Macrophages, a type of immune cell, deplete the metabolic molecule NAD⁺ in the placentas of older mice
Macrophages, a type of immune cell, deplete the metabolic molecule NAD⁺ in the placentas of older mice
On August 27, Nature Communications published a study in which the authors found an age-related decline in NAD⁺ and an increase in macrophage CD38 in human, mouse, and pig placentas. They tested the proposed mechanism and interventions in mice.
The placenta supports exchange between the mother and fetus, while its maternal compartment helps remodel maternal blood vessels during pregnancy. NAD⁺ is a molecule involved in cellular metabolism. The researchers examined placentas collected after full-term births from 13 women aged 20–25 and 13 women aged 35–44. Levels of NAD⁺ and related compounds were lower in the second group. The authors found a similar decline in NAD⁺ in older mice and pigs.
Single-cell analysis of the maternal compartment of mouse placentas revealed an age-related shift. The proportion of stromal cells that help remodel maternal blood vessels fell from 44.8% to 23.9%, while the proportion of macrophages rose from 7.7% to 17.1%. Spatial mapping of placental sections showed that these two cell types were located closer together in older placentas. Among 11 enzymes involved in NAD⁺ metabolism, CD38 showed the largest age-related increase in macrophages.
CD38 on the macrophage surface breaks down NMN, a molecule that cells can use to produce NAD⁺. In a two-chamber system separated by a permeable membrane, NMN increased NAD⁺ levels in stromal cells. This increase did not occur when macrophages were present. Purified CD38 reproduced the effect. After the macrophages were treated with an antibody that blocked the external activity of CD38, their medium once again allowed NMN to increase NAD⁺ in stromal cells.
In eight-month-old mice, the researchers switched off the Cd38 gene in myeloid lineage cells, a group of immune cells that includes macrophages. Mean fetal weight increased from 0.887 to 0.961 grams, while the proportion of fetuses with intrauterine growth restriction fell from 24.4% to 8.9%. In the same mouse model, daily injections of nicotinamide riboside, a precursor of NAD⁺, together with the CD38 inhibitor 78c increased placental NAD⁺ and improved the same outcomes.
In a separate cell experiment, medium from stromal cells obtained from older mice increased CD38 in macrophages. Based on the mouse model, the authors propose the following sequence: age-related inflammation and signals from stromal cells increase CD38, which then consumes NMN that would otherwise be available to neighboring stromal cells.