For decades, researchers chasing the cause of age-related NAD+ decline focused almost exclusively on synthesis — assuming aging cells simply made less of the molecule. Then a quieter explanation emerged: NAD+ isn’t disappearing because production fails. It’s disappearing because a single ectoenzyme, CD38, becomes dramatically more active with age and consumes NAD+ at rates the salvage pathway cannot match. CD38 is now recognized as the dominant NADase in mammalian tissues, and its rise tracks almost perfectly with the inflammatory, senescent, and mitochondrial dysfunction signatures that define biological aging.
What Is CD38?
CD38 is a multifunctional transmembrane glycoprotein originally identified as a lymphocyte surface marker. It functions as an ectoenzyme — meaning its catalytic domain typically faces the extracellular space — and it possesses both NAD+ glycohydrolase (NADase) and ADP-ribosyl cyclase activity. Although it can generate calcium-mobilizing second messengers such as cyclic ADP-ribose (cADPR) and NAADP, the overwhelming majority of its catalytic output is simple NAD+ hydrolysis into nicotinamide and ADP-ribose.[1]
CD38 is expressed across immune cells, endothelium, adipose tissue, skeletal muscle, and brain. Critically, its expression is induced by inflammatory cytokines — TNF-α, IFN-γ, IL-6, and signals from the senescence-associated secretory phenotype (SASP) — which places it at the intersection of immunity and metabolism. In aging tissues, CD38 protein levels rise several-fold, and this increase is now considered the primary driver of the age-related NAD+ decline observed in mice and humans.[2]
How CD38 Drives NAD+ Collapse
Catalytic Inefficiency Favoring Depletion: CD38 is a remarkably inefficient enzyme in stoichiometric terms — it consumes roughly 100 molecules of NAD+ for every molecule of cADPR produced. This means even modest increases in CD38 expression generate disproportionately large drops in cellular NAD+ pools. Mice genetically lacking CD38 maintain NAD+ levels 10–20 fold higher in some tissues compared to wild-type animals and are protected against diet-induced metabolic dysfunction.[1]
Inflammaging as the Upstream Trigger: Work from the Chini laboratory at Mayo Clinic demonstrated that the age-related rise in CD38 is driven primarily by chronic, low-grade inflammation — the phenomenon termed inflammaging. Resident tissue macrophages accumulate with age and upregulate CD38 in response to inflammatory signaling, becoming the dominant cellular source of NAD+ consumption in aged tissue.[2]
Senescent Cell Signaling: Senescent cells secrete a complex mixture of cytokines and chemokines (the SASP) that directly induces CD38 expression on nearby non-senescent cells. This creates a paracrine amplification loop: senescent cells don’t necessarily express the highest CD38 themselves, but their secretome converts surrounding macrophages into high-CD38, high-NADase phenotypes that drain NAD+ from the local microenvironment.[3]
Suppression of Sirtuin and PARP Function: Because sirtuins (particularly SIRT1, SIRT3, and SIRT6) and PARPs both require NAD+ as a substrate, CD38-driven NAD+ depletion functionally silences the downstream effectors of caloric restriction, mitochondrial quality control, and DNA repair. The metabolic phenotype of aged tissue — impaired mitochondrial biogenesis, blunted fatty acid oxidation, accumulated DNA damage — mirrors what is seen with sirtuin loss of function.[4]
Clinical and Preclinical Evidence
CD38 Knockout Phenotype: CD38-null mice display approximately 10-fold higher NAD+ levels in liver and muscle, are resistant to high-fat-diet-induced obesity, show improved glucose tolerance, and demonstrate preserved mitochondrial function in aging. These animals essentially phenocopy several of the metabolic benefits attributed to NAD+ precursor supplementation — but achieved entirely through reduced degradation rather than increased synthesis.[1]
Pharmacologic Inhibition: The CD38 inhibitor 78c, developed as a tool compound, raises tissue NAD+ levels in aged mice and reverses several markers of metabolic aging — including improved glucose tolerance, enhanced exercise capacity, and restoration of mitochondrial respiration in skeletal muscle. Importantly, these benefits were observed when treatment began in already-aged animals, suggesting the NAD+ deficit is functionally reversible.[5]
Macrophage-Specific Role: A 2020 study in Nature Metabolism demonstrated that CD38 expression on tissue-resident macrophages, rather than parenchymal cells, accounts for the majority of NAD+ consumption in aged adipose tissue and liver. Depleting macrophages or knocking out CD38 specifically in the myeloid lineage was sufficient to restore tissue NAD+ levels — establishing the immune-metabolic axis as the primary mechanism.[2]
Natural Compound Inhibitors: Several flavonoids — including apigenin, luteolin, and quercetin — have been characterized as CD38 inhibitors at micromolar concentrations. While their pharmacokinetics make them imperfect therapeutic candidates, these findings provide a plausible mechanism for some of the metabolic benefits historically attributed to polyphenol-rich diets.[4]
Safety Profile and Therapeutic Considerations
CD38 inhibition as a longevity strategy carries important caveats. CD38 plays roles in immune cell trafficking, calcium signaling in pancreatic beta cells, and oxytocin release in the hypothalamus. Complete or chronic systemic inhibition could theoretically impair these functions, although CD38-knockout mice are largely viable and fertile, suggesting substantial redundancy.
