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

Aging contributes to chronic diseases by creating senescent cells, such as macrophages, that promote inflammation. Macrophages can be divided into two functional groups: canonical p16-high cells, which can either cause cancer or provide disease tolerance, and a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD). Until now, the molecular mechanisms behind this specific senotype remained unclear.

To investigate this, researchers employed genetic and multi-omic techniques. Their findings reveal that a p53-p21-dependent program actively suppresses p16, which is crucial for the survival of senescent macrophages. The study also identifies Cyclin D2 as a non-canonical downstream effect of this program. Cyclin D2 moves from the nucleus to mitochondria and lipid droplets, partnering with MIC60 to orchestrate metabolic reprogramming and influence AKT1-mTORC1 signaling, which sustains the senescence-associated secretory phenotype (SASP).

In mice and humans with MASLD, there is an increase in double-positive macrophages that express both Cyclin D2 and p21. Selective depletion of these double-positive macrophages through senolytic treatment can mitigate the disease.

In summary, the research highlights a druggable p53-p21-Cyclin D2 axis that defines the macrophage senotype during aging and MASLD. This discovery could pave the way for novel therapeutic strategies to target and treat these conditions.