A distinct p21-driven macrophage senotype accumulates during aging and liver disease

In a preprint analyzing mice and human liver cirrhosis tissue, researchers investigated a distinct macrophage senotype characterized by high p21 and low p16 expression. Using genetic and multi-omic approaches, the team found that a p53-p21-dependent pathway represses p16 to preserve senescent macrophage viability during acute genotoxic stress. Cyclin D2 acts as a downstream effector that redistributes from the nucleus to mitochondria and lipid droplets. There, Cyclin D2 binds MIC60 to reprogram metabolism and modulates AKT1-mTORC1 signaling, sustaining the senescence-associated secretory phenotype. These Cyclin D2- and p21-positive macrophages accumulate in aging and metabolic dysfunction-associated steatotic liver disease in mice and in human cirrhotic livers, but they can be selectively eliminated with senolytics.