Placental NAD+ Declines with Maternal Age: What New Research Reveals About CD38, NR, and NMN

Key Takeaways

• A newly published study in Nature Communications found that placentas from older mothers had lower levels of NAD+, NADH, and NADP+ than those from younger mothers. Higher placental levels of these molecules were associated with higher infant birth weight, although the human data do not prove cause and effect.
• Mice and pigs showed the same age-related decline in placental NAD+, alongside poorer pregnancy outcomes, suggesting this may be a conserved feature of reproductive aging.
• In aged placenta, NAD+ decline is driven by rising CD38, an NAD-consuming enzyme that becomes more active with age and inflammation.
• In aged mice, restoring NAD+—either with nicotinamide riboside (NR) or with a CD38-blocking drug—improved placental and fetal outcomes.
• CD38 breaks down NMN but has little effect on NR, which may give NR an advantage in tissues, like the aging placenta, where CD38 is highly active.

Delayed childbearing has become increasingly common, bringing greater attention to pregnancy complications associated with advanced maternal age, including fetal growth restriction, preterm birth, and preeclampsia.¹ Part of this increased risk appears to involve the placenta—the temporary but essential organ that delivers oxygen and nutrients to the fetus, removes waste, produces hormones, and helps coordinate immune communication between mother and fetus.²

The placenta naturally undergoes cellular senescence as pregnancy progresses.³ During senescence, cells stop dividing and start secreting inflammatory signals. Some of this process supports normal placental maturation and labor. However, when senescence begins too early or becomes excessive, it may interfere with placental function and fetal growth.³

What drives this age-related placental dysfunction is unclear. To investigate, a team of researchers led by groups at Sichuan Agricultural University and Nanchang University set out to uncover the underlying mechanisms. Their findings, published in Nature Communications, point to a familiar molecule at the center of it: NAD+ (nicotinamide adenine dinucleotide).⁴

How Maternal Age Affects Placental NAD+ and Infant Birth Weight

NAD+ is a coenzyme involved in hundreds of metabolic reactions, and its gradual decline is one of the most consistently observed features of aging across tissues.⁵ An earlier study found depleted NAD+ in placentas affected by inflammation-driven preeclampsia.⁶ This new research by Hua et al. extends that evidence in a different direction: toward maternal age itself, suggesting that NAD+ metabolism may play a broader role in placental function than previously recognized.⁴

The researchers measured 869 metabolites in placentas from younger women ages 20-25 and older women ages 35-44. Of the 60 metabolites that differed significantly between the groups, NAD+, NADH, and NADP+ stood out for their substantial reductions in placentas from older mothers.

Notably, these NAD+ levels correlated with birth weight. Higher placental levels of NAD+ were associated with higher infant birth weight. While this finding shows an association, it does not show cause and effect. Additionally, the researchers analyzed whole placental tissue collected at delivery, so this part of the research did not establish what occurred earlier in pregnancy.

The same pattern of age-related placental NAD+ decline also appeared in mice and pigs. In both species, older mothers had lower placental NAD+ levels, lower fetal weights, fewer live fetuses, and higher rates of pregnancy loss than younger mothers. Finding similar changes across three species suggested that placental NAD+ decline may be a shared feature of reproductive aging and provided a basis for investigating the underlying mechanism in animal models.

Where NAD+ Loss Is Greatest in the Aging Placenta

With that cross-species pattern established, the researchers turned to mouse placentas to pinpoint exactly where the decline was happening. The largest declines in NAD+ and NADH occurred in the decidua basalis and adjacent junctional zone—the outer placental layers where maternal and fetal tissues meet. This region is home to decidual stromal cells (DSCs), uterine-lining cells, which do a lot of the placenta’s heavy lifting: remodeling maternal blood vessels, keeping the mother’s immune system tolerant of the fetus, and supplying nutrients.⁷ 

In aged placentas, DSCs dropped from nearly 45% of cells in this region to under 24%, and the DSCs that remained showed signs of stress: elevated markers of senescence and inflammation.

At the same time, macrophages—immune cells that patrol tissue and respond to damage or distress—more than doubled in this same compartment with age, and spatial mapping showed them clustering closer to DSCs in aged placentas than in younger ones. This proximity turned out to be key to the mechanism discovered.

The CD38 Story: How Inflammation May Accelerate Placental NAD+ Loss

To understand why macrophages were gathering near stressed, NAD+-depleted DSCs, the researchers examined 11 NAD-related enzymes within placental macrophages. One stood out in particular: CD38.

CD38 is a protein found on several cell types, particularly immune cells, and has a well-established role in NAD+ biology.⁸ It is one of the body’s primary “NAD-consuming” enzymes, and its activity is known to increase with both age and inflammation.⁸

The researchers next tested whether inflammation and cellular damage could be driving the rise in placental CD38. They found that inducing inflammation or cellular stress in pregnant mice increased CD38, particularly in the placental region where NAD+ loss was greatest. Because CD38 consumes NAD+, this overlap suggests that the enzyme could be contributing to the local decline.

Further experiments strengthened this connection. Reducing macrophage numbers, blocking CD38 with a drug, or genetically removing CD38 from macrophages helped preserve placental NAD+ levels, reduce inflammation, and improve pregnancy outcomes, including larger litters and heavier fetuses. Together, these findings suggest that CD38 actively contributes to placental dysfunction rather than simply increasing alongside it.

