The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.
- 1Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
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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BibTeX
@misc{torres2026p53p21cyclin,
title = {{The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.}},
author = {G. Torres and I. A. Salladay-Perez and C. Y. Deng and I. Avila and Y. Delgado and G. Tong and J. Munoz-Estrada and L. Estrada and A. Dhingra and W. R. Armstrong and A. Singh and I. Cooper and E. Enriquez and P. Kaushal and J. Ni and K. Chowdhury and C. Pan and L. Stiles and C. Beninca and S. T. Hui and A. Krall and H. Christofk and A. J. Lusis and T. E. O'Sullivan and J. G. Meyer and R. Singh and V. A. Tornini and O. S. Shirihai and M. Bouhaddou and A. J. Covarrubias},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.753597},
url = {https://www.biorxiv.org/content/10.64898/2026.09.22.753597v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.
AU - G. Torres
AU - I. A. Salladay-Perez
AU - C. Y. Deng
AU - I. Avila
AU - Y. Delgado
AU - G. Tong
AU - J. Munoz-Estrada
AU - L. Estrada
AU - A. Dhingra
AU - W. R. Armstrong
AU - A. Singh
AU - I. Cooper
AU - E. Enriquez
AU - P. Kaushal
AU - J. Ni
AU - K. Chowdhury
AU - C. Pan
AU - L. Stiles
AU - C. Beninca
AU - S. T. Hui
AU - A. Krall
AU - H. Christofk
AU - A. J. Lusis
AU - T. E. O'Sullivan
AU - J. G. Meyer
AU - R. Singh
AU - V. A. Tornini
AU - O. S. Shirihai
AU - M. Bouhaddou
AU - A. J. Covarrubias
PY - 2026
DA - 2026/09/22
PB - bioRxiv
DO - 10.64898/2026.09.22.753597
UR - https://www.biorxiv.org/content/10.64898/2026.09.22.753597v1
AB - 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.
ER -