How is NAD made?

When cells produce NAD+ in the body, scientists refer to this process as "biosynthesis." Two cellular pathways in the cell provide for NAD+ biosynthesis: the de novo synthesis pathway and the salvage pathway.

• The production of NAD

The de novo synthesis pathway begins with an essential amino acid known as tryptophan (abbreviated as Trp). Tryptophan is obtained from foods such as meat, cheese, eggs, and fish. The conversion of tryptophan to NAD+ occurs in the aqueous part of the cell known as the cytoplasm, which is located outside the cell's components (organelles).

The salvage pathway for NAD+ biosynthesis uses naturally occurring vitamins. These vitamins include nicotinamide (NAM), niacin (NA), nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR), with niacin being converted to NAD+ through three steps. In the first step, the enzyme NAPRT converts niacin into nicotinic acid mononucleotide (NAMN). In the second step, the enzyme NMNAT converts NAMN into nicotinic adenine dinucleotide (NAAD). Finally, the enzyme NAD+ synthetase (NADS) converts NAAD into NAD+.

The NAD+ biosynthesis in the salvage pathway involves the conversion of nicotinamide into NMN via the enzyme NMNAT through phosphoribosyl transfer. This enzyme then converts NMN into NAD+.

NR is converted into NMN under the action of the enzyme NRK. NMN is then converted into NAD+ through the enzymatic activity of NMNAT.

 

 

• What is it made of?

NAD+ consists of two nucleotides linked by a phosphate group. One nucleotide contains the adenine nucleobase, while the other contains nicotinamide.

NAD+ Biosynthesis Precursors

Braidy et al. (2019). Chemical structures of NAD+ precursors

NAD+ precursor supplements represent a potential therapeutic strategy to slow aging and improve age-related diseases. It has not yet been proven that oral NAD+ can increase NAD+ levels in the body. However, supplementing with precursors (such as NMN or NR) may provide these benefits.

Research shows that NMN supplementation can prevent various diseases, potentially through the elevation of NAD+ levels in the body. NMN supplementation can reduce obesity and protect blood vessels from damage. These benefits have been observed in mouse disease models for Alzheimer's, cognitive impairment, and neuroinflammation. Supplementing with NR also has similar beneficial effects in mice.

Can these beneficial effects observed in mice be applied to humans? Only clinical trials conducted in humans can confirm this.

During aging, which precursor supplement, NMN or NR, promotes higher levels of NAD+ in the body? The debate among scientists continues.

•Is NAD+ a coenzyme or a cofactor?

NAD+ functions as both a cofactor and a coenzyme. Cofactors are non-protein compounds required for enzyme-catalyzed reactions. Coenzymes are "helper molecules" that assist in biochemical transformations.

NAD+ acts as a cofactor in electron transfer reactions in metabolism. However, NAD+ also serves as a coenzyme when binding to proteins known as Sirtuins. The molecule binds to these proteins and subsequently releases them for further use.

•What happens when NAD+ levels decrease?

Numerous studies have shown that NAD+ levels decrease in states of nutritional deficiency (such as obesity and aging). A decrease in NAD+ levels can lead to metabolic issues. These problems may result in diseases, including obesity and insulin resistance. Obesity can lead to diabetes and hypertension.

Low NAD+ levels can trigger metabolic disorders, and high blood pressure and other declines in heart function can send destructive stress signals to the brain, leading to cognitive impairment.

Targeting NAD+ metabolism is a practical nutritional intervention for preventing metabolic diseases and other age-related conditions. Several studies indicate that NAD+ supplementation can improve insulin resistance caused by obesity. In mouse models of age-related diseases, NAD+ supplementation can alleviate disease symptoms. This suggests that the decline in NAD+ levels with age may contribute to the onset of age-related diseases.

Preventing the decline of NAD+ offers a promising strategy for combating metabolic disorders. As the levels of NAD+ decrease with age, it can lead to reduced DNA repair, cell stress responses, and regulation of energy metabolism.