Inhibiting Cyclin D1–CDK6 Suppresses Senescence-Associated Inflammatory Gene Expression and Age-Related Functional Decline

We confirm and extend previous observations that Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated across models of non-proliferating senescent cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation.

This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory cGAS–STING signaling. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the clinical grade CDK4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver.