Cellular resistance to stress, including resistance to oxidative stress thought to play a role in ageing and cancer, is a major biomarker of longevity. Indeed, increased cellular stress resistance may mediate the life-extending effects of longevity genes in mice. Therefore, there is a great interest in identifying additional genes involved in susceptibility to stress and developing new models for elucidating how cells respond to genotoxic stress. This project will employ cutting edge genomic techniques to identify new mammalian genes regulating susceptibility to stress. Mouse stress-resistance cell lines will be generated using RNA interference techniques and the mechanisms of action of the genes involved will be studied. Moreover, transgenic mouse cell lines with candidate genes from the long-lived naked mole-rat (Heterocephalus glaber, which can live over 28 years) will be assayed for alterations in phenotypes associated with longevity, in particular stress resistance. For naked mole-rat genes modulating susceptibility to stress, their functions and how these differ from their mouse homologues will be characterized. Overall, this project will develop new in vitro paradigms for research on ageing. Accomplishing the research goals of this project will reveal new genes associated with cellular biomarkers of longevity in rodents. These genes will form novel foci for further studies and the mechanistic basis of their actions will be studied.
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