Comparative genomics approaches to study species divergence in ageing

Life, ageing and death have been concepts known to man since time immemorial. To this day, human beings have been fascinated by death and focused on stipulating what occurs after the life ends. In comparison, little attention has been given to ageing, which all experience daily and many take for granted. It is only the recent scientific movement that enabled mankind to shift its attention to studying ageing through the field of biology and gerontology. The observation that different species show different ageing phenotypes has intrigued many biologists. Comparative biologists, who study genetic, anatomy and behaviour of different species in order to understand the diversity of life, have been trying to explain the different ageing phenotypes through their divergence in their anatomy, natural habitat and behaviour. And since the expansion of the field of genetics, comparative biologists have been employing genomics to study differences in ageing phenotypes at the genome level. In the last few years, the number of species with their genome sequenced has increased at an impressive rate. However, the number of studies exploiting this wealth of data to study specific phenotypes has remained surprisingly small. Here, we present our work on comparative genomics to study species differences in ageing, that is, why many species age at different rates. We describe three projects which helped us 1) find a correlation between amino acid usage in mitochondrial proteins and maximal lifespan, 2) detect patterns of selection associated with longevity increases in proteins during mammalian evolution, and 3) compare the genes expression level in two closely related mammalian organisms, the naked mole-rat and the wild-type mouse. These projects led to several insights about ageing in mammals. We argue that the lack of detection of proteins with anti-oxidant properties in our analyses, coupled with a similar absence observed in other mammalian studies, suggest that contrary to some lower organisms, reactive oxygen species (ROS) may have a lesser impact on ageing in mammals. However, we found evidence that mammalian species may regulate ROS levels through the optimisation of pathways involved, for instance, in the actin cytoskeleton and lipid peroxidation, as well as through the optimisation of amino acid usage in mitochondrial proteins. Additionally, we discovered that genes involved in two pathways, namely lipid metabolism genes and proteasome-related genes, were associated to ageing in both the protein evolution project and the genes expression analysis, suggesting that these two pathways may be important regulators of mammalian ageing. We also discovered a few interesting genes. For instance, the DNA damage-binding protein 1, DBB1, which has a strong selection pattern related to longevity evolution in mammals. Additionally, we found that alpha-2-macroblobulin, A2M, is over-expressed at more than few hundreds fold in the long-lived naked mole-rat and has previously been associated to ageing. All in all, we present work that is interesting not only because of the original approaches taken to study mammalian ageing, but also because of the significance of the biological implications obtained. We hope to convince the readers that some of the discoveries made are good candidates for further studies by giving ideas of possible follow up experiments