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A new study suggests that NAD+, which declines with age, may be increased via the de novo pathway. This is potentially interesting as it presents an alternative way in which to elevate NAD+ levels versus the better-known approach of using NAD+ precursors such as NR and NMN.

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 [1]. 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 [2]. 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.

Conclusion

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.

Literature

[1] 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.

[2] 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.

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About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
  1. October 31, 2018

    Great work as usual Steve! Will have to check out your book!

  2. November 1, 2018

    Nice article Steve! Even though I take it, my concern with NR has always been the body’s homeostatic feedback mechanisms causing either a mitigating effect or even a harmful effect via enzyme or receptor up/down regulation when this native biomolecule is exogenously supplied.

    Are there any data to suggest that upregulation of ACMSD represents such a pathway? Has anyone looked at expression during NR supplementation?

  3. June 3, 2019

    Is it safe for Kidney patient to take NR or NMN supplement to boost the NAD+ level? So far, no medical practitioner willing to give the opinion. Just wondering if there is any scientist can give their view of NR & NMN to kidney Patient (for my brother)

    My parents have very positive result after taking NR (my mom @75years old) and NMN (my father @85years) for only 2 weeks.

    Regards
    Danny

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