They observed that induction of cellular senescence led to cessation of cell expansion due to the arrest of the cell cycle with the activation of INK4a and RB (important factors for induction of cellular senescence), in both NMR- and mouse-fibroblasts. Just NMR cells slowly and significantly activated cell death, suggesting that senescent cell accumulation in NMRs might be suppressed through their elimination.
They observed that cell death, likely due to an intense reaction to DNA damage, at first increased on day 2 in both mouse and NMR lung cells. After an initial rise on day 2, a fall in cell death was observed and by day 21, cell death had increased once again, only in NMR lung cells.
Treatment with the MAO inhibitor significantly reduced cell death however increased the number of senescent cells only in the NMR lung on day 21.
A naked mole rat being bred at Miura Laboratory, Kumamoto University. Credit: Yoshimi Kawamura and Kyoko Miura from Kumamoto University, Japan
Research Study into Cellular Senescence in NMRs
To this end, a group of scientists from Japan led by Professor Kyoko Miura from the Department of Aging and Longevity Research, Kumamoto University, carried out a series of experiments in vitro and in vivo to understand how cellular senescence happens in NMRs and if there are any species-specific systems that add to suppressing accumulation of senescent cells and their delayed aging. The Department of Aging and Longevity Research, Kumamoto University is the only center in Japan that types NMRs and conducts research on their resistance to aging and cancer.
Describing the rationale behind their study recently released in The EMBO Journal, Professor Miura, states, “Senolysis or the targeted elimination of senescent cells has actually been shown to prevent aging-related decline in mice. Nevertheless, whether the findings in mice are generalizable, remains an open question. In this research study, we found an NMR-specific “natural senolytic” system that might provide an evolutionary rationale for removing senescent cells as a healing method to prevent aging.”
Findings and Methodology
The research study group utilized low concentrations of doxorubicin (DXR)– a DNA-damaging agent– to induce cellular senescence in NMR- and mouse-derived skin fibroblasts in vitro. They observed that induction of cellular senescence led to cessation of cell expansion due to the arrest of the cell cycle with the activation of INK4a and RB (important aspects for induction of cellular senescence), in both NMR- and mouse-fibroblasts. Just NMR cells gradually and significantly activated cell death, suggesting that senescent cell accumulation in NMRs may be reduced through their removal.
Through additional experiments, the scientists observed that there was a build-up of serotonin (a neurotransmitter that sends signals in between nerve cells) in the non-senescent NMR fibroblasts, however not in the mouse fibroblasts. Upon senescence induction, in NMR cells, serotonin was metabolized by monoamine oxidase (MAO; an enzyme extremely triggered in senescent NMR fibroblasts after induction of cellular senescence) and transformed to 5-hydroxyindole acetic acid (5-HIAA; a metabolite), releasing large amounts of hydrogen peroxide (H2O2).
An infographic depicting a distinct “natural senolytic” or natural senescent cell elimination mechanism identified by Japanese researchers, in naked mole-rats, the longest-lived rodent species. They proposed a species-specific system including activation of INK4a-RB-signaling and serotonin metabolism, which increases intracellular oxidative damage and causes subsequent death of senescent NMR cells. Credit: Yoshimi Kawamura and Kyoko Miura from Kumamoto University, Japan
The group proposed that oxidative stress due to the intracellular production of H2O2 predisposed the senescent NMR fibroblasts to the cell death path, therefore leading to senolysis (selective elimination of senescent cells). This was verified by the observation that the addition of MAO inhibitors and antioxidants prevented cell death in NMR fibroblasts.
To validate if a similar mechanism was likewise prevalent in vivo, the team caused cellular senescence in the lungs of mice and NMRs utilizing bleomycin (a DNA-damaging agent). They observed that cell death, likely due to a severe action to DNA damage, initially increased on day 2 in both mouse and NMR lung cells. However, after an initial increase on day 2, a fall in cell death was observed and by day 21, cell death had increased again, just in NMR lung cells.
