CD38-activated macrophages drive age-related placental senescence by depleting NAD+ in decidual stromal cells

Abstract

As delayed childbearing becomes increasingly common, elucidating the mechanisms of age-related placental senescence is critical for the development of effective therapeutic strategies. Here, we integrate metabolomics, single-cell RNA sequencing, and spatial transcriptomics to uncover conserved features of aged placentas in humans, mice, and pigs, namely, increased macrophage CD38 expression and NAD⁺ deficiency. Through pharmacological and genetic approaches, we demonstrate that macrophage CD38 depletes NAD⁺ in decidual stromal cells, thereby promoting placental senescence. Mechanistically, early-onset inflammation and senescence-associated secretory phenotype activity drive CD38 expression in macrophages via the IRF5 pathway. Importantly, treatment with NAD⁺ precursors or CD38 inhibitors attenuates age-related placental senescence, rescues intrauterine growth restriction, and improves long-term metabolic outcomes in offspring. These findings reveal a critical role for macrophage-driven metabolic dysregulation in reproductive aging and establish CD38 as a potential therapeutic target for age-associated pregnancy complications. The authors show that CD38-activated macrophages deplete NAD+ in decidual stromal cells, driving placental senescence and fetal growth restriction during aging. NAD+ restoration in animal models improves pregnancy outcomes and offspring health.