P21+TREM2+-Senescent Macrophages Fuel Inflammaging and Metabolic Dysfunction-Associated Steatotic Liver Disease [NAFLD_time_course]

Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype (SASP); however, the cell types responsible for this pathology remain poorly defined. Here, we identify p21?Trem2? senescent macrophages as a major source of inflammaging. Using primary mouse and human macrophages, we developed a model of DNA damage and cholesterol-induced senescence and applied multi-omic profiling to fully characterize senescent macrophages. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and SASP, driven in part by type-I interferon signaling via secreted mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aged and MASLD mouse livers and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged and MASLD mice. Together, these findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, highlighting a promising, tractable therapeutic target. Overall design: APOE*Leiden-CETP mice were crossed with 3 genetically distinct strains of mice with known response to liver fibrosis48. These strains include: 129/SvJ (fibrosis resistant), C57BL/6J (Medium fibrosis), and BXD19/TyJ (fibrosis prone). Animals were maintained on a 12-hour light–dark cycle with ad libitum access to water. Male mice (8-10 weeks old) were fed a high fat high cholesterol diet (33 kcal% fat from cocoa butter and 1% cholesterol; Research Diets; catalog no. D10042101) for 16 weeks. At the end of the study, mice were fasted for 4 hours beginning at 10:00 am and sacrificed at 02:00 pm.