12 replies to this topic

[SearchHorizon]

A mouse study.

 

https://www.ncbi.nlm...les/PMC6807296/

 

 

[able]

Yes, sounds like it overcomes the fatal flaw of NR.  Very promising.  Is stable in blood and orally bioavailable.  Hope Chromadex gets this to market soon!

 

 

 

 Nevertheless, NR is not stable in circulation, and its utilization is rate-limited by the expression of nicotinamide riboside kinases (NRKs). Therefore, there is a strong interest in identifying new effective NAD+ precursors that can overcome these limitations.

Results

NRH acts as a more potent and faster NAD+ precursor than NR in mammalian cells and tissues. Despite the minor structural difference, we found that NRH uses different steps and enzymes to synthesize NAD+, thus revealing a new NRK1-independent pathway for NAD+ synthesis. Finally, we provide evidence that NRH is orally bioavailable in mice and prevents cisplatin-induced acute kidney injury.

 

Edited by able, 02 February 2020 - 03:46 PM.

[Oakman]

You'd think Chromadex would be all over this... it seems to have great advantage over available precursors... hopefully they..or someone else, is and soon we can try some.

Edited by Oakman, 02 February 2020 - 04:25 PM.

[SearchHorizon]

Are the researchers listed in the paper related to ChromaDex? I have not bothered to check.  Also, not sure about the long term effects.

 

How in the world do you make NRH? If NRH has to be manufactured through the same pathway as NR, then, ChromDex would be making even more money. Any patent filed on NRH would be good for approximately 20 years, which means consumers will be paying a lot for the supplement for the next 20 years. 

 

 

Really, someone has to figure out a cheap way to manufacture NRH. 

 

 

 

 

Edited by SearchHorizon, 02 February 2020 - 04:38 PM.

[johnross47]

I was looking at it ten minutes ago on Google scholar. Brenner is one of the names.

[Fredrik]

I posted about NRH, another paper, back in April. Take a look if you want to read more about reduced NR:

 

https://www.longecit...ro-and-in-vivo/

[SearchHorizon]

I posted about NRH, another paper, back in April. Take a look if you want to read more about reduced NR:

 

https://www.longecit...ro-and-in-vivo/

In that thread, it was a bit unclear whether NRH could be orally administered. In the paper ciated in the OP, it appears that oral administration of NRH works well.

[Harkijn]

Even more powerful than plain NR, that really would be something!

Where Carles Canto is involved, the invention will be owned by Nestle. So it's Nestle that probably will move toward a human safety trial.

When this news came out this was dr. Brenner's take on things:

https://twitter.com/...950211843244033

[SearchHorizon]

BTW, the data from the paper is intriguing - it seems to resolve many issues that were discussed in this forum regarding NR.

 

(1) In one of the threads related to NR, there was a huge discussion on whether NR is absorbed intact through the gut. There was a paper which clearly demonstrated NR is cleaved into NAM and ribose (in mice/rat gut). This is likely the case, because oral NR administration results in a large amount of NAM in the liver, which is consistent with the view that NR is absorbed as NAM and ribose. Any minute amount of NR detected in the liver, some speculated, was from recombining NAM and ribose by the liver. There was other evidence in support of this theory - but essentially, this theory was never refuted.

 

(2) in the paper linked above on NRH, at the liver, a first pass NAM does not show up - but rather NR shows up. This suggests that NRH is absorbed directly at the gut as NR or NRH. Once it is absorbed, then it is free to be converted into NAD. This explain why we don't see much first-pass NAM after NRH absorption. In other words, the NRH bypasses the above, potential problem with NR abosportion at the gut.

 

(3) There are two well known benefits of raising NAD levels. ((A) NAD works like a gear mechanism for translating stress into adaptive response (a famous paper by Sinclair's group showed this); and (2) increased DNA repair through PARP and extend life.

 

For the latter benefit, the NAD level has to rise sufficiently high to increase DNA repair. However, it was unclear if orally administered NAM provided enough NAD conversion.  If you administer NAM, its life-extending effects appear to be smaller than NR (which suggests there is not enough DNA repair). This also raises the question whether NR is sufficient to raise NAD level for the optimum life extension.

 

Since NRH results in much larger NAD increases in different tissues than NR, we avoid the preceding problem of not enough NAD conversion. That is, NRH should have MUCH stronger life-extending effect than NR.

 

(4) There is one more issue regarding SIRT1 inhibition with NAM (or NR). I don't think this is a real issue. Perhaps we can discuss this in another thread.

 

-----------------------

 

The bottom line - NRH suggests huge potential benefits, as it address the major issues with NR and NAM + R.

 

 

[SomethingClever]

Why so coy about (4), @SearchHorizon? You have me curious!

[Harkijn]

 

 

This also raises the question whether NR is sufficient to raise NAD level for the optimum life extension.

 

Thanks for this summary SearchHorizon.

 

What are optimal NAD levels? We just don't know. They go through a diurnal cycle and have been surmised to be tissue-specific. In some of these tissues NR seems to raise NAD.

Just for the record I want to mention that we all want optimum life extension but that noone sofar thinks that NR causes optimal NAD levels which putatively would subsequently lead to optimal life extension.

It will take some  time before this additional NR comes to the market but I join you in hoping they move fast forward!

[SearchHorizon]

Thanks for this summary SearchHorizon.

 

What are optimal NAD levels? We just don't know. They go through a diurnal cycle and have been surmised to be tissue-specific. In some of these tissues NR seems to raise NAD.

Just for the record I want to mention that we all want optimum life extension but that noone sofar thinks that NR causes optimal NAD levels which putatively would subsequently lead to optimal life extension.

It will take some  time before this additional NR comes to the market but I join you in hoping they move fast forward!

There are studies that show babies have around 8 (some milli moles per liter or something). By age 20, this falls to about 2.7. And by age 50 and beyond, this falls to about 1.

 

I'm at 55. To have the NAD of 20-30 year old, I need to at least double or triple my NAD+ levels in tissues and in plasma. It appears that NRH may allow one to reach those levels, without introducing NAM (at this point, let's not worry about sustaining those levels over time - NAD levels vary over 24 hrs).

 

The study used 500 mg/KG. The dosage conversion factor from mice to humans is about 12. This gives about 42 mg/KG. I weight 180 lb, which leads to about 3.5 g per day. This is most likely the UPPER limit. 

Edited by SearchHorizon, 03 February 2020 - 06:14 PM.

[SearchHorizon]

Why so coy about (4), @SearchHorizon? You have me curious!

Nothing mysterious. It is just that I don't have enough information.

 

But basically, it appears that after NAM becomes methylated (for elimination) and turns into Me-NAM, it appears to turn into a SIRT1 promoter. If anything, it seems to enhance the effects of SIRT1. This seems consistent with the reported beneficial effects of oral NAM - but I don't have enough evidence to be reasonably certain.