Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline

2025 · doi:10.1101/2025.08.01.668243
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⚙ AI-generated summary by claude@2026-07, 2026-07-17 ⓘ

This study found that cyclin D1 and CDK6 promote DNA damage and inflammation in senescent cells via CCF formation, and inhibiting CDK4/6 in aged mice reduced inflammation, frailty, and improved physical performance.

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The study investigated how cellular senescence promotes chronic inflammation, focusing on the cell-cycle regulators CCND1 and CDK6 and their links to DNA damage, Senescence Associated Secretory Phenotype (SASP), and interferon-stimulated gene (ISG) expression. Using senescent cell models and aged mouse liver analyses, the authors found that CCND1–CDK6 drives DNA damage accumulation, which generates cytoplasmic chromatin fragments that activate CGAS–STING signaling to increase SASP and ISGs, while TP53 and its target p21 antagonize this pathway. In aged mouse livers, senescent hepatocytes showed increased Ccnd1, and hepatocyte-specific Ccnd1 knockout or palbociclib (a CDK4/6 inhibitor) reduced DNA damage and ISGs and was associated with reduced frailty and improved physical performance. The authors note an explicit limitation that their findings are centered on senescence and aging in hepatocytes and related models, not on other disease contexts. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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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.
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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. Competing Interest Statement The authors have declared no competing interest.

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License: CC-BY-4.0