The Ink4a/Arf locus, which encodes the tumor suppressors p16INK4a and Arf, is a key mediator of cellular senescence. The authors investigated the relationship between Ink4a/Arf expression and aging in rodent models. They found that expression of p16INK4a and Arf increases significantly in almost all rodent tissues with age, while other cell cycle inhibitors show little or no change. This increase is localized to specific compartments within each organ and affects both epithelial and stromal cells. Caloric restriction, which delays aging, attenuates the age-related increase in Ink4a/Arf expression in several organs, including the kidney, ovary, and heart, and correlates with reduced senescence markers and pathology. The increase in Ink4a/Arf expression is driven by Ets-1, a known transcriptional activator of p16INK4a, and an unknown coregulator. These findings suggest that Ink4a/Arf expression is a robust biomarker and potential effector of mammalian aging.The Ink4a/Arf locus, which encodes the tumor suppressors p16INK4a and Arf, is a key mediator of cellular senescence. The authors investigated the relationship between Ink4a/Arf expression and aging in rodent models. They found that expression of p16INK4a and Arf increases significantly in almost all rodent tissues with age, while other cell cycle inhibitors show little or no change. This increase is localized to specific compartments within each organ and affects both epithelial and stromal cells. Caloric restriction, which delays aging, attenuates the age-related increase in Ink4a/Arf expression in several organs, including the kidney, ovary, and heart, and correlates with reduced senescence markers and pathology. The increase in Ink4a/Arf expression is driven by Ets-1, a known transcriptional activator of p16INK4a, and an unknown coregulator. These findings suggest that Ink4a/Arf expression is a robust biomarker and potential effector of mammalian aging.