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Roadmap to boosting cellular NAD+ without NR, NAR, NMN, NAM, NA or l-tryptophan

parp nampt cd38 ampk

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#1 Fredrik

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Posted 15 August 2019 - 03:09 PM


My proposal for a theoretical natural supplement that boosts cellular NAD+ synthesis by NAMPT and AMPK activation and PARP and CD38 inhibition without NR, NAR, NMN, NAM, NA or l-tryptophan. I say theoretical because I´m not planning on taking any of these five until they´re proven safe and proven to enhance health in humans.
 
These five can be supplemented with an adequate (currently unknown) dose of one or several NAD+ precursors targeting the Preiss-Handler, De Novo synthesis and salvage pathways. These could be NR, NMN, NAR, NA and l-tryptophan. 
 
What would you add?
 
1. Troxerutin
2. Grape-seed proanthocyanidins
3. Leucine
4. Apigenin
5. Quercetin
 
(and I would perhaps add 1 g resveratrol in the morning and 1 g extended-release metformin in the evening)
 
 

NAD+ biosynthesis augmentation by NAMPT activation and PARP inhibition

 

1. Troxerutin 

A trihydroxyethylated derivative of the natural bioflavonoid rutin, markedly increased NAD+ levels and potentiated SIRT1 via NAMPT activation and PARP1 inhibition in HFD-treated mouse liver.

“Troxerutin improves hepatic lipid homeostasis by restoring NAD(+)-depletion-mediated dysfunction of lipin 1 signaling in high-fat diet-treated mice.”
https://www.ncbi.nlm...ubmed/25026599/
 

2. Grape-seed PACs (proanthocyanidins)
PACs significantly increased the hepatic NAD+ content by modulating the hepatic concentrations of the major NAD+ precursors as well as the mRNA levels of the genes that encode the enzymes involved in the cellular metabolism of NAD+. Sirtuin 1 (Sirt1) gene expression was also significantly up-regulated in a dose-response pattern. 

“Dietary proanthocyanidins boost hepatic NAD(+) metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats.”
https://www.nature.c...icles/srep24977

“Dietary proanthocyanidins modulate BMAL1 acetylation, Nampt expression and NAD levels in rat liver”
https://www.ncbi.nlm...les/PMC4603780/
 
PARP inhibition
Troxerutin and proanthocyanidins also inhibit PARPs in mice, thereby contributing to increased NAD+ in tissues.
 
 
AMPK activators
 
AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.
https://www.ncbi.nlm...ubmed/19262508/
 
 
3. Leucine
Addition of leucine to high fat diet correlated with increased expression of SIRT1 and NAMPT (nicotinamide phosphoribosyltransferase) as well as higher intracellular NAD(+) levels.

"Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice."
Decrease NAD+ catabolism
 
CD38 inhibition
 
 
4. Apigenin
“Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome.”
https://www.ncbi.nlm...ubmed/23172919/

“Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38”
https://www.ncbi.nlm...les/PMC3609577/
 
 
5. Quercetin
Blocking CD38 with quercetin could significantly relieve kidney dysfunction, kidney pathological changes as well as inflammatory cell accumulation.

“Blockade of CD38 diminishes lipopolysaccharide-induced macrophage classical activation and acute kidney injury involving NF-κB signaling suppression.”
https://www.ncbi.nlm...pubmed/29080804

 
Metformin 
Metformin activates AMPK and increases NAD+ levels by activating the NAD salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT).

SIRT1 was increased through an AMP-activated protein kinase-mediated increase in gene expression of nicotinamide phosphoribosyltransferase, the rate-limiting enzyme of the salvage pathway for NAD(+).

https://www.ncbi.nlm...ubmed/20093281/
 
But, increased NAMPT expression is also reported in some malignancies, calling into question whether increasing NAD+ might support aspects of the tumorigenic process. It´s important to find out if and under what circumstances this may occur. 

https://www.ncbi.nlm...les/PMC3877665/

https://www.ncbi.nlm...pubmed/27186719
 

 


Edited by Fredrik, 15 August 2019 - 03:33 PM.

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#2 Oakman

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Posted 15 August 2019 - 04:47 PM

No need to speculate on a theoretical supplement. I take all on your list except Troxerutin, along with NR, NMN, L-Tryptophan, resveratrol, and more. I would venture others do as well. N=1 studies are alive and on-going as we debate.

 

FYI I'm alive, well, and without negative side-effects. Arguably, I'm better than just well, I'm in excellent health and I'm old to boot. If you want to wait for some study to combine some combo of these, I venture you will wait a long, long, long time... likely forever. And even if if it were to come to pass, however unlikely, it will be years later that any useful results would be released, at best. Depending on how young (old) you are, that may be too late should they be "proven" (whatever that means) to enhance health in humans.

 

Just saying...


Edited by Oakman, 15 August 2019 - 04:49 PM.

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#3 Fredrik

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Posted 15 August 2019 - 05:18 PM

No need to speculate on a theoretical supplement. I take all on your list except Troxerutin, along with NR, NMN, L-Tryptophan, resveratrol, and more. I would venture others do as well. N=1 studies are alive and on-going as we debate.

 

I love speculating on these untried and untested ways to perhaps increase cellular NAD+ in humans. Good to hear that you´ve found something you can put your faith in. And you´re right, when you have beliefs there is no need to speculate about facts. But let those of us that wants to speculate do that.


Edited by Fredrik, 15 August 2019 - 05:26 PM.






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