NAD+ and CD38
What CD38 is
CD38 is a membrane-bound enzyme with NADase activity — it breaks down NAD+ directly, producing nicotinamide and cyclic ADP-ribose as byproducts.[1] Unlike sirtuins and PARPs, which use NAD+ as a functional cofactor or substrate to modify other proteins, CD38's primary described role is simply consuming NAD+ — which is why it's frequently discussed as one of the main drivers of NAD+ decline, alongside PARP activity covered on NAD+ and PARPs.
CD38 and age-related NAD+ decline: established in mice, not directly in humans
The clearest evidence for CD38 driving age-related NAD+ decline comes from mouse studies. One well-cited study found that CD38 protein levels and NADase activity increase in aging mice, tracking with declining tissue NAD+ and mitochondrial dysfunction, operating through a pathway involving the mitochondrial sirtuin SIRT3; mice genetically lacking CD38 were protected from this age-related mitochondrial decline.[2] This is a real, direct, causal demonstration — in mice, using genetic knockout methodology that isn't possible to replicate in humans for obvious ethical reasons. It should be labeled for what it is: strong preclinical evidence in an animal model, not a confirmed human aging mechanism.
What human evidence actually shows
Human evidence on CD38 and aging is more limited, and comes from different kinds of studies than the mouse knockout work above. Research on human immune cells has found that CD38 expression increases with age in certain immune cell populations, and that this relates to regulation of NAD+ and NMN levels in those cells.[3] Separately, a study measuring the NAD+ metabolome directly in blood plasma from healthy human subjects spanning ages 20 to 87 found significant declines in plasma NAD+ and related metabolites with age.[4] These human findings are real, but they are observational and correlational — they show CD38 and NAD+ levels both changing with age in humans, not a controlled experiment proving CD38 causes NAD+ decline in people the way the mouse knockout study demonstrates causation in mice. The strength of evidence for a causal, CD38-driven mechanism is meaningfully greater in mice than it currently is in humans, and this page treats that difference as real rather than glossing over it.
CD38, immune cells, and inflammation
Beyond aging specifically, CD38 is closely tied to immune cell biology and inflammation — its expression rises on certain activated immune cells, and accumulation of CD38-expressing inflammatory cells in a tissue has been linked to local NAD+ depletion in that tissue in preclinical models.[3] This connects CD38 biology to broader questions about inflammation and aging, but again, primarily through animal and cell-based research rather than controlled human intervention studies.
What this page is not claiming
CD38's role as an NAD+-consuming enzyme, and its well-documented rise with age in mice, are genuine findings. None of this establishes that NMN supplementation counteracts CD38 activity in humans, slows human aging, or has been shown to produce any specific outcome related to CD38 biology — no human NMN trial referenced on this hub has measured CD38 activity or expression as an outcome; see NMN Dosage for what these trials actually measured.
Related reading
For the pathway that rebuilds the NAD+ that CD38 breaks down, see The NAD+ Salvage Pathway. For why NAD+ tends to decline with age more broadly, see Why Does NAD+ Decline With Age?. For other major NAD+-consuming enzymes, see NAD+ and PARPs and NAD+ and Sirtuins.
- CD38 is an NADase — it breaks NAD+ down directly, rather than using it as a cofactor like sirtuins or PARPs.
- In mice, CD38 genetic knockout protects against age-related NAD+ decline and mitochondrial dysfunction — a causal, preclinical finding.
- Human evidence is observational: CD38 rises in aging immune cells and plasma NAD+ declines with age, but causation has not been established in humans the way it has in mice.
- No human NMN trial has measured CD38 activity or expression as an outcome.
- Xie N, Zhang L, Gao W, Huang C, Huber PE, Zhou X, Li C, Shen G, Zou B. NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduction and Targeted Therapy. 2020. doi:10.1038/s41392-020-00311-7. PMID: 33028824.
- 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. doi:10.1016/j.cmet.2016.05.006. PMID: 27304511.Mouse genetic knockout study, not a human trial. Funding/COI not independently verified from this paper's own record (no competing-interest statement was present in the accessible primary record; full-text was not accessible to check further).
- Chini CCS, Peclat TR, Warner GM, et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nature Metabolism. 2020. doi:10.1038/s42255-020-00298-z. PMID: 33199925.Mouse and human immune-cell study; observational for the human component. This paper's own disclosed competing interests (verified from this paper's own record) include: the senior author holds a patent on the use of CD38 inhibitors for metabolic diseases licensed to Elysium Health; several co-authors disclose additional industry consulting, equity, or advisory relationships with other companies; the paper states the research was reviewed under the Mayo Clinic Conflict of Interest policy.
- Clement J, Wong M, Poljak A, Sachdev P, Braidy N. The Plasma NAD+ Metabolome Is Dysregulated in "Normal" Aging. Rejuvenation Research. 2019. doi:10.1089/rej.2018.2077. PMID: 30124109.Observational human plasma study across ages 20–87; does not establish CD38 causation directly.