TRAF1 promotes age-related cardiac dysfunction through a three-step mechanism: cardiomyocyte senescence, mitochondrial DNA release, and subsequent macrophage-driven inflammation

Heart failure (HF) is a prevalent age-associated cardiovascular disease characterized by progressive cardiac decline and poor clinical outcomes. The molecular drivers underlying HF pathogenesis remain incompletely understood. This study identifies TNF receptor-associated factor 1 (TRAF1) as a critical regulator of age-related cardiac dysfunction and delineates its underlying mechanisms. Bioinformatics analysis of GEO datasets screened for differentially expressed genes linked to cardiac aging. In vivo , naturally aged (90-week-old) C57BL/6J mice of both sexes received cardiomyocyte-specific TRAF1 knockdown via tail-vein injection of AAV9 carrying a cTnT promoter-driven shTRAF1 construct, and cardiac phenotypes were assessed at 110 weeks of age. In vitro , D-galactose (D-gal)-treated primary cardiomyocytes were subjected to TRAF1 knockdown or overexpression. ROS production, mtDNA leakage, macrophage inflammatory activation, and inflammation were assessed. TRAF1 was markedly upregulated in aged and failing hearts. In vitro , TRAF1 knockdown attenuated D-gal-induced cardiomyocyte senescence and ROS accumulation, whereas overexpression exacerbated these changes. Mechanistically, TRAF1 activated NF-κB signaling and increased Nox2 expression, promoting mtDNA release from senescent cardiomyocytes. This extracellular mtDNA engaged the cGAS-STING pathway in macrophages, amplifying cardiac inflammation. In vivo , cardiomyocyte-specific TRAF1 knockdown in naturally aged mice reduced cardiac ROS levels, cardiac inflammatory macrophage infiltration, and serum pro-inflammatory cytokines, attenuated cardiac hypertrophy, and improved diastolic function (reduced E/A and E/e′ ratios) without affecting ejection fraction. TRAF1 is a pivotal driver of aging-related cardiac dysfunction that integrates oxidative stress and mtDNA release via the NF-κB axis. Targeting TRAF1 may offer a promising therapeutic strategy for age-related cardiac dysfunction in elderly patients. Up-regulated TRAF1 in senescent cardiomyocytes promotes NF-κB-mediated oxidative stress and mtDNA release, which activates the macrophage cGAS-STING-IRF3 pathway to drive pro-inflammatory responses, ultimately exacerbating cardiac functional decline.