The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.
Torres, G.; Salladay-Perez, I. A.; Deng, C. Y.; Avila, I.; Delgado, Y.; Tong, G.; Munoz-Estrada, J.; Estrada, L.; Dhingra, A.; Armstrong, W. R.; Singh, A.; Cooper, I.; Enriquez, E.; Kaushal, P.; Ni, J.; Chowdhury, K.; Pan, C.; Stiles, L.; Beninca, C.; Hui, S. T.; Krall, A.; Christofk, H.; Lusis, A. J.; O'Sullivan, T. E.; Meyer, J. G.; Singh, R.; Tornini, V. A.; Shirihai, O. S.; Bouhaddou, M.; Covarrubias, A. J.
Show abstract
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.
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