Further Discussion about what form of vitamin B3/NAD to consume

If you have comments with references to contribute, send an email to ordman@beloit.edu, SUBJ: NAD

From LPI: 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.

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.

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 for the following:

  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 SIRT1deacetylates FOXO3 and/or FOXO4, thus attenuatingFOXO-induced apoptosis and potentiating FOXO-induced cell-cycle6. Because 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.