GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE344nnn/GSE344240/primaryOK200GenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencing Expression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE344240GEOGSEfalseInhibiting Cyclin D1–CDK6 Suppresses Senescence-Associated Inflammatory Gene Expression and Age-Related Functional DeclineCellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP), including interferon-stimulated genes (ISGs). We confirm and extend previous observations that Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated across models of non-proliferating 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 (CCFs) that activate pro-inflammatory cGAS–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.2026/08/21GSE344240GSM9973429GSM9973428GSM9973427GSM9973449GSM9973426GSM9973448GSM9973447GSM9973425GSM9973424GSM9973446GSM9973445GSM9973444GSM9973443GSM9973442GSM9973441GSM9973440GSM9973439GSM9973438GSM9973437GSM9973436GSM9973435GSM9973434GSM9973433GSM9973455GSM9973454GSM9973432GSM9973453GSM9973431GSM9973430GSM9973452GSM9973451GSM99734503730534290344240Mus musculus