Significance Cellular senescence is important for the maintenance of tissue homeostasis. Dysregulation of senescence is linked to many human diseases, such as cancer, premature aging, and age-related diseases. Although DNA damage response has been linked to senescence, the underlying mechanism is unknown. Here we show that cGAS is essential for the senescence phenotypes, including expression of inflammatory genes. This finding reveals a molecular mechanism of cellular senescence and suggests that modulation of cGAS activity may be a new strategy to treat senescence-associated human diseases that potentially include cancer, neurodegenerative diseases, cardiovascular diseases, and aging.