LONGENES

Identification and functional characterization of genes associated with cellular biomarkers of longevity

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

The naked mole rat can live longer than 28 years, an all-time record for a rodent. Researchers have looked at its stress-resistance genes in a bid to find the key to its longevity.

Descrizione progetto (Article)

Cellular resistance to stress, including resistance to oxidative stress, is thought to play a role in ageing and cancer. Stress resistance may also be a major biomarker for longevity in mammals.

The 'Identification and functional characterization of genes associated with cellular biomarkers of longevity' (LONGENES) project has employed cutting edge genomics to identify new mammalian genes that confer genotoxic stress resistance. The scientists studied relevant candidate genes from the naked mole rat, Heterocephalus glaber, the granddaddy of all rodents, in comparison to short-lived mice.

Using RNA interference techniques to silence genes involved in stress resistance, the scientists identified candidate RNA molecules and genes. They developed a novel method to detect short-hairpin RNA with subtle effects. Screening revealed genes for prioritisation. The researchers developed a bioinformatics pipeline for this purpose.

Genes of particular interest include Edd1 and C1orf112. These affect cell proliferation as well as DNA damage responses when silenced, key processes required to maintain cell integrity. In parallel, interesting genes were cloned and sequenced. Gene analysis revealed several functional changes that may be associated with exceptional longevity. Key processes and genes are associated with mitochondria and oxidation reduction pathways.

The LONGENES project developed the http://www.naked-mole-rat.org/ (Naked Mole-Rat Genome Resource), the leading online mole rat facilities for study of the rodent genome.

Research results have identified new genomic material and processes to study ageing. Applications for the future may well include treatment of age-related diseases.