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Accumulation of senescent cells with age is an important driver of aging and age-related diseases. However, the mechanisms and signaling pathways that regulate senescence remain elusive. In this report, we performed post-genome-wide association studies (GWAS) functional studies on the  CDKN2A/B  locus, a locus known to be associated with multiple age-related diseases and overall human lifespan. We demonstrate that transcription factor CUX1 (Cut-Like Homeobox 1) specifically binds to an atherosclerosis-associated functional single-nucleotide polymorphism (fSNP) (rs1537371) within the locus and regulates the  CDKN2A/B- encoded proteins p14 ARF , p15 INK4b  and p16 INK4a  and the antisense noncoding RNA in the CDK4 (INK4) locus (ANRIL) in endothelial cells (ECs). Endothelial CUX1 expression correlates with telomeric length and is induced by both DNA-damaging agents and oxidative stress. Moreover, induction of CUX1 expression triggers both replicative and stress-induced senescence via activation of  p16   INK4a   expression. Thus, our studies identify CUX1 as a regulator of p16 INK4a -dependent endothelial senescence and a potential therapeutic target for atherosclerosis and other age-related diseases.

Post-GWAS functional analysis identifies CUX1 as a regulator of p16INK4a and cellular senescence