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The question people following NAD+ research eventually reach

People who have been tracking NAD+ biology for more than a year tend to run into a specific gap in the standard narrative. They understand that NMN and NR raise NAD+ by supplying precursors through the salvage pathway. They may have tried one or both. And then they read something about CD38 — an enzyme that actively consumes and degrades NAD+ — and start wondering whether focusing exclusively on synthesis-side precursors is missing half the problem.

That question is specific enough to be worth taking seriously, and apigenin is where the relevant research leads. Apigenin is a flavone found in parsley, celery, chamomile, and several Japanese culinary herbs. It has received research attention specifically because it inhibits CD38 enzymatic activity in cell and animal models, with downstream effects on NAD+ levels. This article covers what those studies actually show, where the gap to human clinical evidence sits, and what the Japanese dietary connection genuinely looks like.

NAD+ decline and the two sides of the maintenance equation

NAD+ levels in most human tissues appear to fall with age. The decline is documented across multiple tissue types — skeletal muscle, liver, adipose tissue, brain — and is associated with reduced activity of NAD-dependent enzymes including the sirtuin deacylases and PARP DNA repair enzymes that each consume NAD+ as a co-substrate.

The standard commercial approach addresses the synthesis side: NMN and NR provide precursors that feed the cellular pathway that manufactures NAD+. That approach has biomarker support in humans, including data from Yoshino et al. 2021 (Science) and Igarashi et al. 2022 documenting NAD+ elevation in blood following NMN supplementation.

What gets less commercial attention is the consumption side. NAD+ is not simply depleted by cellular metabolism alone — it is actively hydrolyzed by specific enzymes. Among these, CD38 is the most quantitatively significant NADase identified in mammalian tissue to date. CD38 was originally characterized as a surface marker on B cells, NK cells, and plasma cells, but it is expressed broadly across tissue types and carries substantial NAD-hydrolyzing activity that occurs continuously.

The evidence that CD38 contributes to age-related NAD+ decline comes primarily from Camacho-Pereira et al. 2016 (Cell Metabolism), which found that CD38 expression increases substantially in mouse tissues with age and that genetic deletion of CD38 preserved NAD+ levels relative to age-matched wild-type controls. Some human tissue datasets show directionally similar patterns, though the age-related trajectory in human tissues has been characterized less completely than in the mouse models.

What the apigenin research actually shows

The apigenin-CD38 connection was documented in Escande et al. 2013 (Diabetes), which showed that apigenin inhibited CD38 enzymatic activity in cell culture, raised intracellular NAD+ levels in mouse cells, and produced metabolic changes in a diet-induced obesity mouse model — including improvements in insulin sensitivity markers and reductions in hepatic fat accumulation.

A few things deserve to be stated precisely here, because the way this research is often cited in supplement marketing gets several of them wrong:

The cell and animal evidence is real and mechanistically grounded. Apigenin’s CD38 inhibitory activity has been replicated across independent research groups and the biochemical mechanism is reasonably well-characterized. The IC50 values measured in these studies — the concentrations at which half of CD38 activity is inhibited — fall in a range that is at least theoretically relevant to what might be achievable in tissues under supplementation.

Human clinical evidence does not exist. No published randomized controlled trials have tested apigenin supplementation for CD38 inhibition or NAD+ preservation in humans. The jump from mouse model metabolic improvements to human clinical outcomes is not bridged by any controlled human intervention data as of the current literature. This is the most important fact to hold onto when evaluating commercial products in this category.

Oral bioavailability introduces a real translation gap. Apigenin is poorly water-soluble, and its oral absorption in humans is variable and concentration-sensitive. It undergoes substantial first-pass metabolism in the gut and liver, and systemic concentrations achieved from standard oral doses are not well characterized relative to the concentrations used in the in vitro CD38 inhibition research. Whether supplement-level oral doses reach tissue concentrations sufficient to inhibit CD38 to a degree that meaningfully affects NAD+ levels in humans remains unverified.

