Genome maintenance and bioenergetics of the long-lived hypoxia-tolerant and cancer-resistant Spalax representatives: a longevity model

Developers

Assaf Malik, Vered Domankevich, Aaron Avivi, Imad Shams, etc.

Description of the technology

The subterranean blind mole rats (the genus Spalax), experience acute hypoxia-reoxygenation cycles in their natural subterranean habitat. At the cellular level, these conditions are known to promote genomic instability, which underlies both cancer and aging. However, Spalax representatives are long-lived animals and are resistant to both spontaneous and induced cancers. This phenomenon is so interesting as to turn some members of Spalax taxon in recent years in one of most curious experimental model of longevity.

To study this apparent paradox, authors of the technology utilized a computational procedure that allows detecting differences in transcript abundance between Spalax and the closely related above-ground Rattus norvegicus in individuals of different ages. Thus, this technology gives the method of a cross-species analysis of brain transcriptome of short-lived and long-lived related taxons. Functional enrichment analysis showed that Spalax whole brain tissues maintain significantly higher normoxic mRNA levels of genes associated with DNA damage repair and DNA metabolism, yet keep significantly lower mRNA levels of genes involved in bioenergetics. Many of the genes that showed higher transcript abundance in Spalax are involved in DNA repair and metabolic pathways that, in other species, were shown to be downregulated under hypoxia. These genes are also required for overcoming replication- and oxidative-stress during the subsequent reoxygenation. These differentially expressed genes may prevent the accumulation of DNA damage in mitotic and post-mitotic cells and defective resumption of replication in mitotic cells, thus maintaining genome integrity as an adaptation to acute hypoxia-reoxygenation cycles.

Practical application

This technology can be very useful for study of ageing processes. It will help to investigate the deepest and sophisticated mechanisms of ageing.

This study allowed to determine that the involvement of genes related to genome maintenance, and DNA repair and replication, protects Spalax against damage induced by oxygen fluctuations, and may also be associated with its longevity and cancer resistance.
The approaches, which underlie this technology, enable to compare the related short-lived and long-lived species, allowing more complete understanding of ageing and longevity.

Laboratories

• Institue of Evolution, University of Haifa, Haifa (Israel)
• Bioinformatics Core Unit, University of Haifa, Haifa (Israel)
• Deparment of Evolutionary and Environmental Biology, University of Haifa, Haifa (Israel)
• BGI-Tech, BGI-Shenzhen, Shenzhen (China)

Links

Publications

• Malik, A. et al. «Genome maintenance and bioenergetics of the long-lived hypoxia-tolerant and cancer-resistant blind mole rat, Spalax: a cross-species analysis of brain transcriptome." 6 Scientific Reports, (2016): 38624.
• Domankevich, v. et al. «Adaptive patterns in the p53 protein sequence of the hypoxia- and cancer-tolerant blind mole rat Spalax." 16 BMC Evol Biol, (2016): 177.
• Malik, A. et al. «Transcriptome analysis of the spalax hypoxia survival response includes suppression of apoptosis and tight control of angiogenesis." 13 BMC Genomics, (2012): 615.
• Avivi, A. et al. «Increased blood vessel density provides the mole rat physiological tolerance to its hypoxic subterranean habitat." 19 Faseb J, (2005): 1314–1316.