CD38 and the Age-Related Decline in NAD+: How It Degrades NAD+ and NMN

NMN, or nicotinamide mononucleotide, has attracted attention as a precursor of NAD+, a coenzyme whose levels decline with aging. Several human clinical trials have reported physiological effects of NMN supplementation¹・²・³・⁴, and the evidence base continues to develop. Declining NAD+, the molecule that NMN is used to replenish, is closely related to several of the 12 biological processes described in the AGING HALLMARKS framework.

Precursor

A substance used by the body as a raw material to produce another molecule; NMN can be converted into NAD+.

As evidence on NMN accumulates, an important question has emerged: How efficiently are supplemented NMN and the resulting NAD+ maintained in the body? One enzyme central to this question is CD38. CD38 increases with aging and can degrade not only NAD+ but also NMN, its precursor. This article reviews the functions of CD38, why it increases with aging, and how these findings add a new perspective to research on NMN supplementation.

What You Will Learn

• What CD38 is and why it increases with aging
• Three mechanisms through which CD38 affects NAD+ and NMN metabolism
• The feedback loop connecting senescent cells, chronic inflammation, and CD38
• Preclinical research on the inhibition of CD38 by plant-derived flavonoids
• Two complementary research perspectives: replenishing NMN and limiting CD38-mediated degradation

What Is CD38?

CD38, or cluster of differentiation 38, was originally identified as a protein on the surface of immune cells⁵. Research has since shown that CD38 functions as an NAD+-degrading enzyme in immune cells, adipose tissue, the liver, and other tissues.

When CD38 breaks down NAD+, it produces molecules including nicotinamide. Because nicotinamide can be reused as a substrate for NAD+ synthesis, CD38-mediated degradation is also part of normal NAD+ metabolism.

Nicotinamide

A form of vitamin B3 corresponding to the “N” in NMN.

During NAD+ degradation, CD38 also produces signaling molecules involved in immune-cell activation and regulation of inflammation. CD38 therefore lowers NAD+ while also performing physiological functions in immune and inflammatory signaling⁶.

Several processes contribute to age-related NAD+ decline, including consumption by PARPs, which participate in DNA repair, and reduced expression of NAMPT, an enzyme required for NAD+ synthesis. CD38 has attracted particular attention because its capacity to consume NAD+ increases several-fold with aging.

CD38 Increases With Aging

In 2016, Dr. Camacho-Pereira and colleagues at Mayo Clinic reported an important finding⁷. In mice, CD38 protein abundance increased two- to threefold across multiple tissues with aging, and the researchers identified this increase as a major contributor to declining NAD+. A similar pattern was observed in human adipose tissue: comparison of samples from people with mean ages of approximately 34 and 61 years found up to a 2.5-fold increase in CD38⁷.

In mice genetically lacking CD38, age-related NAD+ decline was largely prevented, and mitochondrial function remained closer to that of younger animals. This study was the first to identify CD38 as a major driver of age-related NAD+ decline and accelerated subsequent research on CD38 and aging.

Mitochondria

Cellular structures that generate energy.

How, then, does CD38 reduce NAD+ and NMN?

Three Mechanisms Through Which CD38 Affects NAD+ and NMN

Research indicates that CD38 intervenes in NAD+ metabolism through at least three mechanisms.

1. Direct Degradation of NAD+ Through NADase Activity

The best-known function of CD38 is its ability to degrade NAD+ directly. CD38 hydrolyzes NAD+ into products including nicotinamide⁵. This reaction directly consumes the cellular NAD+ pool.

Hydrolysis

A reaction in which water is used to break a chemical bond.

2. Extracellular Degradation of NMN Through Ecto-Enzyme Activity

In 2020, Dr. Chini and colleagues at Mayo Clinic published a study in Nature Metabolism focusing on CD38 as an ecto-enzyme—an enzyme that acts on the outer surface of a cell⁸.

The study showed that CD38 increases on the surface of immune cells with aging and degrades NMN outside cells. In this way, CD38 can consume not only NAD+, the final product, but also NMN, one of its precursors.

3. A Base-Exchange Reaction With NMN, Reported in 2025

In 2025, Dr. Madawala and colleagues at the University of New South Wales reported a previously unrecognized reaction catalyzed by CD38⁹.

Catalysis

Acceleration of a chemical reaction by a catalyst.

The researchers found that CD38 can replace the nicotinamide moiety of NMN with nicotinic acid, converting NMN into NaMN, or nicotinic acid mononucleotide, through a base-exchange reaction. NaMN can serve as a substrate for NAD+ synthesis through the Preiss–Handler pathway. Recent research has also shown that orally consumed NMN can be metabolized through this pathway by the gut microbiome.

This finding indicates that CD38 does more than simply destroy NMN. It can also rewrite the chemical structure of NMN within tissues, producing a different metabolite. How this conversion affects the final efficiency of NAD+ production remains to be determined.

Base-exchange reaction

A chemical reaction in which one part of a molecule, known as a base, is replaced by another. In this case, the nicotinamide in NMN is replaced by nicotinic acid.

Three CD38-Mediated Routes Affecting NAD+ and NMN

1. Direct degradation of NAD+ through NADase activity
2. Extracellular degradation of NMN through ecto-enzyme activity
3. Conversion of NMN into NaMN through a base-exchange reaction

Why CD38 Increases With Aging: A Cycle of Inflammation and Cellular Senescence

Once CD38 had been identified as a major contributor to NAD+ decline, another question followed: Why does CD38 increase with aging? Research points to senescent cells and chronic inflammation.

