Written by the Nuvirox Research Team
Key points
- CD38 is an enzyme that breaks down NAD+. Its activity rises with age, and in mice it is the single largest driver of age-related NAD+ decline.
- Almost all of the causal evidence comes from mice. There is no human trial showing that inhibiting CD38 improves energy, function, or healthspan.
- The practical takeaway is about balance: NAD+ levels reflect both how much you make and how fast you consume it — and inflammation drives the consumption side.
Short answer: CD38 is the enzyme most responsible for age-related NAD+ decline — in mice. It sits on the surface of immune cells, chews through NAD+ as a normal part of its job, and becomes markedly more active with age. Knock it out in a mouse and the animal is largely protected from the NAD+ drop that otherwise accompanies aging. That is a genuinely important mechanistic finding. What it is not, yet, is a human result. No trial has shown that inhibiting CD38 in people improves energy, physical function, or anything a person would notice. The fair reading is that CD38 explains why NAD+ falls, without yet telling anyone what to do about it.
What is CD38, and what does it actually do?
CD38 is a membrane-bound enzyme — a glycohydrolase — that cleaves NAD+ into nicotinamide and signalling molecules including cyclic ADP-ribose. It was first identified as a marker on activated immune cells, long before anyone connected it to aging metabolism. It has a legitimate biological role: the cADPR it produces is a calcium-signalling messenger, and CD38 is part of normal immune activation.
The problem is arithmetic. NAD+ in any tissue is the running balance between synthesis and consumption. Most public discussion of NAD+ focuses entirely on the synthesis side — precursors, salvage pathways, nicotinamide riboside, dietary sources. CD38 sits squarely on the other side of the ledger. And unlike synthesis, which appears relatively stable across the lifespan in several tissues, CD38 activity climbs steadily.
Why does CD38 activity increase with age?
The most persuasive answer is inflammation. Work published in Nature Metabolism traced the rise in tissue CD38 not to existing cells making more of the enzyme, but to the accumulation of CD38-positive immune cells in tissues such as white adipose and liver. Senescent cells — the so-called zombie cells that stop dividing but refuse to die — secrete an inflammatory cocktail that recruits and activates exactly these cells. Clear the senescent cells or suppress their secretions, and CD38 falls while NAD+ partly recovers.
This is the mechanistic bridge between two aging stories that are usually told separately: chronic inflammation and NAD+ decline. They are not parallel processes. In this model, one causes the other.
What human studies actually show
Camacho-Pereira and colleagues, 2016, established the causal link — in mice. This is the paper the entire field cites. The team at the Mayo Clinic showed that CD38 expression and activity rise with age across multiple mouse tissues, that CD38-knockout mice are protected from age-related NAD+ decline, and that the downstream effect on mitochondria runs partly through SIRT3. They also showed CD38 degrades NMN directly, which matters for anyone taking a precursor. It is careful, replicated work. Every subject was a mouse.
A pharmacological CD38 inhibitor reproduced the effect — again in mice. The 2018 follow-up used a small molecule, 78c, in chronologically aged mice. Tissue NAD+ rose, and several metabolic and physical measures improved. This addressed a real objection to the knockout studies: that lifelong absence of an immune enzyme might improve aging for reasons unrelated to NAD+. Inhibiting the enzyme late in life worked too. Still mice.
Human NAD+ decline has been measured directly in the brain. A 2015 study using in vivo magnetic resonance spectroscopy measured NAD+ contents and redox state in healthy human brain across age groups, and found an age-dependent decline. This is one of the cleaner human demonstrations that the phenomenon CD38 explains in mice is happening in people at all. It does not demonstrate that CD38 is the cause in humans.
The honest counterweight: humans already take a potent CD38 blocker, and it is not an anti-aging drug. Daratumumab, a monoclonal antibody against CD38, has been used in thousands of patients with multiple myeloma for years. If blocking CD38 produced obvious systemic rejuvenation, oncology would have noticed. It is a different kind of blockade — antibody-mediated depletion of CD38-expressing cells rather than catalytic inhibition, in people with active cancer receiving other treatments — so this is not a clean test. But it is a reminder that the leap from mouse enzyme biology to human benefit is long and frequently fails.
What about quercetin and apigenin as "CD38 inhibitors"?
Several flavonoids, including quercetin and apigenin, inhibit CD38 in cell-based assays. This is the rationale behind adding them to NAD+ formulas, and it is a real observation. The gap is between an assay result and a person. Inhibiting an enzyme in a dish at concentrations achievable in a dish is not the same as inhibiting it in human tissue at concentrations achievable from a capsule. Oral quercetin has modest and variable bioavailability, and no human trial has shown that dietary quercetin raises tissue NAD+ by inhibiting CD38.
We cover this in more detail in our piece on why quercetin appears in NAD+ formulas. The short version: it is a defensible ingredient with real supporting mechanism and no human NAD+ outcome data. Anyone selling it as a proven CD38 inhibitor in humans is ahead of the evidence.
Study snapshot
| Study | Camacho-Pereira et al., Cell Metabolism, 2016 |
| Model | Chronologically aged mice; CD38-knockout comparison |
| Key finding | CD38-null mice protected from age-related NAD+ decline; effect on mitochondrial function partly SIRT3-dependent |
| Also shown | CD38 degrades NMN in vivo, affecting precursor pharmacokinetics |
| Limitation | No human data; no functional or healthspan endpoint in people |
What CD38 research won't tell you
It will not tell you your CD38 activity. There is no clinically available test, no reference range, and no reason to seek one out — nothing would change based on the result.
