What Is CD38? The NAD+-Consuming Enzyme Linked to Ageing

Many of us notice changes in our energy and recovery as we get older. Workouts take longer to bounce back from, and the resilience we once took for granted seems to need more support.

While these changes are a natural part of ageing, scientists continue to investigate the biological mechanisms that drive them. One area of growing interest is the steady, age-related decline of nicotinamide adenine dinucleotide, commonly known as NAD+, an essential coenzyme for cellular energy production.

At the centre of this research is CD38, an enzyme increasingly recognised as one of the body's primary consumers of NAD+.

Present on the surface of many cell types, CD38 activity rises with age, and researchers have become increasingly interested in its role in NAD+ depletion, chronic inflammation and healthy ageing (Chini et al., 2020).

What Is CD38?

CD38 is a transmembrane glycoprotein, a protein embedded in the outer membrane of cells, found across many tissues but particularly concentrated on immune cells (Hogan et al., 2019).

Its primary role is that of an ectoenzyme, meaning it carries out its enzymatic activity at the outer surface of the cell, using NAD+ and related molecules as its substrates.

Think of NAD+ as fuel circulating through the cell, powering energy production and DNA repair. CD38 acts like a valve, steadily consuming this fuel regardless of whether the cell urgently needs more (Chini et al., 2020).

CD38 has also long been recognised as an immune cell marker, used in clinical settings to help identify certain white blood cells (Hogan et al., 2019).

Why Does CD38 Matter as We Age?

The body relies on NAD+ for hundreds of essential processes, from energy metabolism to genomic repair. Research shows that CD38 expression and activity rise substantially with age across tissues, including muscle, liver and adipose tissue (Camacho-Pereira et al., 2016).

CD38 is considered the primary NAD+-degrading enzyme, or "NADase," in mammalian tissues, and its increased activity is thought to be a significant contributor to falling NAD+ levels with age (Chini et al., 2020).

This has led researchers to investigate whether limiting excessive CD38 activity, or supporting NAD+ synthesis through the salvage pathway, may help maintain healthy energy metabolism as we grow older.

CD38 and Cellular Energy

Every process that depends on NAD+, from mitochondrial energy production to DNA repair enzymes, is affected when NAD+ availability falls.

By breaking down NAD+ and its precursor nicotinamide mononucleotide (NMN), CD38 activity directly reduces the NAD+ pool available for these functions (Chini et al., 2020). Without adequate NAD+, cells become less efficient at producing the energy required for normal physiological function, much as reduced fuel supply slows an engine.

Because of this role, CD38 has become a central focus in research exploring NAD+ metabolism, mitochondrial health and the biology of ageing (Sun, Wang, Xu & Zhao, 2025).

CD38 and Inflammaging

As cells age, some enter a state called senescence and begin secreting inflammatory signalling molecules, a phenomenon known as the senescence-associated secretory phenotype, or SASP (Covarrubias et al., 2020). Research suggests these SASP-derived signals can induce CD38 expression in macrophages and endothelial cells, linking cellular senescence to rising CD38 activity in ageing tissue (Hogan et al., 2019).

This connects CD38 to inflammaging, the chronic, low-grade, sterile inflammation that tends to develop with age, distinct from the acute inflammatory response triggered by infection (Minhas, Liu & Ren, 2020).

During inflammaging, CD38-expressing immune cells accumulate in ageing tissues and actively consume the local pool of NAD+ precursors, creating a self-sustaining cycle in which inflammation drives NAD+ decline, and NAD+ decline may in turn influence inflammatory regulation (Chini et al., 2020).

CD38, DNA Repair and the NAD+ Balance

CD38 is not the only enzyme competing for the body's limited NAD+ supply. NAD+ is also consumed by sirtuins, proteins involved in regulating metabolism and cellular stress responses, and PARPs, enzymes activated in response to DNA damage (Sun, Wang, Xu & Zhao, 2025). Because these enzyme families draw from the same NAD+ pool, elevated CD38 activity can leave less NAD+ available for DNA repair and metabolic regulation, particularly as age-related DNA damage accumulates (Minhas et al., 2020).

Can the Body Offset CD38 Activity?

To a degree, yes. NAD+ is continuously regenerated through the salvage pathway, which relies on precursor molecules such as nicotinamide mononucleotide (NMN) and nicotinamide riboside to rebuild NAD+ (Covarrubias et al., 2020). However, when CD38 activity is elevated, it can degrade these same precursors before they are used for synthesis, effectively working against the salvage pathway.

Studies in aged mice have shown that inhibiting CD38 enzymatic activity can help restore NAD+ levels, supporting the idea that CD38 is mechanistically involved in driving age-related NAD+ decline, rather than simply correlating with it (Camacho-Pereira et al., 2016).

