Context‐Dependent Roles of ANGPTL2 ‐Mediated Inflammaging in Tissue Homeostasis, Pathological Tissue Remodeling, and Longevity

Chronic inflammation is a key driver of aging-related diseases, obesity-associated metabolic disorders, and tumor progression. Aging and obesity contribute to the accumulation of senescent cells, which secrete senescence-associated secretory phenotype (SASP) factors that promote tissue remodeling and chronic inflammation. Here, we investigated the pathological roles of angiopoietin-like protein 2 (ANGPTL2), a potential SASP factor, in a mouse model of high-fat diet-induced premature aging. We found that ANGPTL2 deficiency shortened lifespan but attenuated systemic inflammation, indicating a complex role for ANGPTL2 in aging-related processes. ANGPTL2 was required for maintaining intestinal homeostasis under metabolic stress; however, ANGPTL2 also exacerbated adipocyte hypertrophy and cardiac dysfunction. Furthermore, ANGPTL2-mediated inflammation promoted kidney fibrosis but paradoxically protected against perivascular fibrosis in the liver, indicating its organ-specific effects on fibrotic remodeling. In addition, ANGPTL2 influenced immune responses by driving bronchus-associated lymphoid tissue formation. These findings suggest that ANGPTL2 has context-dependent effects, balancing tissue homeostasis and inflammation-driven pathologies. Our study provides novel insights into the dual roles of ANGPTL2 as a SASP factor in regulating inflammation, fibrosis, and tissue remodeling across different organ systems.