NAD (Vitamin B3): Benefits and Means of Boosting Levels in the Body

First off what is NAD and why all the rage in the anti-aging supplement arena?

NAD stands for nicotinamide adenine dinucleotide and this molecule (along with its' phosphorylated cousin NADP) is the active form of vitamin B₃ (niacin/nicotinic acid and nicotinamide) that is utilized in well over 500 different biochemical processes in the human body. Niacin and nicotinic acid represent two different terms for the same chemical form of vitamin B₃, whereas nicotinamide represents the modified form containing an NH₂ group. The designation NAD⁺ refers to one of the two oxidation states of the vitamin-derived cofactor, the other being NADH.

For the details on vitamin B₃ uptake from the diet and utilization in the body go to the Vitamins page of my website:

Vitamins: Water and Fat Soluble

As for the anti-aging arena, there is clear evidence that systemic levels of NAD decline with age and this decline is contributory to many age-associated pathophysiologies. As a result of this knowledge of the age-related decline in NAD, coupled with the knowledge of the significant importance of NAD and NADP in the overall biochemical processes of the body, numerous supplements have been developed and touted for their anti-aging potential.

So what is the evidence and what should one be considering as a supplement to their diet, if anything?

Two recent papers in the highly prestigious journal Cell Metabolism review the scientific literature of dietary supplementation with derivatives/precursors of NAD and address the potential clinical benefits:

NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

In the early days of studies involving the role of vitamin B₃ (specifically NAD and NADP) in important biological processes the emphasis was on its roles in biological reduction and oxidation reactions. Those reactions where we obtain energy from the food we eat (biological oxidation reactions) and those where some of that energy is utilized in the production of cellular constituents (biological synthesis reactions). However, the the early 2000's several additional, critically important, processes were shown to require NAD. These included the utilization of NAD⁺ as a co-substrate for enzymes of the sirtuin family and the poly-ADP-ribose polymerases (PARP). Sirtuins and PARP function in processes that include mitochondrial metabolism, inflammation, meiosis, autophagy, apoptosis, transcriptional regulation, RNA biogenesis and processing, DNA damage repair, chromatin remodeling, the unfolded protein response (UPR), and circadian rhythms.

Given that the evidence is quite clear that NAD, derived from vitamin B3, is of paramount importance for normal biochemical and physiological processes, and that the levels of NAD decline with age, it is understandable why there has been such high interest in dietary/supplement mechanisms to raise, and keep high, systemic NAD levels.

Numerous studies have been performed with two intermediates in the pathways of NAD synthesis and salvage to look at their efficacy at raising cellular NAD levels and most importantly their efficacy at preventing or ameliorating some of the pathophysiologies of aging that are related to declining NAD levels. The major intermediates that can be taken orally and contribute to the production of NAD are nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). Details of NAD synthesis and salvage are to be found in the Vitamin B3: Metabolism and Functions page of my website.

NMN is synthesized from nicotinamide through the action of an enzyme called nicotinamide phosphoribosyltransferase (NAMPT). The significance of this enzyme is that it is the rate-limiting enzyme for NAD⁺ biosynthesis. NMN is also synthesized from NR through phosphorylation catalyzed by nicotinamide riboside kinases (NMRKs). The conversion of NMN into NAD⁺ is catalyzed by nicotinamide nucleotide adenylyltransferases (NMNATs). Accumulating evidence demonstrates that systemic administration of NMN does indeed enhances NAD⁺ biosynthesis in a variety of tissues including pancreas, liver, adipose tissue (fat), heart, skeletal muscle, kidney, testis, eyes, and blood vessel (aorta). These increase are observed under both normal and pathophysiological conditions.

The results from these types of studies demonstrate that NMN supplementation could offer broad therapeutic potential. In laboratory animals the administration of NMN exerts profound effects on the pancreas such as enhancement of glucose-stimulated insulin secretion, thereby improving glucose tolerance. These results were seen in both aged and diet-induced diabetic mice, In these experiments it was found that NMN not only enhances insulin secretion but also enhances the actions of insulin. These result indicate a strong likelihood that NMN may have utility as one of the arsenal of drugs for the treatment of type 2 diabetes. Additional studies found that oral NMN administration increased adipose tissue functions and normalized multi-organ insulin resistance. Long-term NMN administration has been shown to suppresses age-associated adipose tissue inflammation and improves whole-body insulin sensitivity. Results of studies on the benefits of NMN administration go well beyond its utility in the treatment of diabetes.

Administration of NR has also been associated with beneficial clinical outcomes. Experimental animals given NR as a dietary supplement were shown to be protected from weight gain, were more insulin sensitive, and had increased mitochondrial content in skeletal muscle and brown adipose tissue compared with untreated animals. Results such as these promoted studies to look at the potential therapeutic benefits to NR administration in a number of muscle disorders. Results of several studies showed that NR improved mitochondrial abundance and function in two different mitochondrial myopathies. The administration of NR also is correlated to survival in an animal model of heart failure. NR administration has also been shown to improve stem cell function and partially relieve the muscle wasting phenotype in a mouse model of muscular dystrophy. NR administration has also been reported to have a number of intriguing benefits in the nervous system.

TAKE HOME MESSAGE: Although this posting represents a brief and superficial overview of the literature surrounding the potential health benefits of dietary supplementation with intermediates in the NAD synthesis and salvage pathways, the evidence is rapidly accumulating. I make no recommendation as to which product one should use but I do suggest that in the search for a healthy diet one should begin to consider the potential significance of adding NAD enhancing supplements.