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Sichuan Agricultural University

Nanchang University

Delayed childbearing is a global trend, necessitating a deeper understanding of the molecular mechanisms driving age-related placental senescence to develop innovative therapies. Progress, however, has been hindered partly by the scarcity of unbiased human placental metabolomics data and the complexity of placental heterogeneity. Here, combines unbiased metabolomics, single-cell RNA sequencing and spatial transcriptomics, we systematically characterize age-related placental senescence. We identify elevated macrophage CD38 expression and NAD+ deficiency as hallmark features of placentas from aged mothers in humans, mice, and sows. Pharmacological and genetic interventions reveal that macrophage CD38 leads to a decline in placental decidual stromal cells (DSCs) NAD+ levels, thereby accelerating placental senescence. Mechanistically, early-onset inflammation and the senescence-associated secretory phenotype upregulate CD38 expression in macrophages via IRF5. Consistently, treatment with NAD+ precursors or CD38 inhibitors alleviates age-related placental senescence, mitigates intrauterine growth restriction, and improves long-term metabolic health in adult offspring. This study enhances our understanding of placental senescence, uncovering novel diagnostic biomarkers and potential therapeutic targets for age-related placental disorders in humans.