Introduction: The NAD+ Drain No One Talks About
While NAD+ precursors like NMN and NR have gained popularity in anti-aging research, there’s a lesser-known but equally critical factor that influences NAD+ availability in the body: CD38. This enzyme isn’t just a passive player; it’s a key contributor to the age-related decline in NAD+ levels.
CD38 acts as a cellular “NAD+ consumer,” and its activity increases with age, inflammation, and oxidative stress. Understanding CD38—and how to manage its activity—is essential for anyone looking to optimize cellular energy, DNA repair, and healthy aging.
1. What Is CD38?
CD38 is a multifunctional enzyme found on the surface of many immune and inflammatory cells. Its main function is to break down NAD+ into nicotinamide and other byproducts. Unlike NAD+-consuming enzymes like sirtuins (which play a positive role in DNA repair), CD38 is primarily a degradative enzyme.
- Function: Hydrolyzes NAD+ and other nucleotides
- Location: Expressed in immune cells, especially macrophages and B-cells
- Byproducts: Nicotinamide, cyclic ADP-ribose (cADPR)
2. Why CD38 Increases With Age
As we age, low-grade inflammation becomes more common—a phenomenon known as inflammaging. CD38 is upregulated in response to pro-inflammatory signals such as TNF-alpha and IL-6.
Scientific Data: A 2016 study in Nature Communications showed that CD38 expression increases up to 4-fold in aging tissues, including liver and muscle, and accounts for over 50% of NAD+ consumption in older mice.
3. How CD38 Depletes NAD+ Reserves
NAD+ is a limited resource in cells. When CD38 activity increases, it directly competes with beneficial NAD+-dependent enzymes like sirtuins and PARPs.
| Enzyme | Function | NAD+ Usage |
|---|---|---|
| Sirtuins | DNA repair, longevity genes | Constructive |
| PARPs | DNA damage response | Constructive |
| CD38 | Breaks NAD+ into byproducts | Destructive |
Impact:
- Reduced mitochondrial function
- Impaired energy production
- Accelerated cellular aging
4. CD38 and Chronic Diseases
High CD38 levels are associated with:
- Age-related metabolic decline
- Type 2 diabetes
- Neurodegenerative diseases (e.g., Alzheimer’s)
- Chronic inflammation and immune exhaustion
Clinical Relevance: Studies show that inhibiting CD38 can restore NAD+ levels, improve insulin sensitivity, and enhance mitochondrial activity in aged models.
5. Can CD38 Be Inhibited?
Yes. Several natural and synthetic compounds can reduce CD38 expression or activity:
- Apigenin: A flavonoid found in parsley and chamomile; inhibits CD38 in vitro
- Quercetin: A polyphenol with potential CD38-suppressing properties
- Resveratrol: May indirectly modulate CD38 through SIRT1 activation
Emerging Research: Pharmaceutical CD38 inhibitors are under development, particularly in oncology and aging fields.
Conclusion: CD38—A Hidden Obstacle to Longevity
If you’re supplementing with NMN or NR but not seeing optimal benefits, CD38 could be the reason. This enzyme plays a major role in depleting NAD+ levels as we age, limiting the effectiveness of many longevity strategies.
Combining NAD+ precursors with CD38 inhibitors like Apigenin may offer a smarter path to long-term cellular resilience.