Impaired hypoxic response in senescent mouse brain

'This is the author's version of a work that was accepted for publication in International Journal of Developmental Neuroscience. Changes resulting from the publishing process, such as structural formatting and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in International Journal of Developmental Neuroscience, 29 (6) (2011) 10.1016/j.ijdevneu.2011.06.003'Tissue hypoxia leads to activation of endogenous adaptive responses that involve a family of prolyl hydroxylase domain proteins (PHD1-3) with oxygen sensing properties, hypoxia inducible transcription factors (HIFs), and cytoprotective HIF target genes such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF). The hypoxic induction of these genes is regulated by oxygen-dependent hydroxylation of HIF alpha subunits by PHDs, which signals their proteasomal degradation. In this study, mice of different age were exposed to hypoxia or subjected to cerebral ischemia after hypoxic pre-conditioning. We found an impaired hypoxic response in the brain, characterized by elevated levels and impaired downregulation of PHD1. Furthermore, an attenuated hypoxic activation of VEGF and EPO, as well as of other HIF-target genes such glucose transporter-1 and carbonic anhydrase 9 was found in senescent brain. Finally, we observed a loss of the protective effect of hypoxic pre-conditioning on subsequent cerebral ischemia with increasing age. Thus, the impaired hypoxic adaptation, resulting in compromised hypoxic activation of neuroprotective factors, could contribute to neurodegenerative processes with increasing age, and might have implications for treating age-related disorders.Peer reviewedFinal Accepted Versio