DNA repair in species with extreme lifespan differences

Abstract

Differences in DNA repair capacity have been hypothesized to underlie the great range of maximum lifespans among mammals. However, measurements of individual DNA repair activities in cells and animals have not substantiated such a relationship because utilization of repair pathways among animals—depending on habitats, anatomical characteristics, and life styles—varies greatly between mammalian species. Recent advances in high-throughput genomics, in combination with increased knowledge of the genetic pathways involved in genome maintenance, now enable a comprehensive comparison of DNA repair transcriptomes in animal species with extreme lifespan differences. Here we compare transcriptomes of liver, an organ with high oxidative metabolism and abundant spontaneous DNA damage, from humans, naked mole rats, and mice, with maximum lifespans of ∼120, 30, and 3 years, respectively, with a focus on genes involved in DNA repair. The results show that the longer-lived species, human and naked mole rat, share higher expression of DNA repair genes, including core genes in several DNA repair pathways. A more systematic approach of signaling pathway analysis indicates statistically significant upregulation of several DNA repair signaling pathways in human and naked mole rat compared with mouse. The results of this present work indicate, for the first time, that DNA repair is upregulated in a major metabolic organ in long-lived humans and naked mole rats compared with short-lived mice. These results strongly suggest that DNA repair can be considered a genuine longevity assurance system.

Molecular signatures of longevity: Insights from cross-species comparative studies

“…Phylogenetic regression was performed to identify gene expression with significant association to maximum lifespan or female time to maturity. The expression levels of the genes involved in DNA repair were also found in positive correlation with species longevity, whereas those involved in proteolysis were in negative correlation, which were consistent with the trends observed in the mammalian brain and liver (Fushan et al, 2015; MacRae et al, 2015) and previous cellular studies (Cortopassi and Wang, 1996; Hart and Setlow, 1974). When these fibroblasts were treated with stress-inducing agents such as cadmium and paraquat, those from the long-lived species were more resistant (Ma et al, 2016).…”

Ageing as an Important Risk Factor for Cancer

“…The process of ageing can be well described in cells with damaged DNA-repair activity (19) (Figure 1). Longevity seems to be associated with higher capacity for gene repair, as is apparent in the comparison of short-and long-living organisms (20). However, aging is associated with a reduction of gene repair.…”

Boosting ATM Activity Promotes Longevity in Nematodes and Mice

“…To our knowledge, it is the first time establishing direct causal links between robust DNA repair machinery and longevity. Supporting this notion, the DNA repair efficacy is found enhanced in long-lived naked mole rat 56 , and human longevity is associated with single nucleotide polymorphisms (SNPs) in DNA repair genes/pathways 57,58 . Specifically, an ATM SNP that could enhance the transcription of ATM is associated with longevity in both Chinese and Italian populations 59,60 .…”