The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.

UNLABELLED: Aging drives chronic disease in part through senescent cells, including macrophages, which fuel inflammation. Senescent macrophages are functionally heterogeneous: canonical p16-high macrophages promote tumorigenesis or, in other contexts, disease tolerance, whereas we previously identified a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular basis of this senotype has remained undefined. Using genetic and multi-omic approaches, we show that a p53-p21-dependent program actively represses p16 and is required for senescent macrophage viability. We identify Cyclin D2 as a non-canonical downstream effector that redistributes from the nucleus to mitochondria and lipid droplets, where it partners with MIC60 to drive metabolic reprogramming and modulates AKT1-mTORC1 signaling that sustains the SASP. Cyclin D2-p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis, and can be selectively depleted by senolytic treatment. Together, these findings define a druggable p53-p21-Cyclin D2 axis that specifies macrophage senotype.

HIGHLIGHTS: ● A p53-p21-dependent program drives macrophage senescence while actively repressing p16● p16 repression promotes cell survival during acute genotoxic stress, but is dispensable for cell-cycle arrest and core senescence features in macrophages● Cyclin D2 is a non-canonical p53-p21 effector that relocalizes from nucleus to the cytosol and mitochondria● Cyclin D2 engages the AKT1-mTORC1 pathway and interacts with MIC60 to drive metabolic reprogramming● Cyclin D2+p21+ macrophages are abundant in aging, MASLD, and human liver cirrhosis, and can be targeted by senolytics.