Redefining Aging: How Naked Mole-Rats Challenge Our Understanding of Cellular Senescence

by Klaus Müller
cellular aging

A team of scientists from Kumamoto University in Japan has examined how naked mole-rats (NMRs) resist cellular aging. They identified a unique “natural senolytic” process in NMRs that eliminates aged cells, contributing to their remarkable longevity. Employing both in vitro and in vivo experiments, the researchers uncovered the roles of serotonin metabolism and the monoamine oxidase (MAO) enzyme in this mechanism, providing new perspectives for anti-aging therapies and interventions for age-associated maladies.

Naked Mole-Rats: Pioneers in Aging Resistance

The naked mole-rat (Heterocephalus glaber), indigenous to East Africa, has an extraordinary lifespan exceeding 37 years, setting the record for rodent longevity. Their exceptional resilience against aging and diseases like cancer has captured scientific attention, spurring inquiries into the underlying reasons for their extended lifespans.

The Enigma of Cellular Senescence in NMRs

While earlier research has delved into DNA repair, protein stability, and translation accuracy concerning NMR longevity, the specifics of molecular mechanisms and the role of cellular senescence in their aging resistance remain largely ambiguous.

Cellular senescence is the irreversible halt of cell division, which escalates as organisms age. These senescent cells are more resistant to cell death and accumulate in tissues, leading to chronic inflammation and functional decline in these tissues. The role of cellular senescence in NMRs is not yet fully comprehended.

Research Focus: Cellular Senescence in NMRs

Led by Professor Kyoko Miura of Kumamoto University’s Department of Aging and Longevity Research, the only institution in Japan focused on NMR breeding and aging resistance, the researchers sought to understand how cellular senescence manifests in NMRs. They aimed to identify any unique mechanisms that could inhibit the buildup of senescent cells and slow aging in this species.

In a study published in The EMBO Journal, Professor Miura explains, “The targeted removal of senescent cells, or senolysis, has demonstrated its ability to inhibit aging in mice. But the universality of these findings is still under scrutiny. In our research, we found a species-specific natural senolytic mechanism in NMRs that could serve as an evolutionary basis for therapeutic strategies against aging.”

Research Methodology and Outcomes

The researchers induced cellular senescence in skin cells derived from both NMRs and mice using low concentrations of doxorubicin, a DNA-damaging agent. They noticed that while cell growth stopped in both species, only NMR cells activated cell death significantly. This suggests that NMRs may prevent the accumulation of senescent cells through their removal.

Additional experiments showed that serotonin metabolism and the MAO enzyme played significant roles in inducing cell death in senescent NMR cells. These findings were corroborated by in vivo studies, which also indicated that MAO is pivotal in reducing the number of senescent cells in NMR tissues.

Future Research and Conclusions

“More targeted research on senescent cell removal in NMR tissues is required to understand which types of senescent cells need to be eliminated and when,” states Prof. Miura. The study concludes that the process facilitated by the INK4a-RB pathway in NMRs may assist in the removal of senescent cells, thereby helping these animals defy age-related degeneration.

The research was supported by numerous foundations and agencies, including the Japan Science and Technology Agency, the Japan Agency for Medical Research and Development, and the Japan Society for the Promotion of Science, among others.

Reference: The study, “Cellular senescence induction leads to progressive cell death via the INK4a-RB pathway in naked mole-rats,” was published in The EMBO Journal on July 11, 2023. DOI: 10.15252/embj.2022111133

Frequently Asked Questions (FAQs) about cellular aging

What is the main focus of the research conducted by Kumamoto University?

The research concentrates on understanding the cellular aging process in naked mole-rats (NMRs) and identifies a unique natural mechanism that helps these animals resist age-related deterioration and diseases.

Who led the research team from Kumamoto University?

Professor Kyoko Miura from the Department of Aging and Longevity Research led the research team.

What methods were used in the research?

The team employed both in vitro and in vivo experiments. They induced cellular senescence using low concentrations of doxorubicin in NMR- and mouse-derived skin fibroblasts for in vitro studies. For in vivo experiments, cellular senescence was induced in the lungs of mice and NMRs using bleomycin.

What role does serotonin metabolism and the enzyme MAO play in the cellular aging of NMRs?

Serotonin metabolism and the enzyme monoamine oxidase (MAO) play crucial roles in the unique “natural senolytic” mechanism of NMRs. They are involved in the conversion of serotonin to 5-hydroxyindole acetic acid, which releases large amounts of hydrogen peroxide, leading to oxidative stress and the death of senescent cells.

What makes the naked mole-rat unique in terms of lifespan?

The naked mole-rat has a remarkable lifespan of over 37 years, making it the longest-lived rodent. It also exhibits an extraordinary resistance to aging and diseases like cancer.

What are the future directions of this research?

The research team suggests that further studies are needed to understand which kinds of senescent cells should be targeted for removal and how. This could assist in the development of targeted senolytic drugs.

What are the potential applications of this research?

The findings may contribute to the development of anti-aging strategies and treatments for age-related diseases, including cancer.

Who funded the study?

The study was funded by multiple Japanese agencies and foundations, including the Japan Science and Technology Agency, the Japan Agency for Medical Research and Development, and the Japan Society for the Promotion of Science, among others.

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Tim R. October 13, 2023 - 9:02 pm

Seriously, a mole-rat? Next you’ll tell me cockroaches have the secret to eternal life or something. But ya gotta admit, it’s some pretty groundbreaking research.

Cynthia L. October 14, 2023 - 2:49 am

Fascinating how they focused on cellular aging. But makes me wonder how generalizable these findings really are, like can it work for humans too?

John D. October 14, 2023 - 4:29 am

Wow, this is incredible stuff! Never thought a lil creature like the naked mole-rat could teach us so much bout aging. Science is amazing, man.

Karen S. October 14, 2023 - 9:24 am

im honestly blown away by the depth of this study. It’s not just another ‘we found the fountain of youth’ claim. they actually backed it up with solid science. kudos to the researchers.

Samantha Q. October 14, 2023 - 6:37 pm

I always knew there was something special about those ugly-cute critters! if this leads to breakthroughs in anti-aging, I’m all in. where can i sign up for the next study?

Mike O. October 14, 2023 - 7:25 pm

This sounds like the plot for a sci-fi movie. but hey, if it works, it works. Could be a game-changer for medicine.


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