Supporting Healthy Ageing

While CD38 is an important piece of the NAD+ story, healthy ageing is influenced by many interacting factors, including reduced NAD+ synthesis, senescent cell burden and cumulative DNA damage. Regular exercise, quality sleep, balanced nutrition, stress management and social connection all play important roles in maintaining long-term health and vitality.

Supplements may provide additional support, but they work best as part of a broader strategy addressing multiple pathways at once.

How Longevita™ Addresses CD38-Driven NAD+ Decline

Supplying NAD+ precursors addresses only one half of the equation: synthesis. As the research above shows, consumption, particularly via CD38, is the other half, and rising CD38 activity is itself driven by inflammaging and senescent cell accumulation (Chini et al., 2020; Covarrubias et al., 2020).

This is the scientific rationale behind The Longevita™ Supplement, a doctor-formulated, 12-ingredient longevity formula designed to support cellular health across multiple interacting systems rather than relying on a single ingredient in isolation.

At its core, Longevita™ combines Nicotinamide Riboside Chloride and Nicotinamide (niacin) to support the NAD+ salvage pathway, supplying the substrates cells need to regenerate NAD+ even as CD38 continues to consume it. Alongside these precursors, the formula includes Coenzyme Q10 and Calcium Alpha Ketoglutarate to support mitochondrial function and cellular energy once NAD+-dependent pathways are running.

To help address the inflammatory and oxidative pressure believed to drive CD38 expression, Longevita™ includes Trans-Resveratrol and Pterostilbene, studied for their role in healthy ageing pathways and antioxidant defence, alongside Fisetin, studied for its role in cellular cleanup and renewal. Piperine supports absorption of these co-ingredients, while L-Theanine, Ginseng, Lutein and Hyaluronic Acid extend support to cognition, focus, visual health and skin, reflecting the wide-reaching effects of cellular ageing across the body.

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 ageing at the cellular level involves multiple interacting pathways, so addressing NAD+ decline meaningfully requires more than a single-ingredient approach.

The Bottom Line

CD38 is an enzyme found on the surface of many cells that actively consumes NAD+, and its activity rises significantly with age. Increasingly linked to cellular senescence and inflammaging, CD38 is now considered a key driver, not merely a marker, of age-related NAD+ decline.

While no supplement can stop the ageing process, understanding CD38's role explains why NAD+ precursors alone may not be enough, and why a systems-based, multi-pathway approach may offer more complete support for healthy cellular ageing. Combined with healthy lifestyle habits, this may help support resilience, wellbeing and long-term healthspan.

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 is CD38 and why does it matter for ageing?

CD38 is an enzyme found on the surface of many cells, particularly immune cells, that breaks down NAD+ and its precursors. Research shows CD38 activity rises with age, making it a significant contributor to declining NAD+ availability in ageing tissue.

2. Does CD38 cause inflammaging, or does inflammaging cause CD38 activity?

Research suggests the relationship runs in both directions. Senescent cells release inflammatory signals that can induce CD38 expression, while CD38-driven NAD+ depletion may in turn influence inflammatory regulation, creating a self-sustaining cycle.

3. Can supplements offset CD38 activity?

NAD+ precursors such as nicotinamide riboside can support the salvage pathway, helping cells regenerate NAD+. However, because CD38 also degrades these precursors, researchers increasingly suggest combining precursors with ingredients that support mitochondrial function and address oxidative and inflammatory stress.

4. Is CD38 the only cause of NAD+ decline?

No. Research indicates that age-related NAD+ decline is multifactorial, involving reduced NAD+ synthesis, increased CD38 activity, senescence-driven inflammaging and greater NAD+ consumption by PARPs during DNA repair.

References

Camacho-Pereira, J., Tarragó, M.G., Chini, C.C.S., Nin, V., Escande, C., Warner, G.M., Puranik, A.S., Schoon, R.A., Reid, J.M., Galina, A. & Chini, E.N. (2016) 'CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism', Cell Metabolism, 23(6), pp. 1127–1139.

Chini, C.C.S., Peclat, T.R., Warner, G.M., Kashyap, S., Espindola-Netto, J.M., de Oliveira, G.C., Gomez, L.S., Hogan, K.A., Tarragó, M.G., Puranik, A.S., Agorrody, G., Thompson, K.L., Dang, K., Clarke, S., Childs, B.G., Kanamori, K.S., Witte, M.A., Vidal, P., Kirkland, J.L., De Cabo, R. & Chini, E.N. (2020) 'CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels', Nature Metabolism, 2(11), pp. 1284–1304.

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.

Minhas, P.S., Liu, L., Ren, C.X. et al. (2020) 'Macrophage immunometabolism and inflammaging: roles of mitochondrial dysfunction, cellular senescence, CD38 and NAD', Immunometabolism, 2(3), e200018.

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.