It has for a while been the consensus theory that usual aspects of naked mole-rat biology, such as its extreme cancer resistance and exceptional longevity for its size, are at least in part the outcome of evolving to thrive in the low-oxygen environment found in underground burrows. In most mammals, lack of oxygen followed by its return is quite damaging, but much less so in naked mole-rats. The nature of the mechanisms linking resistance to low-oxygen environments with longevity, and their relative importance when compared to one another, is still up for debate, however. A number of other similar burrowing rodent species are also long-lived and cancer resistant. Here, researchers survey the biochemistry of the blind mole-rat:
The blind mole rat of the genus Nannospalax (hereafter, Spalax) is a subterranean, hypoxia tolerant rodent, evolutionarily related to murines. The last common ancestor of Spalax, mouse, and rat lived ~46 million years ago. Despite the tight evolutionary relatedness of Spalax and murines, they exhibit profound differences in lifespan, propensity to cancer diseases. Although a very common cause of death in rats and mice is cancer, Spalax resists experimentally induced carcinogenesis in vivo and does not develop spontaneous cancer. While both rat and Spalax have comparable body weights, their maximum lifespan is ~4 years and ~20 years, respectively. The naked mole rat (Heterocephalus glaber), another hypoxia-tolerant subterranean species of the Bathyergidae family, separated by ~85 million years of evolution from Spalax, is also long-lived, and was reported to be less sensitive to spontaneous cancers.
Molecular adaptations to subterranean life and longevity where suggested for this species, in a brain transcriptome study. Noteworthy, we have proved that both Spalax and naked mole rat's normal fibroblast secrete substance/s interacting with cancer cells from different species, including a wide variety of human cancer cells, ultimately leading to the death of the cancer cells. In addition, sequence similarities between distantly related hypoxia-tolerant species (diving- and subterranean- mammals) were found in the protein sequence of p53, a master regulator of the DNA damage response (DDR). These studies indicate that adaptations to hypoxia include changes in the DDR that may be linked to cancer resistance, and longevity traits.
Under laboratory conditions, Spalax survives ~3% O2 for up to 14 hours, whereas rat survives such conditions for only ~2-3 hours. Oxygen levels measured in Spalax's natural underground burrows vary between ~21% and 7%, depending on seasonal and ecological conditions. In its natural habitat, Spalax is exposed to acute and transient hypoxia, such as: (i) long-term periods of hypoxia during seasonal rainfalls, which reduce soil permeability to oxygen, and simultaneously reduce the total space available to the animal; and (ii) short-term periods of hypoxia during extensive digging activity, when burrows are clogged by soil pushed to the rear by the animal, forcing it to perform an energy-consuming activity in a small burrow fragment with a limited amount of oxygen. Hence, in its natural habitat, Spalax faces acute cyclical changes in oxygen levels. By the term "acute hypoxia" we refer to short- or long- term hypoxia for a limited period, followed by reoxygenation, which is in contrast to "mild-chronic hypoxia" characterizing habitats, such as high altitudes.
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, yet are required for overcoming replication- and oxidative-stress during the subsequent reoxygenation. We suggest that 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.