A new study suggests that NAD+, which declines with age, may be increased via the de novo pathway.
What is NAD?
Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. 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.
Boosting NAD+ through the de novo pathway
The level of NAD+ available to a cell is dictated by the amount available versus the amount being consumed to fuel the various cellular processes it facilitates. There are a number of pathways through which NAD+ can be produced, including the de novo synthesis pathway, which begins with the most basic building block, the amino acid tryptophan (Trp).
There has also been great interest in the other pathways to creating NAD+, such as via the NAD+ precursor molecules nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), but new research suggests that the de novo synthesis pathway may also be a potential target when it comes to replenishing the age-related loss of NAD+.
Previous research has shown that mutations to the genes that convert Trp to NAD+ via the de novo pathway result in congenital malformations in both mice and humans . They also showed that niacin supplementation during gestation prevented these malformations in mice. Niacin is another way for the body to produce NAD+ and, like NR and NMN, is an NAD+ precursor. This study showed that taking niacin was sufficient in mice to prevent the congenital malformations that would otherwise occur due to the disruption of the de novo pathway.
The new study shows how NAD+ levels are maintained in the cell and also how enhancing the de novo pathway protects against disease. The research team studied α-amino-β-carboxymuconate-ε-semialdehyde (ACMS), a metabolic intermediate responsible for breaking tryptophan down and taking it a step further down the de novo pathway to ultimately become NAD+. ACMS can also be degraded by the presence of the enzyme α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), which essentially limits the amount of NAD+ available via the de novo pathway. This ACMSD-based limit has been observed in nematode worms, mice, and humans.
When the researchers blocked the gene responsible for expressing ACMSD in nematodes, they saw an increase in de novo NAD+ synthesis, sirtuin 1 activity, and improved mitochondrial function. They also demonstrated that blocking ACMSD in mouse liver cells increased NAD+ levels and improved mitochondrial function.
Next, they tested ACMSD inhibition in two mouse models: mice with diet-induced fatty liver disease and mice with acute kidney injury. Given that the liver and kidney are known to heavily express ACMSD, the researchers wondered if blocking ACMSD might lead to a positive health outcome in both of these diseases, so they created an ACMSD-inhibiting drug . The team confirmed that treatment with their ACMSD inhibitor protected against both diseases in the mice.
These results also suggest that boosting NAD+ synthesis via the de novo pathway may be enough to address liver and kidney diseases linked to low NAD+ levels. However, to determine that will require further study and a demonstration that the benefits are due to an increase of NAD+ rather than other interactions caused by blocking ACMSD.
Given that NAD+ precursors like NR, NMN, and niacin may not be as efficient as we might wish for boosting NAD+ levels, the de novo pathway presents another potential avenue to achieve this. Inhibiting ACMSD to enhance this pathway, and thus increase NAD+, warrants further study as an alternative to NAD+ precursors.
 Shi, H., Enriquez, A., Rapadas, M., Martin, E. M., Wang, R., Moreau, J., … & Sugimoto, K. (2017). NAD deficiency, congenital malformations, and niacin supplementation. New England Journal of Medicine, 377(6), 544-552.
 Pucci, L., Perozzi, S., Cimadamore, F., Orsomando, G., & Raffaelli, N. (2007). Tissue expression and biochemical characterization of human 2‐amino 3‐carboxymuconate 6‐semialdehyde decarboxylase, a key enzyme in tryptophan catabolism. The FEBS journal, 274(3), 827-840.