Dysregulation of Wip1 signaling may also play a role in aging. Wip1 expression is significantly reduced in aged mice (65, 95), and Wip1-deficient mice have a premature aging phenotype (74). The lack of Wip1 expression in aged cells results in hyperactivation of the stress response, for example through activation of p53 or p16Ink4a (96, 97). Such an accumulated stress response in stem cells by loss of Wip1 function and subsequent relief of stress signaling inhibition may also be responsible for the premature aging phenotype of Wip1 deficient mice (74).
