Nature agingAug 20, 2026

Blocking cyclin D1-CDK6 reduces age-related inflammation and loss of function

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 23, 2026

Abstract

Cyclin D1 (CCND1) is upregulated in senescent cells and may drive inflammation linked to aging.

Cellular senescence is associated with chronic inflammation due to the senescence-associated secretory phenotype (SASP), which includes interferon-stimulated genes (ISGs).
CCND1 and its partner CDK6 are implicated in promoting SASP and ISG expression in senescent cells by contributing to DNA damage accumulation.
This DNA damage results in the formation of cytoplasmic chromatin fragments that activate pro-inflammatory signaling pathways.
In aged mouse livers, increased Ccnd1 expression is observed in senescent hepatocytes.
Knockout of Ccnd1 in hepatocytes or treatment with the CDK4/6 inhibitor palbociclib reduces both DNA damage and ISG levels in aged mouse liver.
Palbociclib also shows potential to suppress frailty and enhance physical performance in aged mice.

Simplified

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.