Even with that connection established, one mechanistic question remained—and it was raised directly during peer review: CD38 does much of its work at the cell surface, while most NAD+ is located inside cells. How, then, could CD38 on macrophages lower NAD+ inside neighboring DSCs?

Answering the Reviewer: How Extracellular CD38 Creates an Intracellular NAD+ Problem

To address this question, the researchers added a series of cell-culture experiments during peer review. These experiments recreated the interaction between macrophages and DSCs and examined whether CD38 acted directly inside the DSCs or indirectly by changing the environment around them.

The results supported an indirect mechanism. Rather than entering DSCs and draining the NAD+ already inside them, CD38 appeared to reduce the availability of nicotinamide mononucleotide (NMN), an NAD+ precursor.

When DSCs were grown alone, adding NMN increased their NAD+ levels. However, when macrophages were placed nearby, that increase disappeared. Adding purified CD38 produced the same effect without macrophages present, showing that CD38 itself was sufficient to block the NMN-related increase in NAD+.

The researchers then used isatuximab, an antibody that blocks CD38 outside the cell but cannot enter it. Blocking extracellular CD38 restored NMN’s ability to raise NAD+ in the DSCs, confirming that the effect was occurring outside the cells.

Put simply, these experiments show that macrophage CD38 created a supply problem. It broke down NMN in the surrounding environment, leaving less available for DSCs to replenish their NAD+, rather than directly consuming the NAD+ already stored inside them.

Overall, these findings show that extracellular CD38 can limit NMN availability, a distinction that becomes especially relevant when comparing how CD38 interacts with NMN and nicotinamide riboside (NR), another precursor the body can use to produce NAD+.

Nicotinamide Riboside and CD38 Inhibition Improve Placental and Fetal Outcomes

After identifying macrophage CD38 as a driver of placental NAD+ loss, the researchers asked whether interrupting this process could improve pregnancy outcomes. They tested two approaches in aged pregnant mice, both administered daily by intraperitoneal injection: supplying NR and administering 78c, a drug that inhibits CD38.

Both treatments increased placental NAD+, improved fetal weight, and reduced the incidence of intrauterine growth restriction. They also reduced placental senescence, inflammation, and macrophage accumulation while improving placental structure, hormone levels, and the balance between fetal and placental weight. Similar benefits were observed when treatment began later in pregnancy, after fetal growth restriction had already developed.

NR also produced especially broad changes in placental gene activity. It reversed 92.3% of the genes that had increased with placental aging and 88.9% of those that had decreased. This does not mean the placenta was literally made young again. Rather, their overall gene-expression patterns shifted substantially toward that of younger placentas.

A Closer Look: Nicotinamide Riboside Inhibits CD38, Nicotinamide Mononucleotide Does Not

The placental study shows that macrophage CD38 can break down NMN in the environment around DSCs, impacting their NAD+ supply. This finding fits within a broader and growing body of research indicating that CD38 interacts very differently with NMN and NR.

CD38 readily recognizes NMN as a substrate and breaks it down.⁹ NR is structurally similar but lacks NMN’s phosphate group—a difference that gives NR direct, more efficient entry into cells.¹⁰ Earlier research has also shown that NR resists CD38-mediated breakdown.⁹

A 2024 study published in JACS Au examined this difference through structural and enzyme experiments.⁹ As expected, NMN was rapidly broken down by CD38. NR, in contrast, formed a stable bond within the enzyme’s active site and inhibited its activity.

This dual mechanism, more efficient cellular entry plus CD38 inhibition, provides a compelling biochemical framework for NR’s observed superiority: it can both support NAD+ production and may potentially reduce NAD+ consumption, thereby helping preserve cellular NAD+ levels. This proposed mechanism provides a plausible biochemical framework for why NR could perform differently from NMN in environments where CD38 is highly active.

Ex vivo whole blood findings from a 2026 human study led by researchers at Nestlé Research provide additional support for this distinction.¹¹ Although both precursors were rapidly broken down in whole blood, NR degradation followed the CD38-independent purine nucleoside phosphorylase (PNP) pathway. NMN’s breakdown products, by contrast, were consistent with CD38-mediated breakdown. In other words, NR avoided breakdown by CD38, while NMN was consumed through it.

While these findings establish a meaningful biochemical difference between NR and NMN, they do not yet show whether that difference translates into meaningful differences in health outcomes. An important next step will be to determine whether NR’s cellular transport pathway, resistance to CD38-mediated breakdown, and potential CD38 inhibition provide an advantage in tissues where CD38 is unusually active.

What This Research Means for Placental Aging, CD38, and NAD+

This study moves beyond simply observing that NAD+ declines with maternal age and offers a mechanism. Aging and inflammation raise CD38 levels in placental macrophages, which limits the raw materials nearby cells need to maintain their own NAD+. That shortfall appears to contribute to placental dysfunction and slower fetal growth, a pattern seen consistently across mice, pigs, and human placental tissue.

The findings also help explain a broader pattern in NAD+ research: CD38 breaks down NMN efficiently but has much less effect on NR, which may give NR an advantage in tissues, like the aging placenta, where CD38 is highly active. Whether this translates into real clinical benefit, though, is still unknown.

Key questions remain: whether placental NAD+ could serve as a useful biomarker, whether this CD38 pathway plays a similar role in human pregnancy complications, and whether NAD-targeted treatments could be both effective and safe during pregnancy. Answering them will require larger human studies. 

For now, this research provides a clear mechanism and a strong foundation for that work—real progress in understanding reproductive aging, even with meaningful distance left between mouse models and clinical use.

References

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