Disruption of CDK4/6-RARα-NF-κB axis attenuates senescence-associated inflammation and improves function during aging and following chemotherapy.

Senescent cells accumulate following chemotherapy and during aging, where they contribute to dysfunction through the pro-inflammatory arm of the senescence-associated secretory phenotype (SASP), termed NF-κB-associated SASP (NASP). Here we show that short-term inhibition of CDK4/6 with abemaciclib suppresses established NASP in pre-existing senescent cells both in vitro and in vivo. This senomorphic effect reduces the pro-tumorigenic activity of chemotherapy-induced senescent cells and improves physical function in mice following chemotherapy. Genetic knockdown of CDK4/6 phenocopied these effects, confirming a CDK4/6-dependent mechanism. Mechanistically, CDK4/6 inhibition suppressed retinoic acid signaling, and the RARα antagonist agn194310 similarly reduced NASP expression. CDK4 and CDK6 interacted with NF-κB, while CDK4 additionally bound RARα, and these interactions were disrupted by abemaciclib. In aged mice, abemaciclib and agn194310 reduced systemic NASP expression and improved physical performance. Together, these findings identify the CDK4/6-RARα-NF-κB axis as a therapeutic target for senomorphic interventions.