What Uses Up NAD+ in the Body? CD38, PARPs and Cellular Stress Explained

Most conversations about nicotinamide adenine dinucleotide, commonly known as NAD+, focus on how to raise it: which precursor to take, which foods support it, which supplement works best. Far less attention goes to the other side of the equation: what is actually using it up.

This is not a minor detail. Research increasingly suggests that age-related NAD+ decline reflects not just reduced production, but a growing demand from three major enzyme families that consume NAD+ as an essential substrate: sirtuins, PARPs and CD38 (Chini et al., 2025). Understanding what drains the body's NAD+ supply is just as important as understanding how to replenish it.

Why Does NAD+ Get Consumed in the First Place?

NAD+ is not simply a passive fuel source sitting in reserve. It is an active substrate, meaning specific enzymes require it and chemically break it down in order to carry out their functions (Chini et al., 2025).

This is a crucial distinction. Unlike glucose, which is metabolised primarily for energy, NAD+ is consumed by enzymes performing entirely different jobs: regulating gene expression, repairing DNA, and managing calcium signalling and immune responses. Because these enzyme families draw from the same limited cellular pool, rising demand from one can directly reduce what's available for the others (Sun, Wang, Xu & Zhao, 2025).

The Three Major Consumers of NAD+

Research identifies three principal enzyme families responsible for the vast majority of cellular NAD+ consumption: sirtuins, PARPs and CD38 (Chini et al., 2025).

Sirtuins

Sirtuins are a family of seven NAD+-dependent deacetylases in mammals, named SIRT1 through SIRT7, involved in regulating metabolism, gene expression, mitochondrial function and cellular stress responses (Imai & Guarente, 2014). During their catalytic reaction, sirtuins consume NAD+ and break it down into nicotinamide as a by-product, meaning their activity is directly and mechanistically tied to NAD+ availability.

PARPs

Poly (ADP-ribose) polymerases, or PARPs, are DNA repair enzymes, with PARP1 acting as one of the fastest cellular responders to DNA strand breaks (Kobayashi & Imanaka, 2024). PARP1 uses NAD+ directly as a substrate to build long chains of poly (ADP-ribose) at sites of DNA damage, a process that recruits repair machinery but consumes substantial quantities of NAD+ with each activation. The more oxidative DNA damage a cell experiences, the more single- and double-strand breaks occur, and the more PARP1 activity is required, creating a direct link between cellular stress and NAD+ depletion.

CD38

CD38 is a transmembrane glycoprotein, expressed on the surface of many cell types and particularly concentrated on immune cells, that functions as the primary NAD+-degrading enzyme, or "NADase," in mammalian tissues (Hogan et al., 2019). CD38 catalyses the breakdown of NAD+ into nicotinamide and ADP-ribose, and can also convert it into cyclic ADP-ribose, a signalling molecule involved in calcium mobilisation. CD38 expression rises measurably with age and during immune activation, making it a particularly significant contributor to age-related NAD+ decline (Chini et al., 2025).

How Do These Three Systems Compete for the Same NAD+ Pool?

Because sirtuins, PARPs and CD38 all rely on the same finite cellular NAD+ supply, increased activity in one system can meaningfully reduce what's available to the others, a dynamic researchers describe as competitive consumption (Sun, Wang, Xu & Zhao, 2025).

This competition becomes especially significant under conditions of cellular stress. When DNA damage accumulates, whether from oxidative stress, environmental exposures or the normal process of ageing, PARP1 activation rises substantially. Because PARP1's demand for NAD+ can be considerable during active repair, this leaves comparatively less NAD+ available for sirtuin-mediated processes, even when sirtuin protein levels remain unchanged.

Research shows that inhibiting PARP activity in aged cells can help restore both NAD+ levels and sirtuin activity, directly demonstrating this competitive relationship in practice (ChemRxiv, 2025). Similarly, CD38 activity rises during inflammatory and immune activation, and elevated CD38 has been shown to preserve higher NAD+ levels when inhibited or genetically removed in animal models, again illustrating how much cellular NAD+ this single enzyme family can consume (ChemRxiv, 2025).

Why Does This Matter More as We Age?

Ageing appears to intensify demand from all three consumer pathways simultaneously, compounding the effects of any single mechanism in isolation.

