Inhibiting cyclin D1-CDK6 suppresses senescence-associated inflammatory gene expression and age-related functional decline.

Adarsh Rajesh, Aaron P Havas, Rouven Arnold, Kathryn Lande, Xue Lei, Kelly Yichen Li, Armin Gandhi, Ana Catarina Franco, Seung-Hwa Woo, Anthony B Lagnado, Angela Liou, K Garrett Evensen, Linshan Laux, Maggie Klaers, Jake Kircher, Amirhossein Nayeri Rad, Hiroshi Tanaka, Marcos Garcia Teneche, Michael Alcaraz, Karl N Miller, Zoe Yao, Sviatlana Zaretski, Sainath Mamde, Qian Yang, Jessica Proulx, Andrew Davis, Laurence Haddadin, Carolina Cano Macip, Brightany Li, Nirmalya Dasgupta, Zong Ming Chua, Cedomir Stamenkovic, Gabriele Guarnaccia, Hideki Tanizawa, Charlene Miciano, Elizabeth Smoot, Allen Wang, Rebecca A Porritt, Alessandra Sacco, Ken-Ichi Noma, Jeffrey H Albrecht, Laura J Niedernhofer, Joao F Passos, April E Williams, Bing Ren, Kevin Y Yip, Peter D Adams

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. · pubmed

Paper

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.

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Research summary

The study demonstrates that inhibiting the cyclin D1-CDK6 axis reduces senescence-associated inflammatory signaling and improves physical function in aged mice, suggesting a potential therapeutic avenue for mitigating age-related functional decline. This work is relevant because it targets cellular senescence, a fundamental hallmark of aging, rather than merely treating specific age-related diseases, although the findings represent an incremental advance in the field of senolytics/senomorphics rather than a transformative breakthrough.

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