If you’ve been interested in the longevity world for a while, you’ve likely got the main acronyms down by now, from NAD+ to NR to NMN. However, a lesser-talked-about molecule also involved in healthy aging is CD38—an enzyme that depletes NAD+ stores when elevated. Unlike many other longevity-related compounds, CD38 is one that we may want to reduce. But what exactly is CD38, and how does it affect cellular health, aging, and NAD+ stores? Keep reading to learn that and more, including how to inhibit CD38 and why we should.
What is CD38, and What Does It Do?
CD38 (“cluster of differentiation 38”) is a molecule that can act as an enzyme or a receptor, primarily involved with immune functioning, cellular signaling, and energy metabolism. It’s most often found on the surface of immune cells—like T-cells, B-cells, and natural killer cells—but has also been detected inside cells, such as in the mitochondria.
The roles of CD38 are wide-reaching, including modulating immune cell differentiation, regulating cell recruitment, and promoting the release of pro-inflammatory compounds called cytokines during immune responses. Due to this activity with immune activation, CD38 is often used as a biomarker for studying immunity.
Another enzymatic role of CD38 is its ability to convert NAD+ (nicotinamide adenine dinucleotide) into a molecule called cyclic ADP-ribose (cADPR). We need cADPR to regulate calcium signaling—a crucial component of cell division, neurotransmitter release, muscle contraction, and more.
In addition to acting as an enzyme, CD38 is a receptor in cell-to-cell interactions, facilitating processes like cell adhesion, tissue repair, and signaling pathways between immune cells.
However, one of CD38’s most relevant roles in the longevity world is its relationship to NAD+—let’s take a closer look at this connection.
CD38 and NAD+: What’s the Link?
NAD+ is a vital coenzyme needed by all human cells for energy metabolism, DNA repair, cell survival, and so much more. CD38 is a major consumer of NAD+ in mammalian tissues, making it an “NAD-depleting enzyme.”
This is because CD38 needs NAD+ for the many cellular processes it plays a role in—meaning that NAD+ gets depleted when CD38 is more active. As mentioned, one of CD38’s enzymatic roles is converting NAD+ into cADPR (as well as ADP-ribose and nicotinic acid adenine dinucleotide phosphate or NAADP).
While these cellular processes are normal, overexpression or hyperactivity of CD38 can drain NAD+ levels, which are already depleted with age. Studies show that NAD+ can drop by as much as 65% between ages 30 and 70.
Low NAD+ levels are implicated in several age-related disorders, and excess CD38 activity with age can be one cause of this decline. Research has shown that CD38 is required for the age-related loss of NAD+ and mitochondrial dysfunction, two essential factors of accelerated aging.
In addition to aging increasing CD38 activity, pro-inflammatory states—such as infection, illness, excess body fat, metabolic dysfunction, and most chronic conditions—also trigger an overexpression of CD38.
Preclinical research with animals has found that mice without any CD38 activity exhibit greater NAD+ levels, have better mitochondrial function, and are protected against metabolic conditions and becoming obese.
However, it’s important to note that CD38 isn’t all “bad”—it’s only harmful when overactive. Therefore, balancing CD38 activity through inhibition can help it function at normal levels to support immune responses, cell signaling, and metabolic processes without overly depleting NAD+ and contributing to aging.
Can NR Inhibit CD38?
One way to counteract the adverse effects of CD38 overactivity is through NAD+ precursors, including NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide). These molecules can restore some of the lost NAD+, helping to support cellular processes like DNA repair, signaling, and energy production.
Clinical studies have shown that NR successfully elevates NAD+ levels in the blood or skeletal muscle in populations of overweight adults, healthy middle-aged and older adults, and men in their 70s. Due to this elevation of NAD+, trials with oral NR supplementation have suggested that NR supports heart health and brain health.
As NAD+ precursors, NR and NMN can reverse some of the NAD+ pool depletion that occurs with excess CD38 activity. However, another strategy is to reduce CD38 activity to help preserve NAD+ levels before they drop.
Studies have shown that flavonoid antioxidants—like quercetin in onions, apigenin in chamomile, and luteolin in parsley—can inhibit CD38, leading to more balanced expression. Now, a new preclinical study is the first to show that nicotinamide riboside (NR) also acts in this way.
In this novel study, researchers found that NR inhibited CD38 by forming 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 bonded to the glutamate residue of CD38, inhibiting CD38 from doing its enzymatic job of breaking down NAD+.
With these groundbreaking results, NR can be considered a “dual-action” compound that both enhances NAD+ production (by acting as an NAD+ precursor) and balances CD38 activity, helping to preserve NAD+ stores.
What Causes Low NAD+ Levels?
CD38 isn’t the only thing that depletes NAD+. In addition to overactive CD38, some of the main reasons that humans can experience declining NAD+ levels include:
- Aging: Advancing age is the most well-known link to NAD+ loss. With age, NAD+ production declines concurrent with elevated NAD+ consumption (such as from CD38 and other enzymes).
- DNA Damage and Repair: High amounts of DNA damage require enzymes called PARPs to repair it. PARPs are also NAD+-consuming enzymes, further depleting NAD+ stores. We accumulate more DNA damage with age, UV radiation, smoking, environmental toxin exposure, and oxidative stress, requiring more PARPs (and therefore more NAD+) to make repairs.
- Metabolic Dysfunction: Impaired metabolic function (including dysfunctional glucose metabolism) is another pro-inflammatory state that depletes NAD+ and causes oxidative stress.
- Diet and Lifestyle Factors: Ultra-processed foods, high-sugar foods, excessive alcohol, excess body weight, sedentary lifestyle, and chronically poor sleep can all play a role in reduced NAD+ production and poor mitochondrial health.
Overall, there are many factors that contribute to low NAD+ levels, some of which are out of our control (like growing older), while others are well within our abilities to manage. One of the most thoroughly researched ways to support NAD+ stores is with precursors like NR—and the most well-studied form of NR is TruNiagen®.
The key ingredient in Tru Niagen® is a patented form of NR with the strongest clinical backing for its safety and effectiveness in raising NAD+ levels. Over 30 human clinical studies, alongside collaborations with over 200 renowned institutions—such as the Mayo Clinic, National Institute on Aging, and Harvard, to name a few—underscore the credibility of Niagen®. Plus, over 65% of ongoing or completed nicotinamide riboside trials use Niagen®, underlying its safety and efficacy.
Key Takeaways
- The main functions of CD38 are immune system regulation (including immune cell activation, proliferation, and survival), cell migration, release of inflammatory cytokines, and the enzymatic conversion of NAD+ into cADPR and others for calcium signaling processes.
- CD38 is inherently neither good nor bad. Rather, it has adverse effects when overexpressed, with the most prominent being NAD+ depletion.
- Elevated CD38 occurs with age, poor health, impaired mitochondrial health, metabolic dysfunction, and pro-inflammatory states.
- Balancing CD38 can balance its activity to normal levels, where it can still function in immune roles without depleting NAD+.
- A new preclinical study shows that NR is able to inhibit CD38 by binding to its active site.
- NR may now be considered a dual-action compound in that it both boosts NAD+ levels by acting as a precursor and inhibits CD38 to prevent NAD+ depletion before it occurs.
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