It will not tell you that a supplement inhibits CD38 in your body. That claim currently rests entirely on cell and animal work.
And it will not explain persistent fatigue. This is the important one. CD38 biology operates on a scale of decades, producing a gradual metabolic drift — much like oxidative stress, another mechanism that explains cellular aging without explaining anyone's tiredness. It is not the kind of tiredness that arrives over weeks or months and makes someone search for answers. Fatigue that is new, worsening, or accompanied by weight change, breathlessness, fever, or unusual bruising is a reason to see a doctor, not a reason to read about enzyme kinetics. Thyroid disease, anemia, sleep apnea, depression, and medication effects are all far more likely and all far more actionable. Our guide to what standard blood tests miss covers the sequence worth working through.
What this actually changes about how to think about NAD+
One useful thing. If NAD+ is a balance, then loading the synthesis side is only half the picture, and the consumption side is partly driven by inflammation. That reframes several unglamorous interventions — sleep, resistance training, managing visceral fat, treating chronic inflammatory conditions — as NAD+ interventions rather than as separate advice. The meta-analytic evidence that lifelong exercise blunts age-related inflammation is more robust than anything in the CD38-inhibitor literature, and it costs nothing.
It also sets a realistic ceiling on precursor supplementation. If CD38 activity is rising, then supplying more NR or NMN is pushing against a drain that is opening wider. Trials do show that oral precursors raise blood NAD+ meaningfully. They also show that the functional benefits in healthy adults have been modest and inconsistent, which is roughly what you would predict from this model.
Frequently asked questions
Is CD38 bad for you?
No. CD38 is a normal part of immune signalling and calcium regulation, and mice engineered without it have immune abnormalities. The issue is not its existence but its age-related over-activity in tissue. Framing it as a villain oversimplifies a normal enzyme doing its job in an increasingly inflammatory environment.
Does taking NMN or NR get around the CD38 problem?
Partly, and imperfectly. The 2016 research showed CD38 degrades NMN directly in vivo, which means the enzyme reduces how much of an oral dose reaches tissue as usable substrate. Oral precursors still raise blood NAD+ in human trials. They just do so against resistance.
Can I test my CD38 levels?
Not usefully. CD38 is measured in research settings on tissue or isolated immune cells, not as a routine clinical blood test, and there is no validated reference range or action to take based on a result.
Do senolytics lower CD38?
In mice, clearing senescent cells reduced CD38-positive immune cell accumulation and partially restored NAD+. In humans, senolytic trials are small, early, and focused on other endpoints. Nobody has shown this chain works in people.
If inflammation drives CD38, do anti-inflammatory supplements help?
The meta-analytic evidence is mixed and, for some popular compounds, negative. A large systematic review of interventions targeting chronic low-grade inflammation found omega-3 and probiotics reduced IL-6 and CRP, while resveratrol and vitamin D did not. That is worth sitting with before assuming any anti-inflammatory supplement lowers CD38.
From Nuvirox
Why we formulated NAD+ Restore
NAD+ Restore was built around the synthesis side of the ledger, because that is where the human trial evidence actually lives. We are not going to claim it inhibits CD38 — no supplement has shown that in people.
- 500 mg Nicotinamide Riboside Chloride (NR) — one of the two most-researched NAD+ precursors, within the dose range used in published human trials.
- 150 mg trans-resveratrol (Japanese Knotweed) and 50 mg quercetin (Sophora japonica) — polyphenols studied alongside NAD+ pathways for cellular health support.
- 10 mg galactomannans from fenugreek, to support absorption.
- 60-day money-back guarantee — long enough to actually evaluate it the way the research says you should.
The bottom line
CD38 is the best current explanation for why NAD+ falls with age, and the inflammation-to-CD38-to-NAD+ chain is one of the more satisfying mechanistic stories in aging biology. It is also, as of now, a mouse story with a human epilogue that has not been written. Treat it as a reason to take inflammation seriously and to keep expectations calibrated about what any precursor supplement can do — not as evidence that a CD38-targeting product will change how you feel.
References
- 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. PMID: 27304511. DOI: 10.1016/j.cmet.2016.05.006
- Tarragó MG, Chini CCS, Kanamori KS, 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. DOI: 10.1016/j.cmet.2018.03.016
- Covarrubias AJ, Kale A, Perrone R, et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nature Metabolism. 2020;2:1284–1304. DOI: 10.1038/s42255-020-00298-z
- Hogan KA, Chini CCS, Chini EN. The multi-faceted ecto-enzyme CD38: roles in immunomodulation, cancer, aging, and metabolic diseases. Frontiers in Immunology. 2019;10:1187. PMID: 31214171
- Chini CCS, Tarragó MG, Chini EN. NAD and the aging process: role in life, death and everything in between. Reviewed in: The pharmacology of CD38/NADase: an emerging target in cancer and diseases of aging. Trends in Pharmacological Sciences. 2018. PMID: 29482842
- Zhu XH, Lu M, Lee BY, Ugurbil K, Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. PNAS. 2015;112(9):2876–2881. DOI: 10.1073/pnas.1417921112
- Zhang L, et al. NADase CD38 is a key determinant of ovarian aging. Nature Aging. 2023. DOI: 10.1038/s43587-023-00532-9
- Custodero C, Mankowski RT, Lee SA, et al. Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: a systematic review and meta-analysis. Ageing Research Reviews. 2018;46:42–59. PMID: 29803716. DOI: 10.1016/j.arr.2018.05.004
*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. This article is for informational purposes only and is not a substitute for professional medical advice.