Gestational Longevity in Inflammatory Rheumatic Diseases: A Geroscience-Based Hypothesis Linking Maternal Inflammaging to Trophoblast Pyroptosis

Inflammatory rheumatic diseases are associated with premature immune aging and chronic low-grade inflammation, yet their potential influence on placental biology remains incompletely understood. We hypothesize that maternal inflammaging creates a biological susceptibility state at the maternal–fetal interface that predisposes trophoblasts to inflammasome activation and pyroptosis rather than directly triggering pyroptotic cell death. Disease-specific placental stressors may converge on the NOD-like receptor family pyrin domain containing 3 (NLRP3)–caspase-1–gasdermin D (GSDMD) pyroptosis axis. Supporting evidence includes hypoxia-inducible factor 1-alpha/peroxisome proliferator-activated receptor gamma signaling in rheumatoid arthritis, neutrophil extracellular trap-associated glycolysis and NLRP3 lactylation in systemic lupus erythematosus, and anti-beta-2-glycoprotein I–Toll-like receptor 4/NLRP3/GSDMD signaling in obstetric antiphospholipid syndrome. To test this hypothesis, we propose a prospective longitudinal framework integrating maternal biological aging, inflammaging and immune-aging biomarkers, pyroptosis-related markers, ovarian reserve, uteroplacental vascular assessment, and pregnancy outcomes. Mechanistic studies targeting the NLRP3–caspase-1–GSDMD pathway could complement clinical validation. This framework introduces “gestational healthspan” as a translational objective aimed at preserving maternal biological health and placental function while minimising adverse obstetric outcomes.