Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. As an important cofactor, it is involved in fundamental biological processes, namely metabolism, cell signalling, gene expression, and DNA repair, among others. It is a dinucleotide, which means that it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide.

 

In metabolism, NAD facilitates redox reactions, carrying electrons from one reaction to another. This means that NAD is found in two forms in the cell; NAD+ is an oxidizing agent that takes electrons from other molecules in order to become its reduced form, NADH. NADH can then become a reducing agent that donates the electrons it carries. The transfer of electrons is one of the main functions of NAD, though it also performs other cellular processes, including acting as a substrate for enzymes that add or remove chemical groups from proteins in post-translational modifications.

 

NAD+ metabolite and its derivatives are fundamental orchestrators of daily homeostasis in our tissues. The relative amounts of NAD forms (NAD+, NADH, NADP, and NADPH) and their cofactor functions to drive metabolism to either catabolic or anabolic direction, deciding whether nutrients are broken down to synthesize ATP, the cellular energy currency, or used as building blocks for growth and repair. The different NAD forms, their ratio and derived metabolites regulate lipid, nucleotide, glutathione synthesis, and membrane homeostasis. An increased NAD+/NADH ratio is a signal for a low nutrient state activating cellular fasting responses. These responses have been associated with health benefits and longevity. Not surprisingly, NAD+ metabolism has been a key interest of aging biology and therapeutic strategies for degenerative diseases.

 

NAD+ is created from simple building blocks, such as the amino acid tryptophan, and it is created in a more complex way via the intake of food that contains nicotinic acid or other vitamin B3 related NAD+ precursors. These different pathways ultimately feed into a salvage pathway, which recycles them back into the active NAD+ form. 

The depletion of NAD+ has been proposed to promote aging and degenerative diseases in different organisms. Its roles in the context of longevity, aging, and disease are under intense investigation, both in model organisms as well as in humans. NAD+ also activates sirtuins, a family of proteins that repair our DNA and regulate cellular homeostasis. Sirtuins are NAD dependent, they can’t function properly without it. Each time our cells divide, the caps on the ends of our DNA strands become a little bit shorter; this fraying and shortening damages our DNA, but sirtuins act to reduce this process by stabilising these caps, or telomeres. Studies in mice show that feeding them the NAD+ precursor NMN can elongate telomeres, offsetting the risk of damage to their DNA.

 

In summary: numerous studies indicate NAD+ levels decrease significantly during aging, with restoration of NAD+ levels in aged animals extending lifespan and promoting health. NAD+ levels can be increased by:

  • activating enzymes that stimulate synthesis of NAD+,
  • inhibiting an enzyme (CD38) that degrades NAD+,
  • supplementing with NAD precursors, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN)

 

Currently, supplementation with NAD precursors (mainly NMN or NR) is considered a viable and highly efficient strategy of increasing NAD+ levels. What are the differences between all these NAD+ precursor molecules?

 

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