Longevity, cancer-resistance and hypoxia tolerance in the blind mole rat Spalax – a liver transcriptomics approach

The blind mole rat Spalax is a rat-sized subterranean rodent with a remarkable tolerance to strong hypoxic conditions. Additionally, Spalax is highly cancer-resistant and reaches ages of 20 years or more. Unravelling the genomic basis of these adaptations will help understand the underlying adaptive cellular processes and will possibly allow transfer of knowledge to human health research. Here we present transcriptome-wide gene expression data from liver tissue of Spalax specimen raised under normoxic and hypoxic conditions and compare them with respective data from rat. Most importantly, Spalax broadly down-regulates genes from the main liver function pathways glycolysis/gluconeogenesis and cytochrome P450 activity under hypoxia. This potentially energy-saving cellular response is likely a crucial adaptation to low oxygen conditions in Spalax, since rats as hypoxia-sensitive rodents show contrasting patterns with massive up-regulation of a broad set of genes involved in energy metabolism. Three genes with plausible connections to Spalax' cancer resistance and longevity were found to be constitutively more than 10-fold higher expressed in Spalax than in rat: the Werner Syndrome Protein WRN, the mitotic checkpoint protein BUB3 and the alpha2-macroglobulin A2M. Furthermore, interspecific differences in gene expression of hypothetical oncogenes and tumor-suppressor genes suggest tight control of cell cycle processes in Spalax, which could contribute to the striking cancer resistance of these rodents.