Disruption of CDK4/6-RARalpha-NF-kB axis attenuates senescence-associated inflammation and improves function during aging and following chemotherapy

Boshi Wang, Alessio Piccolantonio, Abdullah Altulea, Eugene Berezikov, Marco Demaria

1. 01

   Short-term abemaciclib suppressed established NF-kB-associated SASP (NASP) in pre-existing senescent cells, in vitro and in vivo

2. 02

   Reduced the pro-tumorigenic activity of chemotherapy-induced senescent cells

3. 03

   Improved physical function in mice following chemotherapy

4. 04

   Genetic CDK4/6 knockdown phenocopied the effect, confirming target dependence

5. 05

   Mechanism: CDK4/6 inhibition suppresses retinoic acid signalling; CDK4 and CDK6 bind NF-kB and CDK4 additionally binds RARalpha; abemaciclib disrupts both interactions

6. 06

   The RARalpha antagonist agn194310 reproduced NASP suppression; in aged mice both agents lowered systemic NASP and improved physical performance

Study Design

Preclinical Study

Sample Size

Not reported

Study Duration

Short-term dosing in aged and post-chemotherapy mice

Methodology

In vitro senescence models with established SASP; genetic CDK4/6 knockdown; pharmacological abemaciclib and agn194310 dosing in chemotherapy-treated and naturally aged mice; co-immunoprecipitation of CDK4/6 with NF-kB and RARalpha; systemic NASP transcriptional profiling and physical performance testing.

Limitations

Preclinical mouse and in vitro data only; no human aging trial of CDK4/6 inhibition exists. Abemaciclib and other CDK4/6 inhibitors carry clinically significant neutropenia, diarrhoea, hepatotoxicity, interstitial lung disease and venous thromboembolism risk in oncology use. This is a mechanistic lead for senomorphic drug development, NOT a basis for off-label geroprotective prescribing.