NAD+ (nicotinamide adenine dinucleotide) is a coenzyme present in every cell, essential for energy metabolism, DNA repair, and the activity of longevity-linked proteins called sirtuins. Its concentration falls measurably with age, and researchers have spent the last decade investigating why, and what, if anything, can slow that decline.
One increasingly studied contributor to age-related NAD+ depletion is CD38, an enzyme whose expression rises with aging and inflammatory signaling. Apigenin, a plant flavonoid abundant in chamomile, parsley, and celery, has attracted scientific attention as a natural CD38 inhibitor, although the key results are from test-tube assays, cells and mice given injected or dietary doses [11][12]. This article examines the proposed mechanism, summarizes the preclinical evidence, and is candid about where the science currently stands.
Key Takeaways
- CD38 is an NAD+-consuming enzyme whose activity rises with age and inflammation, and it is now considered a primary driver of the tissue NAD+ decline observed across aging biology [1][2].
- Apigenin inhibited CD38 in test-tube and cell assays, and in obese mice daily injections lowered liver CD38 activity and raised liver NAD+ [11].
- Lower NAD+ constrains sirtuin activity, DNA repair capacity, and mitochondrial function: pathways associated with healthspan in model organisms [3].
- Combining CD38 inhibition with an NAD+ precursor may be more effective than either strategy alone based on preclinical neuroinflammation data, but this combination lacks robust human trial evidence [4].
- The evidence base for apigenin as a longevity supplement is largely preclinical; effective human dose, bioavailability in deep tissues, and long-term safety have not been established in rigorous clinical trials.
Why NAD+ Declines With Age
NAD+ participates in hundreds of enzymatic reactions. In the context of longevity, it serves as the essential substrate for sirtuins: a family of deacylase enzymes that regulate gene expression, mitochondrial biogenesis, and cellular stress responses [3]. It also fuels PARP enzymes involved in DNA damage repair. When cellular NAD+ is abundant, these systems can operate efficiently; when levels fall, their activity is constrained regardless of how much of the enzyme protein is present.
Research published in Aging Cell describes NAD+ metabolism as closely linked to senescence and aging, noting that low NAD+ can promote senescence through DNA damage and mitochondrial dysfunction, while the low NAD+ state of aging may also restrain development of the inflammatory secretions of senescent cells [2]. Multiple mechanisms account for the decline over a lifetime: reduced biosynthesis, increased consumption from DNA damage signaling, and an age-related rise in NAD-degrading enzymes, chief among them, CD38.
CD38: The NAD-Consuming Enzyme That Rises With Age
CD38 is a multifunctional ectoenzyme expressed on immune cells, cardiac tissue, reproductive organs, neurons, and elsewhere. Its primary enzymatic activity is NAD+ hydrolysis: it breaks NAD+ down into ADP-ribose and nicotinamide. Studies using mouse models in which CD38 was genetically deleted showed dramatically higher tissue NAD+ levels and better metabolic profiles compared with wild-type controls [1].
Research note: In the same assay quercetin inhibited CD38 NAD+ase activity with an IC50 of 13.8 micromol/L, close to apigenin’s value [11].
CD38 expression increases with age, partly because aging is accompanied by chronic low-grade inflammation and an accumulation of CD38-expressing immune cells in tissues. A 2024 Nature Aging study identified CD38 as a key determinant of ovarian aging, demonstrating that infiltrating immune cells expressing high levels of CD38 drive NAD+ depletion in ovarian tissue and impair oocyte quality [5]. A 2026 review of CD38 inhibition strategies characterizes the enzyme as a well-validated longevity target and surveys the growing landscape of both synthetic and plant-derived inhibitors under investigation [6].
CD38 activity also appears consequential beyond reproductive aging. A study in Cardiovascular Research showed that inhibiting ecto-CD38 NADase activity preserved cardiac NAD+ levels and protected mice from doxorubicin-induced cardiotoxicity, highlighting tissue-specific consequences of CD38 dysregulation [7].
