Rajesh, Adarsh, Havas, Aaron P, Arnold, Rouven, Lande, Kathryn, Lei, Xue, Li, Kelly Yichen, Gandhi, Armin, Franco, Ana Catarina, Woo, Seung-Hwa, Lagnado, Anthony B, Liou, Angela, Evensen, K Garrett, Laux, Linshan, Klaers, Maggie, Kircher, Jake, Rad, Amirhossein Nayeri, Tanaka, Hiroshi, Teneche, Marcos Garcia, Alcaraz, Michael, Miller, Karl N, Yao, Zoe, Zaretski, Sviatlana, Mamde, Sainath, Yang, Qian, Proulx, Jessica, Davis, Andrew, Haddadin, Laurence, Macip, Carolina Cano, Li, Brightany, Dasgupta, Nirmalya, Chua, Zong Ming, Stamenkovic, Cedomir, Guarnaccia, Gabriele, Tanizawa, Hideki, Miciano, Charlene, Smoot, Elizabeth, Wang, Allen, Porritt, Rebecca A, Sacco, Alessandra, Noma, Ken-Ichi, Albrecht, Jeffrey H, Niedernhofer, Laura J, Passos, Joao F, Williams, April E, Ren, Bing, Yip, Kevin Y, Adams, Peter D (August 2026) Inhibiting cyclin D1-CDK6 suppresses senescence-associated inflammatory gene expression and age-related functional decline. Nature Aging. ISSN 2662-8465
Abstract
Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the senescence-associated secretory phenotype (SASP), including interferon-stimulated genes (ISGs). Here we confirm and extend previous observations that cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated across models of nonproliferating 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 that activate pro-inflammatory cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (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. Further, palbociclib suppresses frailty and improves physical performance of aged mice. These findings demonstrate a role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising target for therapeutic repurposing.
| Item Type: | Paper |
|---|---|
| Subjects: | organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence |
| CSHL Authors: | |
| Communities: | CSHL Post Doctoral Fellows CSHL labs > Amor lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 20 August 2026 |
| Date Deposited: | 04 Sep 2026 13:29 |
| Last Modified: | 04 Sep 2026 13:29 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42306 |
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