Resistance to DNA Damage and Downregulation of Metabolic Processes May Contribute to Low Cancer Rates in Naked Mole Rats

Scientists have revealed that senescent naked mole rat cells downregulate key metabolic processes and are more resistant to DNA damage than their mouse counterparts, providing insight into the resistance of naked mole rats to cancer and aging.

Researchers have demonstrated that cells of naked mole rats (Heterocephalus glaber) undergo cellular senescence similarly to mouse cells but have distinct features that may explain the species’ low cancer and aging rates, such as being more resistant to DNA damage and undergoing metabolic reprogramming. Image credit: Benny Mazur / CC BY 2.0.

Cancer is the uncontrolled growth and division of cells that leads to the formation of tumors that disrupt organ function. Mutations in certain genes, arising through events that damage DNA such as radiation, disrupt the wiring that normally keeps cells from perpetually dividing and thus ultimately drive cancer.

In the animal kingdom, where longer lifespans allow ample time for the accumulation of oncogenic mutations, cancer is a ubiquitous disease.

One way cells avoid cancer is through a process called cellular senescence, a state that permanently prevents the cell from dividing after a certain number of divisions. For example, human fibroblasts growing in a dish can divide a maximum of 50 times before entering this non-dividing senescent state.

Nevertheless, the accumulation of senescent cells can drive the organ dysfunction that is observed during aging, as these cells often do not perform as well as their non-senescent counterparts.

Therefore, scientists think employing cellular senescence is a compromise between preventing cancer and aging.

However, the naked mole rat (Heterocephalus glaber) defies this paradigm, living for 10 times as long as mice yet bearing to surprisingly low rates of cancer. This species has gained considerable interest in the scientific community as it may shed light on ways to prevent cancer in humans.

Researchers from the University of Liverpool’s Institute of Ageing and Chronic Disease (IACD) and other institutions investigated how naked mole rat cells undergo senescence and the properties of these senescent cells.

Published in the Proceedings of the National Academy of Sciences, the group of scientists revealed that naked mole rat cells underwent senescence in response to similar stimuli as mouse cells but that these senescent cells were more resistant to DNA damage.

The group also found that, unlike mouse cells, naked mole rat senescent cells displayed robust downregulation of DNA metabolism.

Dr. Joao Pedro De Magalhaes, an author on this study, said: “our research suggests that naked mole rats are able to inhibit metabolic processes of the senescent cells, resulting in senescent cells that are less pathogenic.”

“In addition, naked mole rat cells are more resistant to DNA damage. Therefore, one hypothesis is that the way naked mole rats are better able to cope with damage to their genome is essential for their longevity and cancer resistance.”

These conclusions further inform scientists on the spectacular longevity and low cancer rates of the naked mole rat, as cells can maintain proper function during senescence by resisting DNA damage and altering metabolic processes.

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Yang Zhao et al. Naked mole rats can undergo developmental, oncogene-induced and DNA damage-induced cellular senescence. PNAS, published online February 5, 2018; doi: 10.1073/pnas.1721160115