Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline
Year: 2025
Type: preprint
Abstract: Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating 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. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.
Authors: Adarsh Rajesh, Aaron P. Havas, Rouven Arnold, Kathryn Lande, K. Garrett Evensen, Kelly Yichen Li, Sainath Mamde, Qian Yang, Armin Gandhi, Karl N. Miller, Marcos Garcia Teneche, Zoe Yao, Jessica Proulx, Andrew Davis, Laurence Haddadin, Michael Alcaraz, Carolina C. Macip, Brightany Li, Xue Lei, Charlene Miciano, Elizabeth Smoot, Allen Wang, Jeffrey H. Albrecht, April E. Williams, Bing Ren, Kevin Y. Yip, Peter D. Adams
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Epigenetics of Aging and Age-Associated Diseases, Beckman Coulter Biomek i7 Hybrid automated workstation, Mitonuclear signaling pathways in senescence-associated inflammation, Cancer Center Support Grant (CCSG), Aging as a Risk Factor and Target for Prevention of Liver Cancer, Spatial mapping senescent cells across the mouse lifespan by multiplex transcriptomics and epigenomics
OpenAlex ID: W4412866894