Cyclin D1 (CCND1) and CDK6 drive senescence-associated inflammatory gene expression by promoting DNA damage and cytoplasmic chromatin fragment formation that activates cGAS-STING signaling, and inhibiting this pathway with palbociclib reduces frailty and improves physical performance in aged mice.
Cyclin D1 (CCND1) is paradoxically upregulated across multiple models of nonproliferating senescent cells.
CCND1 and its kinase partner CDK6 drive SASP and interferon-stimulated gene (ISG) expression in senescent cells.
Senescent hepatocytes in aged mouse livers show increased Ccnd1 expression.
Hepatocyte-specific Ccnd1 knockout reduces DNA damage and ISG expression in aged mouse liver.
Treatment with the clinical-grade CDK4/6 inhibitor palbociclib reduces DNA damage and ISG expression in aged mouse liver.
Palbociclib suppresses frailty and improves physical performance in aged mice.
Cyclin D1-CDK6 signaling is identified as a promising target for therapeutic repurposing to address aging-related inflammation and functional decline.
This research suggests that a protein called cyclin D1 (CCND1), normally associated with cell division, plays an unexpected and harmful role in aging cells that have stopped dividing (called senescent cells). In these senescent cells, CCND1 teams up with another protein called CDK6 to cause DNA damage. This damaged DNA leaks out of the nucleus into the surrounding cell fluid, triggering an alarm system (called cGAS-STING) that floods the body with inflammatory signals. This chronic inflammation is thought to drive many of the harmful effects of aging. The researchers found this process happening in real aged mouse livers, where senescent liver cells had unusually high levels of CCND1. To test whether blocking CCND1/CDK6 could help, the researchers used two approaches in aged mice: one where the Ccnd1 gene was specifically deleted in liver cells, and another where mice were treated with palbociclib, a cancer drug already approved for human use that inhibits CDK4 and CDK6. Both approaches reduced DNA damage and inflammatory gene activity in aged mouse livers. Most strikingly, palbociclib-treated aged mice showed less frailty and better physical performance, suggesting the drug could counteract some functional consequences of aging. This research suggests that palbociclib, which is already used to treat certain cancers, might be repurposed to address inflammation and functional decline associated with aging. The findings point to a new understanding of how a cell cycle protein contributes to the biology of aging, and open a potential avenue for using existing approved drugs to target age-related diseases driven by chronic inflammation from senescent cells.
Rajesh A, Havas A, Arnold R, Lande K, Lei X, Li K, et al.. (2026). Inhibiting cyclin D1-CDK6 suppresses senescence-associated inflammatory gene expression and age-related functional decline.. Nature aging. https://doi.org/10.1038/s43587-026-01196-x