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.

Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. · biorxiv

Paper

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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Research summary

The p53-p21-Cyclin D2 axis drives metabolic reprogramming and defines a distinct senescent macrophage senotype that accumulates with aging and can be selectively depleted by senolytics. This paper is relevant because it identifies a specific, druggable molecular mechanism underlying cellular senescence in macrophages, a key driver of age-related inflammation and metabolic disease, thereby providing a precise target for senolytic interventions aimed at extending healthspan.

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