It’s been well-established in the scientific literature that the compound NAD+ (nicotinamide adenine dinucleotide) is vital for life as we know it, facilitating energy metabolism, DNA repair, cell survival, and much more. We also know that NAD+ levels tend to decline dramatically with age, contributing to age-related disease.
Fortunately, experiencing low NAD+ levels with age is not a hopeless cause—there are several ways to elevate NAD+ to support healthy aging. One such way is with NAD+ precursors, namely nicotinamide riboside (NR).
In this groundbreaking preclinical study, researchers uncover a previously unknown action of NR involving an enzyme called CD38, which has adverse health effects when overexpressed—the most prominent being that it depletes NAD+.
In addition to acting as a precursor to boost NAD+ levels, this study shows that NR also reduces CD38 activity, preventing NAD+ depletion before it occurs. With this “dual-action” potential, NR may be your best bet for supporting NAD+ from all angles.
In this article, learn more about the results of this exciting study, the key takeaways for your health, and the best ways to support your NAD+ levels today.
The ABCs of CD38
First things first—what is CD38, exactly?
Standing for “cluster of differentiation 38,” CD38 is a molecule that can act as an enzyme or a receptor. Some of the main functions of CD38 are immune system regulation, cell migration, and the release of inflammatory cytokines.
The primary enzymatic role of CD38 is the conversion of NAD+ into molecules called cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR). We need cADPR to regulate calcium signaling—a crucial component of cell division, neurotransmitter release, muscle contraction, and more.
Although CD38 has important functions, it has negative effects when overexpressed—which could occur often since elevated CD38 is seen with increasing age, impaired mitochondrial health, and pro-inflammatory states.
CD38 is a major consumer of NAD+ and is known as an “NAD-depleting enzyme.” Essentially, CD38 needs NAD+ for the many cellular processes and conversions in which it plays a role, so NAD+ gets depleted when CD38 is more active.
Preclinical research has shown that mice without active CD38 genes (“CD38 knockout mice”) have greater NAD+ levels, better mitochondrial function, and protection against metabolic conditions and becoming obese.
Therefore, balancing CD38 can restore its activity to normal levels, where it can still function without depleting NAD+ and causing adverse health effects.
Novel Study Finds NR Reduces CD38 Activity, Protecting NAD+ Stores
In this new preclinical study, researchers from the University of Southern California explored the effects of NR on CD38—and to their surprise, NR was found to inhibit CD38.
Past research has shown that CD38 enzymatically breaks down both NAD+ and NMN (nicotinamide mononucleotide), another NAD+ precursor—but it does not act on NR because of structural differences between the compounds.
To test NR’s inhibitory effects, the researchers incubated CD38 with NR or NMN in various conditions, including at room temperature, on ice, and overnight. Unexpectedly, CD38 with NR added showed no enzymatic activity, indicating that NR inhibits the enzymatic breakdown ability of CD38.
They then compared the differences between NR and NMN on CD38 enzymatic activity, finding that CD38 broke down less than 1% of NR after 2 hours. Conversely, 100% of both NAD+ and NMN were fully converted within 2 hours to nicotinamide and ADPR, and nicotinamide and ribose-5′-phosphate, respectively. These results support the idea that NR itself is a CD38 inhibitor.
So, why does NR inhibit CD38 but not NMN? It comes down to NR’s chemical structure. First, CD38 will not break down NR because NR does not have the same 5’-phosphate group that NMN has.
Second, NR forms a stable bond with a glutamate residue on CD38’s active site. Enzymes like CD38 have active sites where substrates can bind and facilitate reactions. A glutamate residue commonly acts as a catalytic amino acid—meaning it speeds up enzymatic reactions—to facilitate reactions at the active site.
Essentially, NR was able to bond to the glutamate residue of CD38, inhibiting CD38 from doing its enzymatic job of breaking down NAD+.
With this novel physiological role of NR uncovered, NR can be considered a “dual action” compound. This means that NR not only promotes the synthesis of NAD+ by acting as a precursor but can help prevent NAD+ depletion before it occurs by inhibiting CD38.
However, due to the preclinical nature of this study, more research is still needed to verify its results, especially in humans.
“Clickable” NR Analog Probe Binds and Labels CD38 in Real Time
A second part of this study created a specialized and “clickable” NR-based probe that allows scientists to perform real-time imaging and labeling of CD38 in live cells. While your first thought with “clickable” might be related to hyperlinks and websites, in this case, it refers to “clicking” two molecular blocks together (think Legos).
This innovative probe utilizes a field called “click chemistry,” which is used to selectively label or image proteins for their identification or quantification.
The research team created a clickable analog of NR (5′-N3-NR) that can bind to CD38 while also penetrating cell membranes.
This process lets scientists attach detectable tags on CD38 through click chemistry reactions and fluorescent dyes. Essentially, the NR analog probe can label and image CD38—both inside and outside of cells—in real time, allowing researchers to better study CD38 in living cells.
Increasing NAD+ Levels With Niagen® NR
Now that we know that NR can support NAD+ levels by promoting its biosynthesis and preventing its degradation, you may wonder what is the most effective NR.
Niagen®, the key ingredient in Tru Niagen®, is a patented form of NR, and the most well-researched, efficient, and safety-reviewed NAD+ precursor on the market. But don’t just take our word for it—check the receipts with over 30 clinical studies demonstrating the safety and efficacy of Niagen® and how it effectively raises NAD+ levels.
Over 30 clinical studies in humans, alongside partnerships with over 200 esteemed institutions—such as the Mayo Clinic, National Institute on Aging, and Harvard, to name a few—underscore the credibility of Niagen®. Notably, over 65% of ongoing or completed nicotinamide riboside trials use Niagen®, underlying its safety and efficacy. Further, 94% of peer-reviewed, published studies using Niagen® are third-party-funded and investigator-driven, supporting its credibility and trustworthiness.
To name just a few, research has shown that Niagen supports heart health in healthy middle-aged and older adults, modestly improves body composition and metabolic rate in healthy obese adults, and impacts muscle mitochondrial biogenesis in humans.
Key Takeaways
- A new preclinical study uncovered a novel physiological role of NR, in that NR inhibits the enzyme CD38.
- CD38 degrades NAD+, and its age-related overexpression can be a key contributor to low NAD+ levels with advancing age that impact health.
- This study shows that NR can be considered a “dual action” compound, as it promotes the synthesis of NAD+ by acting as a precursor while also preventing NAD+ depletion before it occurs (by inhibiting CD38 activity).
- With these doubly beneficial abilities, NR can help to maintain NAD+ levels, translating to support for aging cells, metabolic function, and resistance to age-related diseases.
- Second, the actions of the “clickable” NR analog is another exciting finding, providing scientists with a new tool to study the effects of CD38 in health and disease states.
- One of the best ways to boost NAD+ levels to support healthy aging and longevity is with Niagen®, a patented form of NR and the key ingredient in Tru Niagen®.
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