CD38 has functions beyond NAD+ consumption. CD38 is expressed on immune cells and participates in calcium signaling and immune cell activation. Daratumumab, an anti-CD38 antibody used clinically in multiple myeloma, demonstrates that CD38 inhibition at sufficient levels has measurable immune system effects. Whether commercial apigenin doses achieve immune-relevant levels of CD38 inhibition in healthy adults is not established — but the biology warrants noting before someone assumes supplement-level inhibition is consequence-free.

Japanese foods as a dietary entry point

Apigenin is distributed across a range of plant foods with the highest concentrations in parsley and celery. Several traditional Japanese dietary plants contain meaningful apigenin levels based on food chemistry analyses.

Mitsuba (Cryptotaenia japonica), the herb variously translated as Japanese parsley or Japanese hornwort, is used across a wide range of Japanese cooking contexts — soups, nabemono hot pots, rice dishes, scattered over chawanmushi. Food flavonoid composition analyses have consistently identified mitsuba as a meaningful dietary apigenin source in Japanese food patterns. Unlike European parsley, which appears primarily as a garnish in Western contexts and is rarely eaten in volume, mitsuba appears as a genuine ingredient consumed in substantial amounts in traditional Japanese cooking.

Shiso (Perilla frutescens var. crispa), in both its red and green varieties, contains flavones including apigenin and luteolin. The green shiso in particular is used as a fresh ingredient in Japanese cooking rather than purely decorative — wrapped around grilled fish, sliced into cold tofu preparations, stirred through soba. That usage pattern contributes dietary flavone exposure that differs from garnish-level contact with the plant.

Chamomile tea (Matricaria chamomilla, consumed in Japan as kamitsure or kamomiru) is among the highest-apigenin botanical sources in the food chemistry literature. A brewed cup of chamomile provides measurable apigenin exposure from the flavonoid fraction of the flower heads. Chamomile-based herbal teas are widely available in Japan in both dedicated tea shops and supermarket tea aisles.

Whether cumulative dietary apigenin exposure from these sources reaches concentrations relevant to CD38 inhibition in human tissues is not established. Estimating tissue apigenin concentrations from dietary intake involves multiple uncharacterized steps — gut absorption variability, first-pass metabolism, tissue distribution. What can be said is that habitual consumption of these foods contributes dietary flavone exposure that the typical Western diet does not replicate at comparable levels, within the broader context of a Japanese dietary pattern that carries its own epidemiological associations.

Supplement options and what to evaluate

Commercial apigenin supplements exist primarily as standalone capsule products providing 50–100 mg per serving. A smaller number of NAD+ support formulas combine apigenin with NMN or NR on the rationale that the two approaches address complementary sides of NAD+ maintenance — precursor supply and NADase inhibition. The theoretical basis for that pairing is coherent; whether it produces superior NAD+ outcomes to either component alone has not been tested in any human clinical trial.

For buyers evaluating individual products, a few specifications separate more characterized options from less useful ones:

Source and standardization: apigenin derived from chamomile extract is the most common commercial source. A Supplement Facts panel showing milligrams of apigenin per serving alongside a certificate of analysis confirming that content by HPLC is the minimum useful quality signal. Products that only list “chamomile extract” without specifying apigenin content per serving do not provide the information needed to evaluate dose.

Dose context: commercially available supplements typically provide 50–100 mg per serving. These doses are not derived from dose-ranging human clinical trials for CD38 inhibition — no such trials exist. They represent approximate extrapolations from the in vitro research, adjusted speculatively for human pharmacokinetics. There is no established optimal human dose.

Third-party testing: as with any botanical extract, independent COA documentation covering identity, potency, heavy metals (lead, arsenic, mercury, cadmium by ICP-MS), and microbial contamination is the practical floor for evaluating production quality.

Search apigenin supplement capsules on Amazon — filter for products with explicit apigenin milligram dose on the Supplement Facts panel and available COA documentation.

Search NOW Foods apigenin supplement on Amazon — NOW Foods holds GMP certification and makes COA documentation available on request through their quality team.

Search Life Extension apigenin supplement on Amazon — Life Extension publishes lot-specific COA documentation and has a longer category history in polyphenol supplements.

