NAD Supplements: Myths and Misconceptions - Methyl Donor Depletion

If you have decided to take an NAD+ supplement or believe your clients will benefit from one, the differences between supplements with respect to methylation is a useful consideration when choosing the right intervention. More specifically, if you already use NAD+ precursor supplements, you may be concerned about methylation. This article explains methylation, the differences between supplements and the approach to take to remove the risk of methylation.

DNA Methylation is essential to Gene Expression

If you are familiar with NAD+ supplements such as NR or NMN, then you have likely heard of the methylation problem associated with them. Methylation is a simple reaction that attaches a ‘methyl group’ onto its target. The substance giving up a methyl group is called the ‘methyl donor’ and the molecule gaining the methyl group is ‘methylated’.

DNA methylation is a form of epigenetic regulation – changing the way the cells translate the DNA without changing the DNA code. It most commonly occurs at cytosine residues (one of the four DNA building blocks). Protein methylation also occurs during biochemical reactions. Methyl groups are added onto the protein, particularly lysine and arginine amino acids. The purpose of methylation is to alter gene or protein expression, based on the needs of the cell at that time.

As with all substances in the body there are optimal levels of methyl donors. Unfortunately, with certain NAD+ supplements there is concern surrounding methyl donor depletion.

The method by which cells remove waste Vitamin B3 (niacin, NR and NAM) is to methylate them signaling that they are ready for excretion. These methylated waste products are found in the blood plasma and urine.

Methylation Donor Depletion: is it an issue?

There has been speculation that consuming high concentrations of vitamin B3 can lead to build up of excess products which require methylation to be secreted. This high level of methylation can lead to a lack of methyl donors for other important methylation reactions.

Therefore, several publications will recommend taking a methyl donor supplement (such as tri-methyl glycine, TMG) alongside NR or NMN.

If you take NAD+ precursors such as NR or NMN alone, then methyl donor depletion can be a concern. This is because simply taking a precursor does not address the cause of the NAD+ decline in aged cells.

Precursor Accumulation is only a problem in Damaged Cells

The accumulation of NAD+ precursors is only a problem if the cell cannot convert these to NAD+. In older cells which cannot manufacture NAD+ efficiently anymore, pumping in more precursor can lead to methyl donor depletion. These cells consume and waste lots of NAD+ via enzymes such as PARPs and CD38.

Furthermore, they are unable to produce high levels of NAD+ as the biggest source of NAD+, the salvage pathway is not functioning optimally. The NAMPT enzyme powers the conversion of waste products from the cellular breakdown of NAD+ into fresh new NAD+ that can be used by the cell. As we age the levels of NAMPT in our cells decline. Overall, older cells cannot make as much NAD+ whilst also consuming much greater levels of NAD+.

Therefore, to prevent vitamin B3 accumulation and methyl donor depletion the underlying issues within the cell need to be addressed. By supplying the cell with NAMPT we can repair the salvage pathway, enabling the cell to utilize these precursors. Once the salvage pathway is fixed any NAD+ precursor added to the cell doesn’t hang around for very long, it is used up and converted into NAD+. Reducing the need for methylation. Combining this approach with inhibition of the enzymes that waste NAD+ can lead to a long-term sustainable NAD+ boost.

There are a multitude of products which claim to boost cellular NAD+ and we now know that the risk of methylation associated with taking precursors such as NR and NMN alone can be an important consideration.

Find out more about removing the risk of methylation by fundamentally restoring the cell’s ability to manufacture and recycle NAD.

References;

• Imai, S. I. (2009). Nicotinamide phosphoribosyltransferase (Nampt): a link between NAD biology, metabolism, and diseases. Current pharmaceutical design, 15(1): 20-28.  

  Bogan, K. L., & Brenner, C. (2008). Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr., 28: 115-130. 

  MacKay D, Hathcock J, Guarneri E. (2012) Niacin: chemical forms, bioavailability, and health effects. Nutr Rev. 70(6):357-66