The p53–p21–Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD
Year: 2026
Type: preprint
Abstract: Summary 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
Authors: Grasiela Torres, Ivan A. Salladay-Perez, Christina Y. Deng, Itzetl Avila, Yennifer Delgado, Gregory Tong, Jesús Muñoz-Estrada, Lizeth Estrada, Anika Dhingra, Wesley R. Armstrong, Aishini Singh, Isabella Cooper, Eduardo Enriquez, Prashant Kaushal, Jocelyn Ni, Kushan Chowdhury, Calvin Pan, Linsey Stiles, Cristiane Beninca, Simon T. Hui, Abbigail S. Krall, Heather R. Christofk, Aldons J. Lusis, Timothy E. O’Sullivan, Jesse G. Meyer, Rajat Singh, Valerie A. Tornini, Orian S. Shirihai, Mehdi Bouhaddou, Anthony J. Covarrubias
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Funders: Glenn Foundation for Medical Research, National Institutes of Health, University of California, San Diego, School of Life Sciences and Biotechnology Division of Life Sciences, Korea University, Office of Naval Research, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Office of Behavioral and Social Sciences Research
Awards: G4679579238, G598865872, G9000342382, Multidisciplinary Training in Microbial Pathogenesis, UCLA LIFT-UP (Leveraging Institutional support For Talented, Upcoming Physicians and/or Scientists), Diabetes Research Center (DRC), Exploring the fundamental cellular mechanisms driving cellular senescence in macrophages, Research Training in Cell and Molecular Biology
OpenAlex ID: W7214610432