Above is a response by Dr. Bradley Stanfield to some lingering questions that resulted from an interview he had of Dr. Charles Brenner on Dec. 6th, 2020.
The original interview by Dr. Stanfield can be seen in it’s entirety here, but be warned it is very hard to get through as Dr Brenner rambles a lot and is pretty much the opposite of Dr David Sinclair when it comes to explaining NAD+ science in a clear, interesting manner.
For those that don’t know, way back in 2006, Dr. Brenner’s lab discovered that Nicotinamide Riboside (NR) converts to Nicotinamide Mono Nucleotide (NMN), and on to NAD+, bypassing the need for NAMPT in the salvage pathway. Since then, he has been a leading proponent of NR as a precursor to increase NAD+ in the body. He is the Chief Scientific Advisor for Chromadex, the main manufacturer of NR.
Dr. Stanfield is an MD with a keen interest in all available therapies for life extension and has been exploring research on NAD+ precursors to raise NAD+.
He has made several popular videos on the subject here, in which he strives to remain objective in exploring the science. He has a gift for zooming in on the relevant questions and explaining what the current research show in a straightforward manner that laymen can understand.
Dr. Stanfield is clear that he personally takes NMN sublingually, a method we introduced and have been the main proponents of since 2017. So we took particular interest to see if Dr. Brenner could answer questions about the research and convince Dr Stanfield to switch his personal choice.
Dr. Brenner is clearly frustrated that Dr. Stanfield takes NMN rather than NR. He made a few points that Dr. Stanfield agreed with, but for the most part, Dr Brenner simply insists many studies are wrong, and other researchers don’t know what they were doing.
- Liu et all finding that no NR or NMN escape the liver – Researchers don’t know how to measure NMN and NR properly
- Dollarup et all failed to show metabolic benefit of NR – Research was badly design. Measured the wrong parameters and too short
- SLC12a8 – Research was wrong. Results don’t show any transport of NMN into cells.
- Research showing NMN worked for Friedrichs Ataxia but NR did not – Dr. Brenner claimed to not be familiar with this
- All research that fails to find NR in blood – Researchers don’t know how to measure NR properly
m43:30 After the interview and this response, Dr. Stanfield still believes it likely that sublingual NMN is more effective and will not change his NAD+ precursor at this time.
Rather than going through all the interesting points they covered, we decided to focus this post on a single issue, and are writing a second post to cover other points they discuss.
Dr Brenner doubts research showing SLC12A8 is NMN transporter
This 2019 research that shows the SLC12A8 enzyme takes NMN across the cellular membrane directly, without need for conversion to NR. Dr. Sinclair and others believe this is the dedicated NMN transporter that they have long suspected.
Dr. Stanfield believes the research was quite rigorous and that Dr. Brenner failed to point out proof of a flaw in the research.
m6:30 – Dr. Brenner doesn’t believe the research is valid, and says the study was flawed. He points out they don’t see an increase of NMN inside the cell, except in the first minute. He says there are assays (quantities) found later that bounce around and don’t make sense, and the methodology was not good, resulting in GIGO (Garbage In Garbage Out).
m11:45 “intracellular NMN levels significantly increased at 1 minute time point” (quote from study)
m12:12 “Reading through this, I’m not sure what Dr Brenner is disputing here…..” It makes perfect sense that a cell starving for NAD+ would see an immediate increase in NMN at 1 minute, followed by a slight decrease in NMN as it goes on the NAD+. The assays do make sense.
m9:45 – Dr Stanfield explains HOW they found this enzyme. By knocking out cells internal NAMPT salvage cycle, and the NRK1 pathway which converts NR to NMN, so there was no way for NMN to increase unless there was some other direct pathway.
m10:10 They then looked for genes that were upregulated due to the modifications. SLC12A8 was greatly increased in response.
m16:00 I believe this study is evidence that the NMN transporter does work.
m18:00 Dr Stanfield points out the researchers found this transporter by starving cells of NAD+ to see what genes were upregulated. The body compensates for low NAD+ in cells by upregulating SLC12A8 to help bring more NAD+ into cells that are in crisis.
Genetics don’t lie
In their interview, Dr Brenner was trying to explain why NR is important, even though Liu/Rabinowitz research shows NR (and NMN) are completely metabolized to NAM in the liver.
At m26:16 of the origional interview, Dr. Brenner says Liu/Rabinowitz is flat wrong and that “Genetics doesn’t lie”. Yet he seems to use a different interpretation with the SLC12A8 research.
He refers to studies done in mice that have had NAMPT deleted in skeletal muscle, so they can not utilize NAM to make NAD+, yet show a positive response in the muscle from oral NR. He says that is proof Liu/Rabinowitz is wrong, and NR must circlulate in blood to reach that skeletal muscle.
Dr. Brenner also points to the body response to a shortage of NAD+ by upregulating NRK1 to aid utilization of NR to produce NAD+ at m23:00.
Dr Brenner says that because NAMPT deficient muscle upregulates NRK1, and it helps increase NAD+, that is proof NR does in fact circulate in the blood, even though researchers never find more than trace levels of NAD+ in the blood.
At m18:00 of his response, Dr. Stanfield points out the apparent incongruity in Dr. Brenners logic.
In the SLC12a8 research, they found this transporter by starving cells of NAD+ to see what genes were upregulated. The body compensates for low NAD+ in cells by upregulating SLC12A8 to transport NMN and help bring more NAD+ into cells that are in crisis. Yet, according to Dr. Brenner:
Upregulation of NRK1 is proof cells are desperate for NAD+ and trying to utilize NR as a source
Upregulation of SLC12A8 is not proof cells are desperate for NAD+ and trying to utilize NMN as a source.
We believe that Dr. Brenner is overzealous in his haste to dismiss the SLC12A8 gene as a dedicated NMN transporter. Many other researchers in the field believe the evidence in this research is in favor of SLC12A8 being a transporter.
It is interesting that Dr’s Stanfield and Brenner continue to debate this question on twitter.
Pressed further to explain the research, Dr Brenner again claims the methods were bad, and NMN increase is “noise”, but offers no further clarification.
NMN transporter question is overrated
SLC12A8 may transport SOME NMN but we believe it is not as critical a question as Dr. Stanfield and Brenner seem to think.
We reviewed the research on SLC12A8 when it first came out. We did find find Dr. Stanfields interview and response on the subject informative. But it does not change our belief that:
- There really are no indications that SLC12A8 is a dominant pathway for NMN utilization.
- NMN is able to cross the cellular membrane with help from the CD73 enzyme that resides on the membrane surface.
- NMN is able to enter and restore NAD+ inside a cell more effectively than NR, as shown in this research.