SASP From Senescent Cells Promotes Accumulation of CD38-Positive Immune Cells

Two important studies published in Nature Metabolism in 2020 examined this mechanism⁸¹⁰.

Senescent cells accumulate with aging and release inflammatory cytokines, including IL-6 and TNF-α, through the senescence-associated secretory phenotype, or SASP. These inflammatory signals induce CD38 expression on macrophages and other immune cells, promoting the accumulation of CD38-positive macrophages in adipose tissue and the liver.

SASP

The senescence-associated secretory phenotype, in which senescent cells release inflammatory and other signaling molecules into surrounding tissue.

Cytokines

Signaling molecules that regulate inflammation and immune responses.

Macrophages

Immune cells that engulf and process pathogens, damaged cells, and other material.

Removing senescent cells reduced CD38 expression and partially restored NAD+ levels in experimental models⁸.

Chronic Inflammation, Increased CD38, and Declining NAD+

Taken together, the findings suggest a feedback loop in which chronic inflammation increases CD38, higher CD38 accelerates NAD+ consumption, and lower NAD+ contributes to further loss of cellular and tissue function.

Breaking this cycle may require not only supplying NAD+ precursors but also limiting degradation.

A New Perspective on NMN Supplementation From CD38 Research

Because CD38 is a major enzyme that degrades NAD+ and NMN, researchers are investigating the hypothesis that suppressing CD38 might allow NAD+ to be maintained more efficiently.

Research on CD38 Inhibitors

In 2018, Dr. Tarragó and colleagues developed a synthetic compound called 78c that selectively inhibits CD38 and tested it in aged mice¹¹. Treatment restored tissue NAD+ levels and improved several age-sensitive physiological measures, including glucose tolerance, muscle function, exercise capacity, and cardiac function.

Glucose tolerance

The body’s capacity to regulate blood glucose after glucose intake.

This study provided important preclinical evidence that CD38 inhibition may influence age-related metabolic dysfunction. It did not establish efficacy or safety in humans.

Plant-Derived Flavonoids: Apigenin and Quercetin

Alongside synthetic compounds, research has identified CD38-inhibiting activity in naturally occurring plant compounds.

In 2013, Dr. Escande and colleagues at Mayo Clinic found that the plant-derived flavonoids apigenin and quercetin inhibited CD38 NADase activity¹².

Flavonoids

A class of polyphenolic compounds found in plants.

• Apigenin is found in plants including chamomile, edible chrysanthemums, parsley, and celery. In obese mice, apigenin suppressed CD38 activity, increased hepatic NAD+ levels, and improved glucose and lipid metabolism¹².
• Quercetin is found in onions, broccoli, apples, and other foods. Cell studies found that it inhibited CD38 and increased intracellular NAD+ in a dose-dependent manner¹². Quercetin has also shown anti-inflammatory effects, raising the hypothesis that it might influence chronic inflammation upstream of CD38 induction¹³.

These flavonoids generally act more mildly than synthetic inhibitors and have a history of dietary exposure. However, the doses used in experimental studies may exceed the amounts available from an ordinary diet. Whether food intake alone can inhibit CD38 sufficiently remains unknown.

NMN Combined With CD38-Inhibiting Compounds

These findings suggest two complementary perspectives for understanding NMN supplementation.

NMN supplies a precursor for NAD+. However, supplemented NMN and newly produced NAD+ may be degraded by the higher levels of CD38 associated with aging. Researchers have therefore proposed combining NMN to increase supply with CD38-inhibiting compounds to reduce degradation as a potential strategy for maintaining NAD+ more efficiently.

Two Complementary Perspectives

NMN: Supplies a precursor for NAD+ and may increase input.

Apigenin and quercetin: May inhibit CD38 and reduce NAD+ consumption.

Combining these approaches could potentially maintain NAD+ more efficiently, but this hypothesis requires clinical testing.

A 2026 animal study reported that combined administration of NMN and apigenin improved muscle function and bone density and reduced markers of cellular senescence in aged mice more effectively than either treatment alone¹⁴. These findings suggest that precursor supplementation and reduced degradation may act additively in mice. They do not demonstrate the same effect in humans.

Understanding CD38 as a major consumer of NAD+ provides an additional perspective on NMN research. The possibility of modifying CD38 with naturally derived compounds remains an active preclinical research area.

Summary

Age-related NAD+ decline is associated with several aspects of aging. Over the past decade, research has identified CD38, an enzyme that increases with aging and inflammation, as a major contributor to this decline.

CD38 directly degrades NAD+, degrades NMN outside cells, and can convert NMN into NaMN through a base-exchange reaction. Research is also clarifying a feedback loop in which senescent cells and chronic inflammation increase CD38, accelerating NAD+ loss.

These findings suggest that research on NMN supplementation should consider both increasing the supply of NAD+ precursors and reducing CD38-mediated degradation. Plant-derived flavonoids such as apigenin and quercetin are being studied as possible CD38 inhibitors. However, most evidence for this strategy is preclinical, and effective doses, safety, and benefits in humans remain to be established.

Foods such as parsley, celery, onions, and broccoli contain flavonoids and can form part of a balanced diet. It is not yet known whether ordinary dietary intake inhibits CD38 enough to produce measurable effects on NAD+ in humans.

References

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