Upon hypoxia, several cytoprotective factors such as vascular endothelial growth factor (VEGF) and erythropoietin (Epo) are induced under the influence of hypoxia inducible factors (HIFs). HIF is a heterodimer composed of an aand a bsubunit. Under normoxic conditions, the asubunit is hydroxylated by a family of prolyl hydroxylase domain proteins (PHD1-3), leading to its proteasomal degradation. Under hypoxic conditions, HIF-a is stabilized and actives transcription of HIF target genes. Evidence exists that this hypoxic adaptive response is impaired in the elderly. Aim: To understand the effect of aging on the hypoxic adaptive response and its potential functional consequences. Methods: Mice (3 mo to 21 mo old) breathed 8% O₂ for 2 h or 12 h. mRNA and nuclear extracts were isolated from brain and heart and qRT-PCR or Western blot analysis performed. To test functional consequences of aging, mice were preconditioned (6% O₂) for 4 h. 72 h later, cerebral ischemia was induced by occluding the middle cerebral artery for 45 min. After 24 h of reperfusion, brain infarct volume was quantified. Results: Hypoxia downregulated PHD1 mRNA expression in the brain of young, but not old mice. No change was found in the heart. In contrast, hypoxia upregulated PHD3 mRNA expression in the heart of young, but not old mice, while no change was observed in the brain. Hypoxia-induced HIF1-a activation was comparable in young and old mice in the brain, while it was impaired in the heart of senescent animals. Hypoxia-induced upregulation of VEGF and Epo mRNA expression was impaired in both brain and heart of old mice. Finally, hypoxic preconditioning resulted in smaller infarct volumes in young animals, but had no protective effect in old mice. Conclusion: The adaptive response to hypoxia is compromised in old mice. The effect of aging is organ-specific and has negative functional consequences. These results could have implications for treating age-related disorders.