Macrophage CD38 drives age-related placental senescence by depleting NAD+

In humans, mice, and pigs, aged placentas exhibit increased macrophage CD38 expression and NAD+ deficiency. Researchers used metabolomics, single-cell RNA sequencing, and spatial transcriptomics to map these conserved features during reproductive aging. Through genetic and pharmacological tests, the team found that CD38 on macrophages depletes NAD+ in neighboring decidual stromal cells, accelerating placental senescence. This CD38 rise is triggered by early-onset inflammation and senescence-associated secretory phenotype activity through the IRF5 pathway. Administering CD38 inhibitors or NAD+ precursors attenuated placental senescence, rescued intrauterine growth restriction, and improved long-term metabolic health in offspring.