Both hypoxia and aging affect the morphology and the function of rat myocardial tissue. Moreover the heart tries to counteract the impaired function by activating specific signalling cascades. Here we report the involvement of CREB protein in "in vivo" response to hypoxic challenge and during aging in rat hearts. CREB is activated in parallel to HIF-1alpha nuclear translocation in the young after hypoxia exposure followed by reoxygenation, while this kind of response is not so dramatic in the old, neither in terms of CREB activation, neither in terms of HIF-1alpha expression and translocation, suggesting in the old the existence of an impaired oxygen-sensing mechanism or an adaptation of the cells to hypoxia. Moreover in the young a PKC alpha/Erk pathway seems to be involved in the activation of HIF-1alpha along with CREB, suggesting an attempt of the young to counteract the damage evoked by hypoxia, while in the old a PKC alpha/p38 MAPK/CREB pathway could determine the occurrence of both aging and aged cell hypoxia response.