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Might NAD+ Precursors Exacerbate Inflammatory Disease?

nicotinamide riboside nicotinamide nampt autoimmune disease colitis

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#31 stefan_001

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Posted 24 September 2017 - 08:33 PM

Hi Michael, interesting study indeed. Wrt SIRT1 I understood the study to suggest that increased NAMPT leads to signalling causing SIRT1 down regulation:
-Increased Nampt and NF‐κB p65 expression and decreased Sirt1 expression in response to HG conditions over time.

And that NMN not only activates SIRT1 via more NAD+ as is usually shown but also:
-The results indicated that NMN was able to activate Sirt1 by inhibiting the Nampt pathway.
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You're misreading either my post, or the first study, or both: when I say, above, "The study in the opening post found that FK866, an inhibitor of NAMPT, inhibited inflammation [...] with evidence that it worked via inhibiting levels and activity of the NAD+-dependent enzymes PARP1 AND CD38 (both previously implicated in inflammation) as well as and multiple sirtuins (most profoundly SIRT6, but also a rather striking effect on SIRT1), surprisingly," note that I am referring to "the study in the opening post," which indeed did find:

FK866 impairs mucosal NAD recycling resulting in a dampened PARP/SIRT-mediated inflammatory response ... FK866 reduced mucosal abundance of various SIRT (online supplementary figure 3A) during intestinal inflammation with the most pronounced effect on Sirt6 (figure 4B,D). Again this was paralleled by a markedly decreased enzymatic function as measured by deacetylase activity (figure 4C).

Their supplementary figure 3A shows that SIRT1 protein levels are more than doubled in DSS-IBS mice vs. water-treated non-IBD controls, and FK866 reduced it down even below that control baseline. (Quantitation of immunoblots is a soft science, but that's a very large and obvious effect).


Both those quotes come from the Chinese study. I was only writing about that one. But that SIRTs appear more active as result of NAMPT upregulation in your opening post cited study is rather different than the chinese study statements which seem counter intuitive.In the abstract it says this:

The present results demonstrate that the expression of vimentin and fibronectin was directly implicated in endogenous Nampt upregulation. The expression levels of Poly(ADP‑ribose) polymerase‑1, NF‑κB p65, forkhead box protein O1 and B‑cell lymphoma 2‑like protein 4 were also significantly increased at 96 h compared with control group (P<0.01) respectively in response to endogenous Nampt upregulation. Furthermore, the expression level of Sirt1 was significantly reduced (P<0.05)

When you say:
And that NMN not only activates SIRT1 via more NAD+ as is usually shown but also:
-The results indicated that NMN was able to activate Sirt1 by inhibiting the Nampt pathway.
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... those are results from the second, Chinese study, which does report to the contrary that NMN was able to increase gene expression of Sirt1 in association with decresed expression of NAMPT. (Despite their sloppy use of language, they provide no data on "activation" (increased activity) of SIRT1 — just increased gene expression). So that's another oddity in all of this. I would certainly trust protein levels more than gene expression readouts, which can always be nullified posttranslationally.

I wondered about that too.

stefan_001 wrote: Or?

I have read couple studies indicating that during aging the salvage effectives goes down and there is compensation via increased NAMPT. So perhaps we are seeing here a NMN specific anti aging effect via direct signalling pathway leading to more sirt1 apart fom the nad+ boosting.

All the studies I've seen show either no effect of aging on NAMPT (Chini & Sinclair) or downregulation (Imai, Radak, and importantly Miao, which as you spotted the other day gives the first human data on this question in addition to more mouse data, finding a "decrease of NAD+ content in livers from elderly patients compared with those from middle-aged patients and found that the NAMPT-mediated NAD+ salvage pathway, but not indolamine 2,3-dioxygenase (IDO)-mediated NAD+ de novo pathway, was impaired in livers from elderly humans compared with those from middle-aged patients." One caution is that these are all "patients" with either hepatolithiasis or hepatocellular carcinoma, rather than otherwise-healthy aging people. Still, even among patients, the levels were down with age.

Agree,seems I have some dyslexia when writing english should say "compensation via increased NAMPT in disease".

I am aware of no proposed mechanism or data to support a role for NMN in controlling SIRT1 expression, and the only role of which I'm aware for NMN in SIRT1 activity is via NAD+. Are you aware of any such?

No I am not but I am wondering whether NMN supplementation can really supply enough NAD+ to overcome a downregulating feedback loop which has increased NAMPT to fuel SIRTs and other processes. And if so does it require continuous dosing.

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stefan_001 wrote: then again that only makes sense if the NMN adds more NAD+ than is reduced by the NAMPT inhibition. Unless the path of action is still different and that NMN blocks the NAMPT pathway that inhibits SIRT1 without actually inhibiting NAMPT. Mmmm...
I agree with your first sentence; I'm not clear on what you're suggesting with the second, but their entire thesis is that NMN is providing product inhibition of the NAMPT enzyme, and support that with expression data.
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The second part is just more speculation, would there be a mechanism where NAMPT controls SIRT1 expression that does not go via NAD+? Reason is as I wrote earlier: I am wondering whether NMN supplementation can really supply enough NAD+ to overcome the downregulating feedback loop in a situation of higher NAMPT to fuel SIRTs and other processes.
Perhaps it can but again in that case does it mean that one should use NMN or NR more in a continuous way to keep NAMPT downregulated during the entire day.


Overall somewhat contradictory situations:

1) In the chinese study the NMN / NR supplementation appearently downregulates NAMPT which has the consequence that SIRT comes up and that would mean more netto NAD+ (as there are no other known mechanisms)

2) In your opening post study I could imagine that the NMN / NR supplementation also downregulates NAMPT but that could only lead to SIRT coming down to more normal levels if the supplementation provides less netto NAD+



ofcourse different situations different effects. Or then sometimes NAD boosting is good and sometimes harmfull. How do you see that?

Edited by stefan_001, 24 September 2017 - 09:25 PM.

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#32 sthira

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Posted 25 September 2017 - 04:26 AM

I am getting tired arguing. Each person has a different understanding based on the same data. If you keep chasing your own tails it will never ends. NR and NMN are the holy grails of anti aging. This statement will end my discussions about the validity of NR in this forum.

The more I read into longevity science the more I realize that my ignorance is increasing faster than my knowledge.

For everything I learn, two things appear that I didn't know. The number of things I don't know is growing faster than the things I think I know.

That's the game for all of us, dude, like it or not.

It's when we think we "know" -- that is when we've probably got it all wrong. Biology is way too tangled up to simplify it all into this one clean path, as if one commodity Vitamin/Drug (Chromadex, of course, shrewdly wants NR to be both) will now save millions of lives from the vast complications of aging to death.
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