Apigenin as a CD38 Inhibitor
Apigenin (4′,5,7-trihydroxyflavone) inhibited CD38 in a purified human CD38 enzyme assay, with an IC50 of 10.3 micromol/L for NAD+ase activity, and in human lung cells with an IC50 of 14.8 micromol/L; in cells lacking CD38 apigenin did not change NAD+ levels. In obese mice fed a high-fat diet, daily apigenin injections for one week lowered liver CD38 activity and raised liver NAD+. These are test-tube concentrations and injected doses, not oral supplement doses [11].
In a test-tube assay, apigenin and quercetin blocked the CD38 enzyme at similar concentrations (IC50 of 10.3 and 13.8 micromol/L)
In the lab, apigenin and quercetin blocked CD38 at similar concentrations.
Recombinant human CD38 enzyme assay and human A549 lung cells. Not a human trial. Source: Escande et al., Diabetes 2012
Data table
| Item | Value |
|---|---|
| Apigenin, purified human CD38 | 10.3 micromol/L |
| Quercetin, purified human CD38 | 13.8 micromol/L |
| Apigenin, human lung cells | 14.8 micromol/L |
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A 2024 Frontiers in Nutrition review examining apigenin at the intersection of sleep and aging discusses this dual relevance to longevity biology: its sedative effects, although how apigenin acts at GABA-A receptors is disputed, on one hand, and a mouse finding that apigenin nearly doubled liver NAD+ on the other [8]. That review was funded by Tally Health, and two of its authors are full-time Tally Health employees [8][13][14]. The authors suggest these properties may converge: sleep disruption independently accelerates NAD+ depletion, so a compound that supports sleep quality while also inhibiting a major NAD-consuming enzyme could have complementary relevance to healthy aging.
It is important to be direct about the current evidence ceiling. The bulk of direct apigenin-CD38 data remains in cell culture and animal models. Human pharmacokinetic data on apigenin are limited, oral bioavailability is variable and influenced significantly by gut microbiota and food matrix, and no large randomized controlled trials have yet confirmed that apigenin raises circulating or tissue NAD+ in humans to a clinically meaningful degree.
Not every result points the same way. In middle-aged rats on a high-calorie diet, apigenin failed to prevent obesity and did not affect sirtuin or CD38 levels, and in a cell-free chemistry test apigenin acted as a prooxidant that used up NADH [20][21].
Downstream Effects: Sirtuins, Senescence, and Neuroinflammation
If CD38 inhibition raises NAD+ in tissues, the downstream beneficiaries would include sirtuins. Sirtuins require NAD+ as a co-substrate for their enzymatic activity; without sufficient NAD+, their function slows regardless of protein expression [3]. SIRT1 and SIRT3 in particular are associated with mitochondrial quality control, suppression of inflammatory signaling, and extended lifespan in model organisms.
CD38 activity is also implicated in the senescence-associated secretory phenotype (SASP): the pro-inflammatory cytokines and proteases that senescent cells release into surrounding tissue. A 2026 study of a Panax notoginseng-derived formulation found that modulating CD38 alongside SASP markers extended lifespan in C. elegans and reduced markers of cellular inflammaging [9], suggesting the CD38-NAD+ axis intersects with senescence biology broadly across multiple tissues and model systems.
In neuroinflammation research, a dual approach combining CD38 inhibition with nicotinamide riboside (NR) supplementation reduced microglial and astrocytic inflammatory activation in a lipopolysaccharide-challenged model, with the combination outperforming either intervention alone [4]. This raises the hypothesis that pairing an NAD+ precursor with a CD38 inhibitor like apigenin might be more effective than either strategy in isolation, though this precise combination has not been tested directly in humans.
Skin and Tissue-Specific Evidence
A 2024 paper in Cells examined skin aging specifically, proposing that exogenous NAD+ supplementation becomes more effective when paired with suppression of CD38 expression [10]. The authors found that CD38-mediated hydrolysis limits the intracellular longevity of supplemented NAD+ in skin cells, and that inhibiting CD38 expression extended the elevation of intracellular NAD+ following supplementation. Apigenin was among the plant-derived candidates discussed in this synergistic inhibition context.
While skin offers an accessible tissue for mechanistic study, the relevance to systemic aging depends on oral delivery and meaningful distribution to deeper tissues: heart, brain, skeletal muscle, and ovary among them. The extent to which dietary or supplemental apigenin achieves relevant intracellular concentrations in those compartments in humans is not firmly established by currently published data.
