Hypoxia metabolism in ageing

supply to tissues and a reduction in tissue pO 2. A diminished vascularization in ageing alters the diffusion of O 2 at the capillary tissue level, and at an advanced stage, this can lead to tissue hypoxia. Molecular O 2 sensors mediate the response to O 2 deprivation through the regulation of protein expression, enzyme activities, and metabolic regulating factors [1]. HIF1α is perhaps the best-studied responsive mechanism. A critical role in vascularization and angiogenesis is played by VEGF, a HIF1α target. This crucial proangiogenic factor is also regulated at the mRNA level by a non-HIF pathway, DEAD-box RNA helicase [2]. Deficient O 2 supply together with a reduced ability to induce HIF1α expression may contribute to the aetiology of ageing. On the other hand, low O 2 levels lead to neovascularization that can contribute to pathological events such as tumour growth and macular oedema. Furthermore, intermittent or continuous cellular hypoxia represents a source for oxygen radical production that is responsible for the inexorable decline of tissue morphology and physiology with age. In ageing, neovascularization appears to be attenuated which might be linked to impaired HIF1α induction. Other compensatory mechanisms might also take place in conditions of O 2 limitation [1]. Our recent study made use of an integrated model of a human colorectal cancer cell line and genetically identical cell line lacking HIF1α expression, in a hypoxic environment [3]. This allowed the distinction between HIF1α-dependent and HIF1α-independent metabolic pathways, in particular for lipid metabolism. We observed that a number of lipid metabolic steps had a HIF1α-independent regulation in hypoxia, a trait that may have implications also in the ageing process. HIF2α expression and induction was independent of HIF1α [3]. HIF2α is associated with impaired fatty acid (FA) β-oxidation, increased cellular lipid storage, and has a pro-proliferative effect on cells, which can be an advantage for tumor growth. In well-oxygenated cells, FA β-oxidation represents an important source of energy that can account for up to 80% of supply in cardiomyocytes. In our results, FA-synthase did not show up-regulation in hypoxia, indicating that O 2 limitation did not induce Editorial the de novo FA biosynthesis [3]. This was in accordance with previous data reporting hypoxic cancer cells scavenging lipids from the extracellular environment to form lipid droplets [4]. In ageing, hypoxic oxidative stress causes peroxidation that transforms FA into hydroperoxide derivatives. These biochemical reactive species represent one of the major players …