Senescent Macrophages are Important in Liver Aging and Liver Disease
Senescent cells accumulate with age, but not all senescent populations are equal. Evidence suggests that some types of senescent cell cause more harm than others, and the research here is an example of this. Researchers find that a population of senescent macrophages in liver tissue acts as an important driver of chronic inflammation and dysfunction in liver aging and the metabolic liver disease associated with excess fat tissue that leads to cirrhosis and cancer. Senolytic therapies that selectively destroy the senescent macrophages reduce liver inflammation and liver dysfunction in mice, proving the point.
Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21+Trem2+ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling.
We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.