The Role of Genome Maintenance in Aging and Longevity

Abstract

The accumulation of DNA damage and mutations with age contributes to the aging phenotype of declining cellular and tissue function. Genome maintenance mechanisms are highly conserved systems that have evolved to protect the genome from DNA damage and mutations by coordinating critical cellular processes, promoting cell survival and genome integrity. These mechanisms include DNA repair system and the pathways that regulate the DNA damage response, programmed cell death, and cellular senescence. In this work, we tested the hypothesis that long-lived species, such as human and naked mole rat, have superior genome maintenance systems than short-lived species, such as mouse, and that this superior genome maintenance capacity is evident in their genomes as higher copy numbers of genome maintenance genes, and in their transcriptomes as higher expression levels of genes involved in DNA repair. To investigate this, we performed comparative genome and transcriptome analyses between the naked mole rat with human and mouse, with a focus on genes involved in genome maintenance. The naked mole rat is the longest-lived rodent with a lifespan approximately ten times that of the mouse (31 years), and is an interesting model for studying longevity and genome maintenance. Specifically, we analyzed copy number variation of genome maintenance genes in these three species, and we found that the naked mole rat genome contains higher copies of several important genome maintenance genes. We also found that the naked mole rat has a lower germline mutation rate than the short-lived mouse, which we feel could reflect superior DNA repair capacity in this long-lived species. We then performed gene expression analysis in liver tissues from human, mouse, and naked mole rat and we found that both the human and naked mole rat liver had a higher expression of essential DNA repair genes. Finally, we showed that, in liver, the long-lived naked mole rat and human had significant upregulation of most DNA repair pathways compared to mouse. These findings demonstrate that longer-lived species possess more robust genome maintenance than short-lived species, and highlight the role of genome maintenance in the aging process--supporting the hypothesis that genome maintenance serves as a longevity assurance mechanism.