Open Questions and Honest Limitations
The CD38-NAD+ hypothesis for apigenin is mechanistically coherent and supported by converging preclinical work, but several important gaps remain before strong clinical conclusions can be drawn. Doses effective in mouse studies do not translate straightforwardly to humans due to differences in body surface area, metabolism, and tissue distribution. The human-equivalent dose required for meaningful CD38 inhibition has not been established in clinical trials. Bioavailability from chamomile tea likely differs substantially from an isolated supplement capsule, and inter-individual variation driven by gut microbiota composition adds further unpredictability.
The 2026 review of CD38 inhibition strategies acknowledges that while the target is well-validated and the preclinical rationale is strong, the field is actively working toward clinical translation and human evidence remains limited [6]. Additionally, apigenin inhibited CYP1A2, CYP2C9, and CYP3A4 drug-metabolizing enzymes in lab studies, which raises the possibility of interactions with warfarin, certain statins, and other medications processed by these pathways [15][16][17][18]a practical consideration that anyone weighing supplementation should discuss with a physician.
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As an Amazon Associate we earn from qualifying purchases. Apigenin products differ mainly in what else is in the capsule (some are plain apigenin, others blend it with L-theanine, valerian root or magnesium) so check the label for the actual apigenin dose per serving, and prefer products that publish third-party testing.
A Note on the Evidence
The majority of apigenin-CD38 evidence comes from cell culture and animal models; effective human doses, deep-tissue bioavailability, and long-term safety profiles are not yet established in rigorous clinical trials. Individuals on warfarin, statins, benzodiazepines, or other CYP1A2-, CYP2C9-, or CYP3A4-metabolized drugs should consult a physician before supplementing, and apigenin should not be combined with sedatives or alcohol without medical guidance. These statements have not been evaluated by the FDA; apigenin is not intended to diagnose, treat, cure, or prevent any disease.
Frequently Asked Questions
What is CD38 and why does it matter for aging?
CD38 is an enzyme that breaks down NAD+, a coenzyme critical for energy metabolism and longevity-linked pathways including sirtuins and DNA repair. Its activity increases with age and inflammatory signaling, making it a significant driver of the NAD+ decline documented across aging tissues [1]. Researchers now identify CD38 as one of the primary therapeutic targets for restoring NAD+ in aging [6].
How does apigenin inhibit CD38?
In a purified human CD38 enzyme assay apigenin inhibited CD38 NAD+ase activity with an IC50 of 10.3 micromol/L, and in obese mice daily injections lowered liver CD38 activity and raised liver NAD+ [11]. The precise binding conformation in human tissues and the concentration required for meaningful in vivo inhibition remain under active investigation.
Does apigenin raise NAD+ in humans?
Direct human evidence is limited. The strongest data come from cell culture and rodent studies. A 2024 review in Frontiers in Nutrition discusses apigenin’s relevance to aging biology including its CD38-inhibiting properties, but does not report human clinical trial data confirming NAD+ elevation in people [8]. Translating this mechanism to measurable human benefit remains an open research question.
Can I take apigenin with NMN or NR?
The theoretical rationale for pairing an NAD+ precursor with a CD38 inhibitor is supported by one preclinical neuroinflammation model showing additive benefit [4] and by a skin cell study suggesting CD38 inhibition prolongs the cellular life of supplemented NAD+ [10]. However, this specific combination has not been tested in human trials. Individuals considering stacking supplements should consult a healthcare provider, especially those on medications affected by CYP1A2, CYP2C9, or CYP3A4 inhibition.
Is CD38 relevant to tissues beyond general metabolism?
Yes. Research has linked CD38 activity to ovarian aging and oocyte quality [5], microglial neuroinflammation [4], cardiac stress responses [7], skin cell NAD+ retention [10], and the senescence-associated secretory phenotype that drives inflammaging [9]. This broad tissue distribution makes CD38 an unusually wide-ranging target in aging biology.
Who should be cautious about apigenin supplementation?
