Preclinical study results showcase that CD38, an NAD-consuming enzyme more active with age and inflammation, leads to NAD+ depletion in placental tissue, while restoring NAD+ with the precursor NR improved placental, fetal, and offspring outcomes in aged mice

Niagen Bioscience, Inc. (NASDAQ:NAGE), the global authority on NAD+ (nicotinamide adenine dinucleotide) with a focus on the science of healthy aging, today announces the publication of independent preclinical research in Nature Communications led by a team at Sichuan Agricultural University identifying the CD38 enzyme as a primary driver of NAD+ decline in aging tissue, and that nicotinamide riboside (NR) restored NAD+ and improved placental, fetal, and offspring outcomes in aged mice despite elevated CD38.

The researchers measured NAD+ and related metabolites in human placental tissue from younger and older mothers and found older placentas held less NAD+, NADH, and NADP+. Higher placental levels of the NAD+, NADH, and NADP+ metabolites were associated with higher infant birth weight. Mice and pigs showed the same age-related decline alongside poorer pregnancy outcomes, suggesting a broader feature of reproductive aging rather than specific to one species.

Andrew Shao, PhD, Senior Vice President, Global Scientific & Regulatory Affairs at Niagen Bioscience stated, "This paper demonstrated age-related decline in placental tissue NAD+, reaffirmed that CD38 consumes both NAD+ and NMN, and showed the positive reproductive effects of increasing NAD+ with NR."

Niagen Bioscience did not conduct, fund, or design this study, and the NR used was not the Company’s Niagen ingredient. The Company is highlighting the work because the results speak to the mechanism behind NAD+ decline and how different NAD+ precursors behave in tissue where that mechanism is most active.

The demand side of NAD+ decline

This research provides insight into how NAD+ consumption increases with age by overactivation of CD38. CD38 is a multifunctional ectoenzyme, and its expression increases with age in multiple cell types, particularly on the surface of immune cells, contributing to metabolic changes and age-related inflammation. In addition, CD38 degrades another precursor, nicotinamide mononucleotide (NMN). This CD38 action exacerbates inflammation, which drives CD38 activity, and so on.

The authors traced the source to CD38-expressing macrophages accumulating in aged placental tissue and depleting NAD+ in neighboring decidual stromal cells. Across several experiments, the authors showed that the CD38 enzyme acts on NAD+ and NMN outside the cell, before they can cross the cell and be used.

CD38 consumes NMN, while previous research shows NR inhibits CD38

The analysis examined how CD38 inhibition vs. NAD+ boosting with NR affects NAD+ in placental tissues and reproductive outcomes. Consistent with previous findings, the study also demonstrated NMN is also a substrate for CD38. NMN cannot enter the cell directly because it carries a phosphate group, which prevents it from crossing the cell membrane intact. Because NMN must be converted first, it is left outside the cell and exposed. The authors observed that CD38 breaks down NMN, while previously published research demonstrates NR actually inhibits CD38 activity (Kao et al., 2024). This suggests that in tissues with high CD38 activity, NR is more effective than NMN because NMN may not survive long enough to be used by the cell.

Preclinical study overview

The investigators analyzed human placental tissue from younger and older mothers in mouse and pig models. They profiled NAD+ and related metabolites, identified the cell population responsible for the decline, and then tested whether restoring NAD+ changed outcomes. They attempted restoration in two ways: oral NR and CD38 inhibitor(78c).

Key findings

  • Across humans, mice, and pigs, placental aging was consistently associated with lower NAD+, NADH, NADP+, identifying a conserved metabolic signature of reproductive aging.
  • Higher placental levels of these metabolites were associated with higher infant birth weight.
  • Aged mice and pigs showed the same decline in placental NAD+ alongside poorer pregnancy outcomes.
  • Mechanistic studies showed that CD38 macrophages depleted NAD+ in neighboring stromal cells
  • In aged pregnant mice, NR administration or CD38 inhibitor restored placental NAD+, improved fetal growth, and shifted placental gene expression toward a younger profile.
  • CD38 degraded NMN outside the cell, blocking its ability to elevate NAD+ levels. Previously published research shows that NR inhibits CD38, suggesting NR may be more effective in tissues where CD38 activity is high (Kao et al., 2024).