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SUBJ: THE CONCLUSION THAT CURRENT RESEARCH SUPPORTS TAKING BOTH NIACIN AND RESVERATROL ON A DAILY BASIS

READER QUESTION: Resveratrol and niacin supplements may have antagonistic effects. Is it wise to take both? Roc’s answer: This is a complicated question, for which I studied the literature and asked experts’ advice. The conclusion is that most research currently supports taking both reservatrol and niacin supplements on a daily basis.

DISCUSSION AND EVIDENCE THAT BROUGHT THE CONCLUSION

FIRST STATEMENT: Reader’s question: Thanks for looking at this and replying if you have any thoughts.  This is the first time I have sent a request like this, but it is a great question. “Like you I supplement with niacinamide 500 mg daily but now after reading this extract from the article published by LONGEVITY MEDICINE REVIEW, the full article is in the link below, I am wondering whether my use of this  supplement is counterproductive as I have recently started supplementing Resveratrol to help with sirtuin activity. 
 Extract -- Nicotinamide, produced by sirtuin enzymes in their use of NAD+ in deacetylation, is a potent inhibitor of their activity—a seemingly instantaneous feedback loop. It has been estimated that physiological concentrations of nicotinamide are sufficient to reduce basal Sirt1 activity in mouse cells by up to 20-fold.5  (Nicotinamide [a.k.a. niacinamide] is the form of niacin sometimes used as a supplement because it does not cause flushing, but it also does not reduce cholesterol,  most likely because it is an inhibitor of sirtuin activity. These issues are further discussed below in the section:  
Nicotinamide inhibits sirtuin activity by re-entering the enzyme’s catalytic site immediately after its release. There, nicotinamide combines with a reaction intermediate (an ADP-ribose peptide-imidate complex), which—via the salvage pathway—is used in the regeneration of the original acetylated lysine and NAD+ Link -- http://www.lmreview.com/articles/view/resveratrol-niacin-nicotinamide-riboside-key-players-in-activating-sirtuins-to-mimic-calorie-restriction-extend-lifespan-part-i/
SECOND STATEMENT: ROC RESPONSE:
Wow. Heavy duty explanation with a lot of delightful biochemistry.  Attached are the key sentences that I extracted to contemplate.  Then, on to whether to take vitamin B3 supplements.  The reason I began taking them was an article I shared from reading, which stated as one ages, one becomes much worse at absorbing B3, so cells are deficient in it. Here is the report in Science recently:
Science 17 June 352: 1396: Boosting NAD+ levels in mice, and likely in older people, improves respiration, stem cell maintenance, tissue preservation, and inhibits aging pathways.
As niacin is water-soluble, the body will excrete what it does not require.  In particular, the NAD+/NADH ratio is the critical factor in the sirtuin activation, and that would depend on good nutrition and staying in good athletic condition.
So my first very tentative conclusion, esp. based on the Science article, is to continue with my niacin supplements.  But I will eventually send out a special news notes announcement, to see if any of the many readers/experts that read it will have any comments.
Thanks so much. 
Roc
THIRD STATEMENT: FM: gerry

The high-cytosolic NAD+ levels would then stimulate the Sirt1 deacetylation of the FOXOs and PGC-1α, thus causing the induction of mitochondrial biogen-esis , thus decreasing mitochondrial oxidative stress.


Should one take niacin and resveratrol?
1. Nicotinamide, produced by sirtuin enzymes in their use of NAD+ in deacetylation, is a potent inhibitor of sirtuin enzyme activity. Nicotinamide inhibits sirtuin activity by re-entering the enzyme’s catalytic site immediately after its release. There, nicotinamide combines with a reaction intermediate (an ADP-ribose peptide-imidate complex), which—via the salvage pathway—is used in the regeneration of the original acetylated lysine and NAD+ 

2.  physiological concentrations of nicotinamide are sufficient to reduce basal Sirt1 activity in mouse cells by up to 20-fold.

3.  Boosting NAD+ levels in mice, and likely in older people, improves respiration, stem cell maintenance, tissue preservation, and inhibits aging pathways.

4. As niacin is water-soluble, the body will excrete what it does not require.  In particular, the NAD+/NADH ratio is the critical factor in the sirtuin activation, and that would depend on good nutrition and staying in good athletic condition.

5. During the glycolytic conversion of glucose to pyruvate, cytosolic NAD+ is reduced to NADH. The high-cytosolic acetyl-CoA generated from the pyruvate via mitochondrial citrate would drive not only hi-stone acetylation but also FOXO and PGC-1α acetylation, inactivating these proteins. Mammalian SIRT1 deacetylates FOXO3 and/or FOXO4, thus attenuatingFOXO-induced apoptosis and potentiating FOXO-induced cell-cycle 
 
6. Be-cause the Sirt1 deacetylase cannot use NADH as a substrate, the acetylated FOXOs and PGC-1α would remain inactive, thus downregulating mitochondrial biogenesis and OXPHOS and shifting metabolism toward glycolysis.

By contrast, oxidation of fatty acids or ketones occurs entirely within the mitochondrion. The mitochondrial acetyl-CoA would still be exported to the cytosol via citrate to acetylate histones and stimulate transcription. However, only the mitochondrial NAD+ would be ac-tively reduced to NADH, leaving the cytosolic NAD+ more oxidized.

The high-cytosolic NAD+ levels would then stimulate the Sirt1 deacetylation of the FOXOs and PGC-1α, thus causing the induction of mitochondrial biogen-esis , thus decreasing mitochondrial oxidative stress.

Thanks to a distinguished reader at the Center for Molecular and Mitochondrial Medicine and Genetics and Departments of Biological Chemistry, Ecology and Evolutionary Biology, and Pediatrics, University of California at Irvine, Irvine

FOURTH STATEMENT: To Gerry: After reading your kind response, I am trying to simplify the explanation for me and others.  It seems to me the key phrase is "The high-cytosolic NAD+ levels would then stimulate the Sirt1 deacetylation of the FOXOs and PGC-1α, thus causing the induction of mitochondrial biogenesis , thus decreasing mitochondrial oxidative stress."

This would indicate that insuring an adequate supply of NAD+ via niacin supplements is likely to favor increased healthspan, as mitochondrial health is critical.

Granted that all of these hypotheses are based on simple assumptions - which I have favored throughout my research career - it is worthwhile to take  resveratrol and niacin supplements simultaneously.
Thanks, Roc

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