Why It's Important to Methylate While Taking Nicotinamide Riboside
Supplementation with nicotinamide riboside (NR), a vitamin B3 analog, has been demonstrated to increase mitochondrial numbers and benefit mitochondrial function, which ultimately increases NAD+ and the cellular energy molecule ATP.*
NAD+ levels decline with aging and stress.
NAD+ is also used by the body’s enzymes that help protect our cells, including the sirtuin enzymes that help us age healthfully. And when our cells are damaged, another set of enzymes called PARPs kick in to repair the damage. But PARPs use a lot of NAD+ as well. Luckily, we can increase our NAD+ levels in several ways. In addition to NR supplementation, NAD+ levels are increased by physical exercise. Caloric restriction can also increase the amount of NAD+ in our blood and tissues.
Clinical studies on NR supplementation have shown that it can increase NAD+ and ATP,1-3 with trends toward supporting blood pressure regulation and blood pressure elasticity, both of which are elements of desirable cardiovascular health.3* Supplementation of NR in animal studies has shown decreased fat accumulation in skeletal muscle and support for insulin regulation,4* although human studies have not yet seen these results.
With many positive benefits of NR supplementation now being elucidated, one topic has been mostly ignored in the research – the effect of NR supplementation on methylation.*
Although NAD+ is used by the body to create ATP, NAD+ is also metabolized to a methylated nicotinamide molecule, l-methylnicotinamide (MeNAM).*
Why is this important? Much research has been conducted on methylation, and I have written about it here and in other publications during the last two decades. Methylation is the transfer of a methyl group (one carbon and three hydrogens) from one molecule to another in the body and is a fundamental element of our biochemistry.
The methylation process creates neurotransmitters, antioxidants, and many other important substances in the body.*
- Coenzyme Q10
- Nitric Oxide
Optimal methylation also helps detoxify numerous undesirable substances in the liver and in our tissues, including estrogen and neurotransmitters.*
The process of metabolizing NAD+ stresses the “methyl pool,” the molecules that donate methyl groups. A methyl group needs to be added to NAD+ to create MeNAM, which uses up methyl groups that are needed for other biochemical reactions.
One study looked at the effect of eight weeks of NR supplementation on MeNAM and found significant increases in this metabolite in the blood and urine.*1 Although this isn’t bad, we need to be aware that in some individuals, especially those with either genetic or lifestyle issues that inhibit normal methylation, this might inhibit the methylation of other substances.
Many individuals in the United States – some estimates are as high as 60% – have a genetic defect in a critical enzyme involved in methylation – MTHFR.
MTHFR is the enzyme that creates active folate from inactive folic acid in food and supplements. Individuals with this genetic defect can have a significantly decreased ability to methylate substances.
This situation can result in an increase in the amino acid metabolite homocysteine, a decrease in the creation of the above-mentioned amino acids and other important molecules, and subsequent decreased detoxification.
A clinical study of niacinamide supplementation showed not only an increase in MeNAM, but also an increase in homocysteine levels, which is an independent risk factor for heart disease.*
This study also showed a decrease in the detoxification of two neurotransmitters.5 Unlike the niacinamide study, a study of nicotinamide riboside detected no increase in homocysteine after NR dosing.1 These inconsistent results might be due to genetic SNPs in susceptible individuals, which was not tested in either study.
These research results are why Thorne adds betaine (trimethylglycine) to our ResveraCel product. Betaine contains three methyl groups that can be donated to methylation processes. With betaine, and the sirtuin and NAD+ cofactors resveratrol and quercetin phytosome, ResveraCel is the most effective and safest premier NAD-promoting product on the market.*
- Conze D, Brenner C, Kruger C. Safety and metabolism of long-term administration of NIAGEN (Nicotinamide Riboside Chloride) in a randomized, double-blind, placebo-controlled clinical trial of healthy overweight adults. Sci Rep 2019 Jul 5;9:9772.
- Airhart S, Shireman L, Risler L, et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS One 2017;12:e0186459.
- Martens C, Denman B, Mazzo M, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD(+) in healthy middle-aged and older adults. Nat Commun 2018;9:1286-1297.
- Cantó C, Houtkooper R, Pirinen E, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 2012;15:838-847.
- Sun W, Zhai M, Li D, et al. Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels. Clin Nutr 2017;36:1136-1142.