CD38 expression rises with age across multiple tissues, partly driven by the accumulation of senescent cells that secrete inflammatory signals capable of inducing CD38 expression in nearby immune cells (Covarrubias et al., 2020). At the same time, cumulative DNA damage over decades increases baseline demand on PARP1, and researchers describe this pattern as the "hyperactive PARP" hypothesis, in which chronically elevated PARP activity becomes a persistent drain on the NAD+ pool (ChemRxiv, 2025).

This convergence- rising CD38 activity, rising PARP demand and a stable or declining sirtuin requirement all drawing from a shrinking NAD+ supply- helps explain why age-related NAD+ decline is now understood as a multifactorial process rather than the result of any single enzyme (Chini et al., 2025).

Is Reducing Consumption a Viable Strategy?

Alongside supplying more NAD+ precursors, researchers have also explored whether reducing excessive consumption might help preserve NAD+ levels, an approach sometimes described as the "third way" to support NAD+ status, alongside boosting precursor supply and enhancing synthesis (NutritionFacts.org, 2025).

Naturally occurring flavonoid compounds, including apigenin, quercetin and luteolinidin, have been studied for their ability to competitively inhibit CD38 catalytic activity, which is believed to increase cellular NAD+ availability and support activation of NAD-dependent enzymes such as sirtuins (Hogan et al., 2019). These compounds have shown a favourable safety profile in human studies, although researchers note they generally lack the specificity of purpose-built pharmaceutical inhibitors.

Importantly, researchers caution that chronic, indiscriminate PARP inhibition is not a straightforward anti-ageing solution, since DNA repair remains essential for cellular survival. The more promising strategy, researchers suggest, is reducing the underlying oxidative damage that drives excessive PARP activation in the first place, for example through improved antioxidant defences, rather than blocking the repair response itself (ChemRxiv, 2025).

Supporting Healthy Ageing

Because NAD+ consumption is driven by cellular stress, inflammation and DNA damage as much as by ageing itself, supporting healthy NAD+ status works best as a broad strategy rather than a single intervention.

Regular exercise and caloric moderation have both been shown to elevate cellular NAD+ levels, while chronic inflammation and metabolic stress are consistently associated with accelerated NAD+ consumption (Chini et al., 2025). Reducing oxidative stress through diet, sleep and stress management may help lower the baseline demand placed on PARP1 and other repair pathways.

Supplements may provide additional support, but they work best as part of a broader, multi-pathway approach addressing both NAD+ supply and the factors that drive excessive consumption.

How Longevita™ Addresses NAD+ Consumption and Supply Together

The research summarised here points to a clear conclusion: supporting NAD+ status effectively requires addressing both sides of the equation, supplying adequate precursors while also reducing the oxidative and inflammatory pressure that drives excessive consumption by CD38 and PARPs.

This is the scientific rationale behind The Longevita™ Supplement, a doctor-formulated, 12-ingredient longevity formula designed to target the key hallmarks of ageing by promoting cellular energy, helping manage senescent cell burden, and strengthening antioxidant and inflammation defence systems.

At its core, Longevita™ combines Nicotinamide Riboside Chloride, which boosts NAD⁺ levels to activate sirtuins and enhance DNA repair, with Nicotinamide, which sustains NAD⁺ pools for mitochondrial energy and antioxidant defence, replenishing supply on the production side of the equation. On the consumption side, the formula addresses the inflammatory and oxidative drivers of excessive CD38 and PARP activity: Calcium Alpha Ketoglutarate reduces inflammaging via epigenetic modulation, while Fisetin supports the clearance of senescent cells, the very cells shown to secrete signals that induce CD38 expression in ageing tissue.

To further reduce the oxidative stress that drives PARP overactivation, Longevita™ includes Trans-Resveratrol, which activates SIRT1 for mitochondrial function while promoting autophagy and DNA repair, and Pterostilbene, which activates SIRT1/AMPK pathways with superior bioavailability. Coenzyme Q10 preserves mitochondrial ATP production and reduces oxidative stress system-wide, Piperine upregulates antioxidant enzymes and enhances mitochondrial biogenesis via PGC-1α, and Ginseng activates antioxidant pathways and promotes autophagy via SIRT1 and FOXO signalling. L-Theanine, Lutein and Hyaluronic Acid extend support to cognition, visual health and skin.

