NAD+ Production Pathways
Given low cellular NAD+ is one of the major causes of aging and the physical symptoms associated with it, boosting NAD+ is increasingly becoming a therapeutic target - not just to reduce the signs of aging itself but also for tackling the long term conditions associated with aging such as neurodegenerative and cardiovascular diseases.
However, the biology associated with NAD+ production and depletion in the body is complex; NAD can be made from five different precursors via three different pathways involving a number of enzymes. NAD can also be recycled, degraded and switched between its oxidised (NAD+) and reduced (NADH) states. Furthermore, the NAD molecule itself is, in most biological scenarios, too large to pass into the cell. This means the body relies primarily on the cell making NAD+ itself.
Understanding the cell’s different NAD+ production mechanisms and the ways in which they interact with each other has, therefore, become a critical approach to addressing the symptoms and condition associated with aging.
Precursors to NAD+ Production
An NAD precursor can be thought of as the raw material that is used by the body to make NAD+. There are 5 different precursors that the body can use to make NAD+:
Tryptophan
Nicotinic acid (NA)
Nicotinamide (NAM)
Nicotinamide riboside (NR)
Nicotinamide mononucleotide (NMN)
Whilst structurally different, nicotinic acid and nicotinamide are collectively known as niacin. Niacin is also known as vitamin B3.
NAD precursors can enter 3 main biological pathways that convert the precursors into NAD+:
The salvage pathway
The Preiss-Handler pathway
The de novo pathway (sometimes known as the Kynurenine pathway)
The Salvage Pathway
The salvage pathway is considered to be the primary source of cellular NAD+ production. It can utilise a range of precursors (NAM, NR or NMN) and it enables the cell to efficiently recycle waste products into new NAD+. Importantly, it is the salvage pathway that is most associated with the way in which youthful cells generate higher levels of NAD+.
NAD+ is used up in the cell in order to activate proteins that are essential to functions such as energy production, DNA repair and immunity. When NAD+ is used up in the cell it gets broken back down into the precursor nicotinamide (NAM). The salvage pathway is able to recycle this nicotinamide as a precursor for further NAD+ production – without the need to access any additional precursor ingredients. It does this via an enzyme called NAMPT. NAMPT is, therefore, incredibly important in the body’s NAD+ production.
However, NAMPT declines with age and this has a direct and significant impact on the salvage pathway; the cell’s youthful ability to efficiently recycle NAD+ deteriorates with age. Furthermore, if nicotinamide is not recycled via the salvage pathway, the cell must excrete it through a process called methylation to avoid a build-up within the cell. This means that this potential precursor for further NAD+ production is discarded.
Increasing NAMPT is, therefore, critical to restoring the cell’s youthful ability to produce NAD+.
The Preiss-Handler Pathway
This pathway begins with the precursor nicotinic acid which is converted to nicotinic acid mononucleotide (NAMN) by an enzyme called nicotinic acid phosphoribosyltransferase (NAPRT).
This NAMN (and also NAMN from the de novo pathway) is then converted into nicotinic acid adenine dinucleotide (NAAD) by a family of enzymes called the NMN adenylyl transferase enzymes (NMNATs). There are three of these enzymes (NMNAT1-3) which are found in different parts of the cell. Finally, NAAD is converted to NAD+ by an enzyme called NAD+ synthase (NADSYN).
The De Novo Pathway
In the de novo pathway, NAD+ is synthesised from tryptophan which undergoes a series of reactions to form quinolinic acid. Quinolinic acid is then converted to nicotinic acid mononucleotide (NAMN) which enters the Preiss-Handler pathway (see above) to complete its conversion to NAD+. This method of NAD+ synthesis occurs primarily in the liver and kidneys and makes only a minor contribution to NAD+ production.
Given these different pathways, the interactions between them and the range of elements involved it has become clear that NAD+ production is, in fact, a complex network which demands an approach that considers the system as a whole.
Find out more about a Whole System Approach to Boosting NAD+.