In lab enzyme studies apigenin inhibited CYP1A2, CYP2C9 and CYP3A4 drug-metabolizing enzymes, so individuals taking warfarin, certain statins, or other medications processed by these pathways should consult a physician before use, although human interaction data are lacking. Injected apigenin reduced movement in rats, but how it acts at GABA-A receptors is disputed, so caution with benzodiazepines, melatonin, or alcohol is a precaution rather than a documented interaction [15][16][17][18][19][13]. These statements are informational and not a substitute for personalized medical advice.
References
- Tarragó MG et al. A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD(+) Decline. Cell metabolism (2018). PMID 29719225
- Chini CCS et al. NAD metabolism: Role in senescence regulation and aging. Aging cell (2024). PMID 37424179
- Lappalainen Z et al. Sirtuins: a family of proteins with implications for human performance and exercise physiology. Research in sports medicine (Print) (2011). PMID 21253976
- Roboon J et al. Inhibition of CD38 and supplementation of nicotinamide riboside ameliorate lipopolysaccharide-induced microglial and astrocytic neuroinflammation by increasing NAD(). Journal of neurochemistry (2021). PMID 33871064
- Yang Q et al. NADase CD38 is a key determinant of ovarian aging. Nature aging (2024). PMID 38129670
- Zhang Z et al. Emerging chemical strategies for CD38 inhibition: restoring NAD(+) metabolism and disease control. Bioorganic & medicinal chemistry (2026). PMID 42033923
- Peclat TR et al. Ecto-CD38-NADase inhibition modulates cardiac metabolism and protects mice against doxorubicin-induced cardiotoxicity. Cardiovascular research (2024). PMID 38271281
- Kramer DJ et al. Apigenin: a natural molecule at the intersection of sleep and aging. Frontiers in nutrition (2024). PMID 38476603
- Guo Y et al. Quansanqi (derived from Panax notoginseng (Burk.) F. H. Chen) tablets extend the lifespan and ameliorate cellular inflammaging via regulating CD38 and senescence-associated secretory phenotype. Journal of ethnopharmacology (2026). PMID 41297726
- Kang S et al. Novel Approach to Skin Anti-Aging: Boosting Pharmacological Effects of Exogenous Nicotinamide Adenine Dinucleotide (NAD(+)) by Synergistic Inhibition of CD38 Expression. Cells (2024). PMID 39513906
- Carlos Escande et al. Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38. Diabetes (2012). PMID 23172919
- Mou A et al. Dietary apigenin ameliorates obesity-related hypertension through TRPV4-dependent vasorelaxation and TRPV4-independent adiponectin secretion. Biochimica et biophysica acta. Molecular basis of disease (2024). PMID 39218272
- Campbell EL et al. The dietary flavonoids apigenin and (-)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABA(A) receptors. Biochemical pharmacology (2004). PMID 15451406
- Goutman JD et al. Flavonoid modulation of ionic currents mediated by GABA(A) and GABA(C) receptors. European journal of pharmacology (2003). PMID 12586201
- Fei Lin et al. Inhibitory effect of Selaginella doederleinii hieron on human cytochrome P450. Frontiers in Pharmacology (2023). PMID 36874034
- Kondža M et al. Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids. Molecules (Basel, Switzerland) (2021). PMID 34069400
- Wang Z et al. Inhibitory Effect of Apigenin on Losartan Metabolism and CYP2C9 Activity in vitro. Pharmacology (2016). PMID 27287328
- Shimada H et al. Differential mechanisms for the inhibition of human cytochrome P450 1A2 by apigenin and genistein. Journal of biochemical and molecular toxicology (2010). PMID 20806393
- Salehi B et al. The Therapeutic Potential of Apigenin. International journal of molecular sciences (2019). PMID 30875872
- de Castro JM et al. Oral apigenin prevents obesity-related muscular atrophy, but not obesity itself, in middle-aged rats fed a high-calorie diet. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (2025). PMID 40652723
- Chan T et al. Oxygen activation during peroxidase catalysed metabolism of flavones or flavanones. Chemico-biological interactions (1999). PMID 10475612
These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease. Content is for informational purposes only and is not medical advice; consult a qualified healthcare provider before starting any supplement. As an Amazon Associate we earn from qualifying purchases.
