What naked mole-rats can teach us about healthy longevity

What animal can live for up to 40 years and show remarkable resistance to cancer? Meet the naked mole-rats (Heterocephalus glaber), an extraordinary mammal that challenges our assumptions about aging and age-related diseases. Professor Kyoko Miura from Kyushu University’s Faculty of Medical Sciences studies how naked mole-rats resist aging and cancer. Her work benefits from research at the only breeding colony of naked mole-rats among Japanese research institutes, one of the largest in the world. Fascinated by the extraordinary biology of naked mole-rats, she shifted her research focus from advanced iPS cell research to this field. Starting with just 30 naked mole-rats, she has spent the past 16 years building one of the world’s largest colonies and studying their unique biology. Through the story of her research and her tiny, palm-sized creatures, we explore clues to living well throughout life.

Exceptionally long-lived and cancer-resistant naked mole-rats challenge conventional views of mammalian aging

What kind of animals are naked mole-rats?

Most mammals, including humans, become increasingly likely to die as they age. In contrast, naked mole-rats show little increase in mortality risk. They also exhibit remarkable resistance to aging and an extremely low incidence of cancer.

Most mammals, including humans, become increasingly likely to die as they age. In contrast, naked mole-rats show little increase in mortality risk. They also exhibit remarkable resistance to aging and an extremely low incidence of cancer.

Why do naked mole-rats show remarkable resistance to age-related diseases such as cancer, diabetes, and heart disease? Our goal is to identify the factors and the mechanisms underlying this resistance. Understanding these processes could inform new strategies to reduce susceptibility to age-related diseases.

What led you to pursue research on naked mole-rats?

Early in my career, I conducted basic research on iPS cells, focusing on their tumorigenic risk and potential for treating spinal cord injuries. While conducting this research, I learned that naked mole-rats are remarkably resistant to cancer. I was intrigued by this finding.

Around that time, advances in genome sequencing technologies made it possible to rapidly sequence the genomes of a wide range of animal species, which motivated me to shift my focus toward genomics. Until then, most genomic research had been limited to model organisms such as humans and mice. I realized, “These technologies would allow me to investigate naked mole-rats from a genomic perspective.” I shifted my research focus from iPS cells to naked mole-rats.

A year and a half without offspring: overcoming a research setback

Could you describe what sets your laboratory apart from others?

Currently, our laboratory maintains about 1,950 naked mole-rats, forming one of the world’s largest naked mole-rat colonies. Naked mole-rats are naturally long-lived animals and reproduce quite slowly, which makes colony management challenging.

I established this research colony 16 years ago with only 30 naked mole-rats provided by another researcher. At the beginning, I optimistically thought, “Since they are rodents, they will probably reproduce exponentially.” (laughs) However, we had no baby naked mole-rats for the first year and a half. “I was really worried that my research might end there.”

Since then, we have continuously refined the breeding environment in collaboration with animal caretakers, students, and research staff, developing pairing strategies while assessing the compatibility of breeding pairs. As a result, the population of naked mole-rats has gradually increased. Currently, our colony is the only captive naked mole-rat colony maintained by Japanese institutions and one of the largest captive colonies in the world. This unique resource enables research across multiple levels, from genomes to cells and organs.

A serendipitous discovery by a graduate student opens a new path for aging research

Could you share any memorable stories from your research so far?

Generally, the accumulation of senescent cells is believed to contribute to chronic inflammation and the progression of various age-related diseases in mammals. However, naked mole-rats have a unique program to eliminate senescent cells on their own. Several years ago, a student's accidental oversight led to a serendipitous discovery that helped researchers uncover a previously unknown biological mechanism.

When we experimentally induced cellular senescence in cultured cells, naked mole-rat cells underwent senescence much like mouse cells. At the time, we considered the experiment complete. However, the student who ran the experiment happened to leave the cell culture dish in the incubator for two weeks.

Later, she came to me with the cell culture dish and said excitedly,
“Professor Miura, only the senescent cells of naked mole-rats were dead!”
Her report inspired me.
“Once cells become senescent, they might be eliminated through a predetermined program. We will elucidate the mechanism.”

This observation ultimately led us to uncover the mechanism. This kind of serendipity is one of the most exciting aspects of research.

What do you keep in mind when mentoring your students?

The more fascinated you are by your research, the more actively you will pursue it. However, it often takes time to realize how exciting research can be. Students may initially be passive, but I try to help them identify early on what makes a research question intriguing and worth pursuing.

I hope students become fascinated by research in our laboratory. Even if their career paths vary, I want them to maintain a broad range of interests and pursue their goals with commitment. I encourage my students to tackle a research project and see it through. This experience will build their confidence, no matter what career path they choose.

Toward healthy longevity for all: building a healthier future across the lifespan

What is your outlook for your future research?

My primary goal is to elucidate why naked mole-rats are remarkably resistant to disease even as they age. Today, people are living longer than ever before as populations worldwide continue to age. However, healthy life expectancy still lags behind life expectancy by nearly 10 years, meaning many people spend their later years living with health-related limitations. We hope our findings will help narrow this gap and contribute to a society where people can live out their natural lifespan free from life-threatening diseases.

In fact, humans and naked mole-rats share many genes and fundamental physiological characteristics as mammals. Why do humans age and become more susceptible to disease, whereas naked mole-rats appear to resist aging and remain less susceptible to disease?

In short, if we can uncover the genetic mechanisms behind naked mole-rats' resistance to aging and age-related diseases and apply those insights to humans, we may become less susceptible to disease. Our ultimate goal is not merely to extend life expectancy to 200 or 300, but to help people live active, healthy lives and live out their natural lifespan in good health. With this goal in mind, I remain dedicated to my research on naked mole-rats.