CD38 is tied to age-related placental NAD+ decline in preclinical study

According to a new announcement from Niagen Bioscience, a preclinical study published in Nature Communications identifies the enzyme CD38 as a driver of age-related placental NAD+ decline.¹^,² Placentas from older mothers held less NAD+, NADH, and NADP+ than placentas from younger mothers, and higher levels were associated with higher infant birth weight.² In aged pregnant mice, oral nicotinamide riboside (NR) or the CD38 inhibitor 78c restored placental NAD+ and improved fetal growth.²

The study authors cite rising rates of delayed childbearing as the rationale for defining mechanisms of placental aging.¹ They describe this mechanistic understanding as critical for developing effective therapeutic strategies for age-associated pregnancy complications.¹ The paper was published online August 27, 2026, as an accepted manuscript, and Niagen announced the findings September 21, 2026.¹^,²

Investigators at Sichuan Agricultural University in China, with a collaborator from the Department of Obstetrics and Gynecology at The Second Affiliated Hospital of Nanchang University, integrated metabolomics, single-cell RNA sequencing, and spatial transcriptomics.¹ Across human, mouse, and pig placental tissue, aging was consistently associated with lower NAD+, NADH, and NADP+ and with increased NAD+-consuming enzymes, including CD38.¹^,² Aged mice and pigs also showed poorer pregnancy outcomes, which the announcement characterizes as a conserved metabolic signature of reproductive aging.²

Using pharmacological and genetic approaches, the investigators traced the decline to CD38-expressing macrophages accumulating in aged placental tissue and depleting NAD+ in neighboring decidual stromal cells.¹^,² Early-onset inflammation and senescence-associated secretory phenotype activity drove macrophage CD38 expression through the IRF5 pathway.¹ According to the announcement, the resulting NAD+ depletion fueled further inflammation in mice, creating a self-reinforcing cycle.²

Nicotinamide riboside and CD38 inhibitor 78c improve outcomes in aged pregnant mice

In aged pregnant mice, both oral NR and 78c restored placental NAD+, improved fetal growth, and shifted placental gene expression toward a younger profile.² The study authors report both approaches attenuated age-related placental senescence, rescued intrauterine growth restriction, and improved long-term metabolic outcomes in offspring.¹ According to the announcement, investigators detected no signs of maternal toxicity.²

In mouse cells, CD38 degraded nicotinamide mononucleotide (NMN), another NAD+ precursor, outside the cell and blocked its ability to raise NAD+ levels.² The announcement pairs this finding with previously published research showing NR inhibits CD38 and concludes NR may be more effective in tissues with high CD38 activity.² The announcement does not describe a direct comparison of NR and NMN in aged pregnant animals.²

Niagen Bioscience, which manufactures an NR ingredient, did not conduct, fund, or design the study, and the NR used was not the company's Niagen ingredient.² The study authors declared no competing interests, and funding came from Chinese national research programs.¹

Andrew Shao, PhD, senior vice president of global scientific and regulatory affairs at Niagen Bioscience, said in the announcement the paper "demonstrated age-related decline in placental tissue NAD+."² He added the study "showed the positive reproductive effects of increasing NAD+ with NR."²

The announcement acknowledges additional clinical research is needed to confirm these findings.² The human placental data are associational, and neither NR nor 78c was evaluated in pregnant patients.¹^,² For ob-gyns managing pregnancies of advanced maternal age, the work offers a mechanistic framework for age-related placental dysfunction and identifies CD38 as a candidate target for future clinical investigation.¹

REFERENCES

1. Hua L, Yang X, Gao D, et al. CD38-activated macrophages drive age-related placental senescence by depleting NAD+ in decidual stromal cells. Nat Commun. Published online August 27, 2026. Accessed September 24, 2026. doi:10.1038/s41467-026-77217-5

2. Newly published preclinical study demonstrates CD38 as a driver of age-related NAD+ decline, older mothers have lower NAD+ levels in placental tissue, and NAD+ restoration with nicotinamide riboside (NR) improves pregnancy outcomes. News release. Niagen Bioscience. September 21, 2026. Accessed September 24, 2026. https://www.businesswire.com/news/home/20260921027362/en/