Formulated by a doctor and longevity specialist, and manufactured in a GMP-certified, USFDA-registered facility with third-party testing for potency and contaminants, Longevita™ is built on the premise that supporting NAD+ status means addressing supply and consumption together, not raising precursor levels in isolation.

The Bottom Line

NAD+ decline is not solely a story of reduced production. Three major enzyme families, sirtuins, PARPs and CD38, actively consume NAD+ as an essential substrate, and all three place growing demand on the same limited cellular pool as we age. Rising CD38 activity, driven by senescence and inflammation, and rising PARP demand, driven by accumulating DNA damage, together help explain why NAD+ decline accelerates with age far beyond what reduced synthesis alone would predict.

Understanding what consumes NAD+, not just how to raise it, offers a more complete picture of cellular ageing, and reinforces why a systems-based, multi-pathway approach addressing both supply and demand may offer more meaningful support for long-term cellular health.

Explore The Longevita™ Supplement, a doctor-formulated, 12-ingredient longevity formula designed to support NAD+ status, mitochondrial function and cellular resilience as part of a daily routine.

FAQs

1. What are the three main enzymes that consume NAD+?

Sirtuins, PARPs and CD38 are considered the three major consumers of cellular NAD+. Sirtuins regulate metabolism and gene expression, PARPs repair DNA damage, and CD38 breaks down NAD+ as part of immune and inflammatory signalling.

2. Why does CD38 activity increase with age?

CD38 expression is induced by inflammatory signals released by senescent cells, a process linked to chronic low-grade inflammation, or inflammaging, that develops with age.

3. Do PARPs and sirtuins compete for the same NAD+?

Yes. Because both enzyme families draw from the same limited cellular NAD+ pool, elevated PARP activity in response to DNA damage can leave less NAD+ available for sirtuin-mediated processes, even without a change in sirtuin protein levels.

4. Can reducing NAD+ consumption help as much as increasing supply?

Some researchers believe so. Alongside supplying NAD+ precursors, reducing excessive CD38 and PARP activity, for example by lowering oxidative stress and inflammation, is considered a complementary strategy for preserving cellular NAD+ levels.

References

ChemRxiv (2025) 'Boosting NAD+ for anti-aging: mechanisms, evidence, and implications for future trials', ChemRxiv preprint, DOI: 10.26434/chemrxiv-2025-nl80r.

Chini, C.C.S. et al. (2025) 'NAD+ biology in ageing and chronic disease: mechanisms and evidence across skin, fertility, osteoarthritis, hearing and vision loss, gut health, cardiovascular–hepatic metabolism, neurological disorders, and muscle', Endocrinology and Metabolism.

Covarrubias, A.J., Kale, A., Perrone, R., Lopez-Dominguez, J.A., Pisco, A.O., Kasler, H.G., Schmidt, M.S., Heckenbach, I., Kwok, R., Wiley, C.D., Wong, H.S., Gibbs, E., Iyer, S.S., Basisty, N., Wu, Q., Kim, I.J., Silva, E., Vitangcol, K., Shin, K.O., Lee, Y.M., Riley, R., Ben-Sahra, I., Ott, M., Schilling, B., Scheibye-Knudsen, M., Verdin, E. & Newman, J.C. (2020) 'Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages', Nature Metabolism, 2(11), pp. 1265–1283.

Hogan, K.A., Kang, K.A., Chini, C.C.S. & Chini, E.N. (2019) 'The multi-faceted ecto-enzyme CD38: roles in immunomodulation, cancer, ageing, and metabolic diseases', Frontiers in Immunology, 10, Article 1187.

Imai, S. & Guarente, L. (2014) 'NAD+ and sirtuins in ageing and disease', Trends in Cell Biology, 24(8), pp. 464–471.

Kobayashi, H. & Imanaka, S. (2024) 'Mitochondrial DNA damage and its repair mechanisms in ageing oocytes', International Journal of Molecular Sciences, 25(23), 13144.

NutritionFacts.org (2025) 'The third way to boost NAD+', NutritionFacts.org, Volume 68.

Sun, J.Y., Wang, Z.F., Xu, W.H. & Zhao, J. (2025) 'NAD+ glycohydrolases-CD38 as a therapeutic target in ageing: physiological roles, molecular mechanisms, and future opportunities in anti-ageing research', Biochemical and Biophysical Research Communications, in press.