whatever it was, broke down into NAD precursors or tryptophan and then our cellular metabolism built it back up into NAD coenzymes.

This is the way it works.”

Many Conditions of Metabolic Stress Disturb the NAD System

“…and finally something that my lab discovered that i think is as important as our discovery of the Nicotinamide Riboside kinase pathway — that many conditions of metabolic stress disturb the NAD system.

Even though we have these four very important NAD coenzymes that mediate all of these metabolic transformations you would think that our cells have stable supplies of the NAD coenzymes.

It turns out that’s not the case.

i could name you 8 different types of metabolic disruption from DNA damage, storms of reactive oxygen species, coronavirus infection, inflammation, probably time zone disruption, certainly obesity in mouse, heart failure almost certainly in humans, peripheral neuropathy, central brain injury.

And many of these things are common enjoyable things like sunlight, reactive oxygen stress, certainly noise sufficient to produce hearing loss disrupts the NAD system.

Many types of metabolic stress disturb the NAD system.

This readers / viewers / listeners is the use case for supplementation with NAD precursors — that conditions of metabolic stress disturb the NAD system.

Maybe aging does.

Probably aging does.

Frankly the evidence that aging disturbs the NAD system is much lower quality evidence than everything else that i told you about like infection, inflammation, DNA damage, reactive oxygen — THAT clearly disturbs the NAD system.

In mouse systems, in some tissues, aging clearly disrupts NAD — but it’s not been done by the people that i put the most trust into in terms of their analytical methods.

So the use case for NAD precursor supplementation is that as we go through the stresses of life our NAD systems become disturbed.

And in many of the conditions in which the NAD system is disturbed the genes that our group discovered — the Nicotinamide Riboside (NR) kinase genes get upregulated — which means the damaged tissues are looking for NR in order to restore healthy levels of NAD.

NMN to me makes no sense because with NMN the phosphate has to come off to be NR in order to be used through the NR kinase pathway.

Sirtuins a very minor part of the story.

Most of it is not evidence-based.

Resveratrol doesn’t activate Sirtuins.

Sirtuins mostly don’t have roles in conditions of metabolic stress in which the NAD system is disturbed.

I don’t endorse any of that stuff.

I could debunk it if you want. It gets too technical.

But basically what i want to tell people is that NAD is a central regulator of metabolism.”

Why Supplement with NR?

“NR is one of three vitamin precursors of NAD.

All of them are great.

But, high-dose Nicotinic Acid causes flushing, high dose Nicotinamide inhibits some of the enzymes that we’re trying to stimulate.

For sure it inhibits Sirtuins.

I’m not convinced how central Sirtuins are to the biology of NAD. I’m much less convinced than others in my peer group.

The advantage of NR is that NR doesn’t cause flushing, NR doesn’t inhibit PARPs or Sirtuins, and NR can be utilized as an NAD precursor in all of the cells and tissues in the body and in particular in those that are undergoing conditions of metabolic stress.

That’s my story.”

On NR Bioavailability

“…We have work that we’ve not yet published in which we have labeled Nicotinamide Riboside (NR) and we have tracked it in I think 5 or 6 different tissues. Work is not published yet.

There are things that we’ve done in my mouse model of heart failure in which oral Nicotinamide Riboside (NR) was addressing a problem in the failing heart where NAMPT expression is going down and Nicotinamide Riboside kinase pathway is going up.

There’s always work in preparation.

But Nicotinamide Riboside is orally available and analytical methods are always getting better.

…Nicotinamide Riboside (NR) corrects tissue NAD status when tissue NAD status is under attack.

That’s what i want you to understand.

Dr Brenner’s Current Lab Work:

…BrennerLab.net.

That’s our lab website and you can see we have kind of 5 main interests and all of them involve conditions of metabolic stress in which the NAD system is disrupted.

So that includes inflammation coronavirus infection, we’ve gotten into Zika virus as well.

We are interested in postpartum as a metabolic stress.

We’ve seen in the postpartum period and it may be true in gestation as well that Mom’s NAD system is taxed and that she does better — this is in a rat and a mouse — when she’s boosting with NAD precursors.

We have found particular types of malignancies in which the NAD system is disturbed.

There, we’re not trying to support NAD metabolism or we’re trying to kill cells but with our insights into what’s happening in various gene pathways.

We’re interested in heart failure and neuroprotection as well.”

Nicotinamide Riboside (NR):

“Nicotinamide Riboside (NR) has been as you know commercialized as Niagen.

That’s the only safe form and patent-protected form of Nicotinamide Riboside.

You can go to ClinicalTrials.gov and you can see probably 40-50 registered clinical trials.”

If I’m 29 and healthy should I take NR?

“…boosting NAD has potential activity that’s antiviral, almost certainly has activity in promoting resistance to DNA damage and better DNA repair, better resistance to damage from the sun and reactive oxygen species, things that occur in mouse models of obesity like reactive oxygen stress, things that occur in models of neurodegeneration.

So, it’s basically preventative, it’s preventative medicine.

Certainly it’s preventative medicine in rodents and the use case in humans would be in building resiliency.“

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https://www.youtube.com/watch?v=u_KBthslx3Q