Future Directions and Conclusion
Treatment with the MAO inhibitor considerably suppressed cell death but increased the number of senescent cells only in the NMR lung on day 21. This suggests that MAO plays a role in causing cell death and reducing the variety of senescent cells following the induction of cellular senescence in NMR lung cells. These results are constant with the in vitro findings and suggest that MAO adds to reducing the build-up of senescent cells in NMR tissues..
” Further research studies focusing on the senescent cell removal mechanism in NMR tissues are required to comprehend which sort of senescent cells ought to be gotten rid of, when, and how. Such studies may assist the advancement of much safer and targeted senolytic drugs,” says Prof. Miura while going over future steps.
Overall, these findings recommend that INK4a-RB-mediated cell death might facilitate the elimination of senescent cells in NMRs, helping them withstand aging-related degeneration. We are positive that by highlighting a natural senolytic mechanism in this long-lived types, this research study would contribute to the advancement of anti-aging techniques and targeted therapies versus age-related illness such as cancer.
Recommendation: “Cellular senescence induction results in progressive cell death through the INK4a-RB path in naked mole-rats” by Yoshimi Kawamura, Kaori Oka, Takashi Semba, Mayuko Takamori, Yuki Sugiura, Riyo Yamasaki, Yusuke Suzuki, Takeshi Chujo, Mari Nagase, Yuki Oiwa, Shusuke Fujioka, Sayuri Homma, Yuki Yamamura, Shingo Miyawaki, Minoru Narita, Takaichi Fukuda, Yusuke Sakai, Takatsugu Ishimoto, Kazuhito Tomizawa, Makoto Suematsu, Takuya Yamamoto, Hidemasa Bono, Hideyuki Okano and Kyoko Miura, 11 July 2023, The EMBO Journal.DOI: 10.15252/ embj.2022111133.
The study was funded by the Japan Science and Technology Agency, the Japan Agency for Medical Research and Development, the Japan Society for the Promotion of Science, the Takeda Science Foundation, the Mitsubishi Foundation, the Kanzawa Medical Research Foundation, the Japan Foundation for Aging and Health, the KOSE Cosmetology Research Foundation, the Princess Takamatsu Cancer Research Fund, the Nakatomi Foundation, the Naito Foundation, the Foundation for Promotion of Cancer Research, the Kato Memorial Bioscience Foundation, the MSD Life Science Foundation, the Inamori Foundation, the SGH Foundation, the Terumo Foundation for Life Sciences and Arts, the Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care, and the Frontier Salon Foundation.
Scientists from Kumamoto University studied the cellular aging procedure in naked mole-rats (NMRs), discovering an NMR-specific “natural senolytic” mechanism that eliminates senescent cells, possibly contributing to their resistance to aging. The research study, utilizing both in vitro and in vivo approaches, determined the role of serotonin metabolism and the enzyme MAO in this process, using insights into anti-aging techniques and treatments versus age-related diseases.
Researchers from Japan have actually found an unique species-specific system used by naked mole rats to resist age-related degeneration and illness.
The naked mole-rat (NMR), or Heterocephalus glaber, is a rodent native to East Africa that boasts an amazing life expectancy of over 37 years. This makes them the longest-lived rodents. Their remarkable resistance to aging and diseases like cancer has ignited the interest of the clinical community, leading researchers intending to unwind the mechanisms adding to their durability.
Understanding Aging in NMRs
Previous studies have actually checked out the role of DNA repair mechanisms, protein stability, and translation precision (accurate conversion of RNA to proteins) in this regard, but the molecular mechanisms/factors behind their aging resistance stay largely unclear. The contribution of cellular senescence to their aging resistance is poorly understood.
Cellular senescence (cellular aging) is defined by the irreparable arrest of cell division, which progresses with age. Senescent cells are less susceptible to cell death and collect in the tissues as they age, promoting chronic inflammation and jeopardizing the function of these tissues. While cellular senescence plays an essential function in aging, little is learnt about its function in NMRs.