For readers not yet ready for a standalone supplement: increasing chamomile tea consumption (two to three cups per week), incorporating mitsuba into soups and nabemono, and using shiso as a genuine ingredient rather than a garnish represent low-friction dietary adjustments. Whether these changes affect CD38 activity in human tissues is not established, but they add dietary flavone exposure in a whole-food context alongside other plant compounds that carry their own evidence associations in Japanese longevity diet research.

Interactions and safety considerations

CYP enzyme inhibition: Apigenin inhibits cytochrome P450 enzymes including CYP1A2 and CYP2C9 in cell culture research. CYP1A2 metabolizes caffeine, theophylline, several antidepressants, and antipsychotics. CYP2C9 metabolizes warfarin, certain NSAIDs, and some oral antidiabetic agents. The clinical significance of CYP inhibition at commercial supplement doses in living humans has not been characterized in pharmacokinetic interaction studies. For anyone on these medication classes, discussing apigenin supplementation with a prescribing clinician before starting is the appropriate step.

Aromatase inhibition: Apigenin has been characterized as a weak inhibitor of aromatase (CYP19A1) in cell culture research. Aromatase converts androgens to estrogens; inhibition at sufficient concentrations could theoretically affect circulating estrogen levels. Clinical relevance at commercial supplement doses in humans has not been established in controlled studies, but individuals with hormone-sensitive conditions or on hormone therapy should raise this signal with their clinician.

Antiplatelet activity: Apigenin has shown antiplatelet effects in preclinical models. For anyone taking warfarin, aspirin, clopidogrel, or similar anticoagulant or antiplatelet agents, the mechanistic overlap warrants a conversation with a prescribing physician before combining.

Thyroid considerations: Older animal studies using very high doses identified anti-thyroid effects. The relevance to human supplement doses is not well-characterized, but individuals with thyroid conditions or on thyroid medications should mention apigenin supplementation to their prescribing clinician.

Pregnancy and lactation: No controlled human safety data exists at supplement doses. Standard precautionary avoidance applies.

Active cancer treatment: Flavonoids with CYP-inhibitory activity have an unresolved research history regarding interactions with chemotherapy agents metabolized through the same enzyme pathways. Apigenin-specific data in oncological treatment contexts is absent from published clinical literature. This is a decision for the treating oncologist, not a supplement purchase.

Who should have a clinician conversation before starting

Anyone on multiple medications — particularly warfarin, antidepressants, antipsychotics, or drugs metabolized by CYP1A2 or CYP2C9 — should discuss apigenin supplementation explicitly with a prescribing clinician before starting. The drug interaction profile is not fully characterized in humans, which means the risk is not quantified rather than confirmed absent.

Anyone with a hormone-sensitive condition, active thyroid condition, bleeding disorder, or currently in active cancer treatment belongs in the same category.

For everyone else tracking NAD+ biology and looking for evidence-informed supplement options beyond NMN and NR: apigenin as a CD38 inhibitor is a mechanistically coherent hypothesis grounded in real mouse model and cell biology data. The Escande 2013 Diabetes and Camacho-Pereira 2016 Cell Metabolism papers establish a plausible chain from CD38 activity to NAD+ levels in animal systems. That chain does not extend to confirmed human clinical outcomes — the human evidence base for this specific application currently sits at zero controlled trials.

Engaging with it as an evidence-informed hypothesis, at the doses commercial products provide, with clinician awareness of the drug interaction signals above: that is a reasonable position for someone following this research. Expecting confirmed human longevity outcomes: that is running ahead of the evidence.

The complementary reading for the synthesis side of the NAD+ equation is the NMN supplement guide and scientific evidence overview, and the NAD precursor comparison: NMN vs. NR for the practical buyer-facing questions.

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Sources: Escande C, Nin V, Price NL, et al. Flavonoid apigenin is an inhibitor of the NAD+ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes. 2013;62(4):1084–1093. | Camacho-Pereira J, Tarragó MG, Chini CCS, et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metabolism. 2016;23(6):1127–1139. | Yoshino M, Yoshino J, Kayser BD, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224–1229. | Arai Y, Watanabe S, Kimira M, et al. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse association between onion consumption and plasma LDL cholesterol concentration. J Nutr. 2000;130(9):2243–2250 (Japanese dietary flavone intake reference).