Introduction and Objective: Age-associated metabolic disorders are closely linked to chronic inflammation orchestrated by macrophages. While mitochondrial dysfunction in these cells is central to the process, how Optic atrophy 1(OPA1) influences metabolic aging remains unclear. Methods: We generated myeloid-specific OPA1 knockout, OPA1-overexpressing, OPA1-overexpressing/STAT6-knockout, and OPA1/cGAS double knockout mice to assess age-related metabolic and inflammatory phenotypes and molecular mechanisms. Results: OPA1 expression in adipose tissue macrophages declined with aging. Myeloid OPA1 deficiency promoted a pro-inflammatory shift specifically in perivascular macrophages (PVMs) in vivo. This transition was further characterized in vitro, where OPA1 loss triggered senescence in M2-polarized macrophages. Consequently, OPA1-deficient PVM senescence drove age-associated metabolic deterioration. Conversely, OPA1 overexpression rescued PVM anti-inflammatory function and alleviated age-related metabolic dysfunction. Mechanistically, OPA1 deficiency impaired the IL-4/STAT6 axis by activating the mtDNA-cGAS/STING signaling pathway. This functional link was confirmed in vivo by OPA1-overexpressing/STAT6-knockout, and OPA1/cGAS double knockout mice. Conclusion: We identify the OPA1-mtDNA-cGAS-STING-STAT6 axis as a key driver of PVM senescence and metabolic aging, revealing a novel therapeutic target for age-related metabolic diseases. Disclosure L. Yao: None. D. Wang: None. X. Lyu: None. R. Qi: None. L. You: None. J. Yan: None. C. Hu: None. Funding National Science Fund for Distinguished Young Scholars (82325010)
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