The clinical experience with daratumumab — a monoclonal anti-CD38 antibody used in multiple myeloma — has provided some human safety data, though that drug acts primarily by depleting CD38-expressing plasma cells rather than by enzymatic inhibition. Interestingly, daratumumab-treated patients show measurable increases in circulating NAD+ metabolites, indirectly supporting the CD38-NAD+ axis in humans.[3]
Small-molecule CD38 inhibitors remain in preclinical development. Tool compounds like 78c have demonstrated efficacy in rodents without overt toxicity, but no oral CD38 inhibitor has yet completed human longevity trials. The most accessible interventions currently available — flavonoid-rich dietary patterns, senolytic strategies that reduce SASP-driven CD38 induction, and exercise (which lowers inflammaging) — work indirectly on this axis.
CD38 Inhibition vs NAD+ Precursor Supplementation
The dominant commercial approach to age-related NAD+ decline has been precursor supplementation — nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). These compounds reliably raise NAD+ levels in tissues, but they do so by pushing more substrate into a system whose primary problem is excessive consumption rather than insufficient supply. In aged tissues with elevated CD38, much of the supplemented NAD+ is rapidly hydrolyzed back to nicotinamide — which can then feedback-inhibit sirtuins.
CD38 inhibition addresses the upstream cause: the leak rather than the inflow. In principle, combining a CD38 inhibitor with a precursor would be synergistic — restoring synthesis capacity while preventing accelerated degradation. Preclinical work supports this combinatorial logic, though no human trials have yet tested the combination.[5]
A complementary approach involves senolytics — drugs that selectively eliminate senescent cells and thereby reduce the SASP-driven inflammatory signaling that induces CD38 in surrounding macrophages. This represents an indirect but mechanistically coherent strategy for restoring tissue NAD+ homeostasis by treating the upstream inflammatory driver rather than the enzyme itself.[3]
The Bigger Picture
What makes CD38 a particularly compelling target in geroscience is the convergence it represents. Inflammaging, cellular senescence, mitochondrial dysfunction, and metabolic decline have historically been studied as parallel hallmarks of aging. The CD38-NAD+ axis suggests they may share a single enzymatic bottleneck — one in which inflammatory signals drive CD38 expression, CD38 depletes NAD+, NAD+ depletion silences sirtuins and impairs mitochondrial function, and the resulting cellular dysfunction generates more inflammation. Breaking this loop at the CD38 step may prove more tractable than addressing each downstream consequence individually.
References
- Aksoy P, et al. “Regulation of intracellular levels of NAD: a novel role for CD38.” Biochemical and Biophysical Research Communications. 2006;345(4):1386-1392.
- Covarrubias AJ, et al. “Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages.” Nature Metabolism. 2020;2(11):1265-1283.
- Chini CCS, et al. “CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels.” Nature Metabolism. 2020;2(11):1284-1304.
- Escande C, 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.
- Tarragó MG, et al. “A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline.” Cell Metabolism. 2018;27(5):1081-1095.
