Japanese Researchers Unveil Mechanism Behind Naked Mole-Rats’ Longevity and Cancer Resistance
In a groundbreaking study conducted by Japanese researchers, the unique mechanism that allows naked mole-rats (NMRs) to resist aging and age-related diseases, including cancer, has been unveiled. NMRs, which have the longest lifespan among rodents, can live for over 37 years. However, the exact mechanisms that contribute to their longevity have remained largely unknown.
The study, published in The EMBO Journal, identifies a species-specific natural senolytic mechanism in NMRs. This mechanism involves serotonin metabolism and the INK4a-RB signaling axis. By understanding this mechanism, researchers hope to gain valuable insights into aging resistance and develop strategies to combat age-related diseases.
Naked mole-rats, scientifically known as Heterocephalus glaber, are native to Eastern Africa. Their exceptional ability to delay aging and resist age-related diseases has made them a subject of extensive research. Previous studies have explored factors such as DNA repair mechanisms, protein stability, and translation accuracy in NMRs, but the molecular mechanisms responsible for their aging resistance have remained unclear. Furthermore, the role of cellular senescence, or cellular aging, in their resistance to aging has been poorly understood.
To shed light on these mechanisms, a team of researchers from Kumamoto University in Japan conducted a series of experiments both in vitro and in vivo. The researchers aimed to understand how cellular senescence occurs in NMRs and whether there are specific mechanisms that contribute to suppressing the accumulation of senescent cells and delaying aging.
The Department of Aging and Longevity Research at Kumamoto University, the only center in Japan that breeds NMRs and conducts research on their resistance to aging and cancer, played a vital role in this study. Professor Kyoko Miura, the leader of the research team, explained that senolysis, or the targeted removal of senescent cells, has been shown to inhibit aging-related decline in mice. The team aimed to discover an NMR-specific natural senolytic mechanism that could provide a therapeutic strategy to prevent aging.
The researchers induced cellular senescence in both NMR- and mouse-derived skin fibroblasts in vitro using a DNA damaging agent called doxorubicin. They observed that senescent NMR cells gradually activated cell death, unlike mouse cells. This finding suggested that senescent cell accumulation might be suppressed in NMRs through their targeted removal.
Further experiments revealed that non-senescent NMR fibroblasts accumulated serotonin, a neurotransmitter involved in signaling between nerve cells. This accumulation did not occur in mouse fibroblasts. When senescence was induced in NMR cells, serotonin was metabolized, releasing large amounts of hydrogen peroxide. The oxidative stress induced by hydrogen peroxide contributed to cell death and the selective removal of senescent cells in NMRs. Inhibition of the enzyme monoamine oxidase, which metabolizes serotonin, prevented cell death in NMR fibroblasts.
To confirm if a similar mechanism occurred in vivo, the researchers induced cellular senescence in the lungs of both mice and NMRs using a DNA damaging agent called bleomycin. In both species, an initial increase in cell death was observed. However, by day 21, cell death had increased only in NMR lung cells. Treatment with the monoamine oxidase inhibitor reduced cell death and increased the number of senescent cells only in NMR lung cells, supporting the findings from the in vitro experiments.
Professor Miura emphasized that further research is needed to explore senescent cell removal mechanisms in NMR tissues. Understanding which types of senescent cells should be removed and when and how they should be targeted could aid the development of safer and more effective therapies to combat aging-related diseases.
The discovery of the unique mechanism underlying the longevity and cancer resistance of naked mole-rats could have significant implications for anti-aging strategies and the development of targeted therapies. By highlighting this natural senolytic mechanism, the study paves the way for future research aimed at enhancing healthy aging and preventing age-related diseases like cancer.
