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Shelly Albaum

Editor, Science of NAD

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  • Shelly Albaum

Why Not Raise NAD by Inhibiting CD38?

Updated: Dec 6, 2022

If the problem is that the enzyme CD38 is chewing through all your NAD, it seems intuitive to want to plug the leak, to turn off the CD38.


Indeed, many substances can suppress the activity of CD38, and when they do, NAD levels go up. And those increased NAD levels have shown positive impacts. But don't uncork the champagne just yet...


CD38 - Friend or Foe? Diagram of CD38 molecule

Suppressing Enzymes That Consume NAD


If NAD levels are running low, there are two basic strategies to consider: Increasing supply and reducing demand. When we talk about replenishing NAD with NAD precursors, we are talking about increasing supply, different ways to increase your body's ability to synthesize NAD.


But there is another approach that is just as logical, which would be to cut demand, to reduce your body's use of NAD. Then, instead of wasting NAD on things that you don't need, more NAD will be available for the things that you do need.


The culprit driving down your NAD levels turns out to be an enzyme called CD38:


We demonstrated that levels and activity of CD38 increase during aging, and that this enzyme is, at least in part, responsible for the age-related NAD decline. For example, genetic ablation of CD38 protects against age-related NAD decline and mitochondrial dysfunction...


Mice engineered to overexpress CD38 have lower levels of NAD+ and exhibit age-related mitochondrial dysfunction


CD38 is the tempting target here, because it is the enzyme that is chewing through NAD faster than your body can make it, probably due to chronic inflammation. We don't want the inflammation, so we don't want the CD38, so why not just turn off the CD38, and then chronic inflammation won't result in chronic NAD deficits?


It can be done. There are a number of substances that will suppress the activity of CD38, and some of them are natural flavonoids, like Quercetin, Apigenin, Luteolin, Luteolinidin, and Kuromanin that you can buy on amazon. So not only do we have studies on this, but we also have humans experimenting on themselves -- it's easy to do!


But maybe not wise.


So Why Not Suppress CD38?


The good news, is that inhibiting NAD-degrading enzymes does raise NAD levels. The bad news is that we don't know much about the potential negative side-effects. Specifically, we don't know whether the CD38 is using up NAD in order to accomplish something important that we don't want stopped.


Here's what the science says. First, inhibiting CD38 does work. It does raise NAD levels:


Several CD38 inhibitors have been developed or are being developed, because the enzyme is one of the main drivers of age-related NAD+ decline. In mice, luteolin, a flavonoid, inhibits CD38, increases NAD+ levels and protects the myocardium and endothelium following myocardial ischaemia. In a clinical trial, luteolin had neuroprotective properties in children with autism. Apigenin, another flavonoid inhibitor of CD38, increased NAD+ levels in human cells and mouse tissues. It also improved lipid and glucose homeostasis in a mouse model of obesity. In a more recent study apigenin was found to not only inhibit CD38 but also lower the expression level of the enzyme. In the kidneys of diabetic rats apigenin increased the intracellular ratio of NAD+/NADH and mitochondrial antioxidative enzyme activity was enhanced. The compound 78c, a derivative of 4-aminoquinoline, inhibits CD38 and in mice increased the NAD+ levels in heart, liver and muscle. Treatment of mice with 78c prevents NAD+ decline during ageing, and old mice treated with the compound exhibited improved muscle function, reduced DNA damage and ameliorated metabolic dysfunction. It has also been shown that 78c protects against postischemic endothelial and cardiac myocyte injury in mice...



Expression of CD38 in various tissues is remarkably elevated with aging, and NAD consumption is also accelerated in correlation with CD38 levels. In contrast, CD38 deficiency in mice eliminates NAD decline during aging


BUT, scientists urge a large dose of caution before suppressing CD38:


Before any of these inhibitors are used in clinical trials, their mechanism of action should be elucidated. In addition, it will be important to determine if they cause any deleterious side effects.


CD38 inhibition would likely have unforeseen effects, as it is a highly complex molecule capable of numerous functions


Inhibition of CD38 may also result in a deleterious impact on immunological function. CD38/cADPR also signals oxytocin release, which regulates many social behaviors, and inhibiting this process may induce several forms of mental impairment... In addition, CD38 plays an important role in the immune system, and knockout of CD38 has been shown to increase susceptibility to bacterial infection.


For example, CD38 levels are elevated in some types of cancer, so eliminating CD38 might slow cancer progression. However, other types of cancer require NAD pools for the cancer to grow, and CD38 might be starving the cancer of NAD and thus slowing the cancer's growth:


Therapeutic strategies that target CD38 activity would likely be effective in solid tumors in addition to hematologic malignancies like multiple myeloma. The exception to this may exist for those tumor types which require increased NAD+ pools for metabolic needs like fatty acid and lipid synthesis, as described in prostate cancer.


Conclusion


In sum, CD38 inhibition likely would provide some benefit, but also likely would involve some risks:


The therapeutic potential of these NAD analog inhibitors may be limited due to the inhibitory effect they may have in several other NAD dependent enzymes, which raises concerns about their specificity. Thus, these “non-specific” effects may limit their in vivo applicability.

Until we better understand the risks associated with inhibiting NAD-0consuming enzymes, it might be safer and more prudent to increase the supply of NAD by replenishing with NAD precursors rather than to reduce demand for NAD.

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