The naked mole rat: A model of successful aging (Dr. Rochelle Buffenstein — Calico Life Sciences)

Translating Aging

Rochelle Buffenstein is one of the world’s leading authorities on the naked mole rat, a fascinating animal that has emerged as an important model for research in longevity science. Dr. Buffenstein is currently a senior principal investigator at Calico Life Sciences, a subsidiary of Alphabet, that is seeking to better understand the biology that controls aging and lifespan.

Today Dr. Buffenstein joins host Bob Hughes to explain why the naked mole rat is such a powerful model of successful aging. She talks about their resistance to cardiovascular disease, cancer, and neurodegeneration, and what this means for improving human health. You’ll hear about the role of Nrf-2 signaling in maintaining optimal health, looking beyond common animal model systems to understand aging more deeply, and the advantages of looking at health and longevity in naked mole rats versus mice. Dr. Buffenstein also discusses the typical hallmarks of aging and inflammation as they present in the naked mole rat, their unusual reproductive activity, and what this can teach us about human fertility.

In this episode, you’ll learn why this unique and resilient creature is a “super organism” of sorts, and why Dr. Buffenstein believes they contain the blueprint for how to live long and successfully healthy lives.

Episode Highlights:

• Introduction to naked mole rat as a powerful model of successful aging
• How Dr. Buffenstein came to study these animals and what is unique about their aging process
• Naked mole rat’s reduced susceptibility to cardiovascular disease and cancer
• Research on whether they are resistant to neurodegeneration
• Central mechanism that provides generalized protection may be at play
• Nrf-2 signaling pathway and its role in maintaining optimal health
• Thinking beyond common model systems to learn about molecular processes of aging
• Studying aging in a long-lived system is more pertinent to humans
• Advantages of looking at slow aging process in a natural context
• The Methuselah Mouse Prize (Mprize) is being offered to the first person who can make mice live longer than five years
• Ultimate cause of death in naked mole rats is unknown
• Hallmarks of aging and inflammation process as they relate to naked mole rat
• Naked mole rats lack natural killer cells, which are very important for fighting viruses
• Innate and adaptive immune systems
• Unusual reproductive activity for naked mole rats
• They have adapted to a particularly harsh and hostile environment
• Dr. Buffenstein believes they contain the blueprint for how to stave off many of the adverse effects of aging

Quotes:

“A naked mole rat is a mouse-sized rodent that stands out as an especially powerful model of successful aging, primarily because it is known to live an incredibly long time. It seems to be exceptionally resistant to most age-associated diseases like cancer and cardiovascular disease. And even reproductive senescence.”

“We believe that given this phenotype that these animals are a very good example that aging does not need to be inevitable, and that they hold the blueprint for how to live long and successfully healthy lives.”

“I got my first grant, looking at how it is that they're able to live 17 years. Little did I know then that these animals would be exceeding 39 years of age in my care.”

“The fact that these animals don't seem to show any age-related change in cardiac function to me is remarkable. If we could understand the mechanism behind that, we might be able to come up with ways to improve human heart function and human health.”

“[Naked mole rats] seem to be resistant to just about everything.”

“We think that the mechanisms that protect them against aging might be the same as some mechanisms that protect them against cancer as well.”

“We know that broccoli and the cruciferous vegetables all upregulate Nrf-2 naturally.”

“I think the traditional model organisms have played a very important role in understanding aging. Because while evolutionary distance all of these models share an important feature, and that is, as they get older, their health declines and their probability of dying increases.”

“I think that yes, we've learned a lot from mice, and we've learned how we can manipulate aging or health span, to some extent, but nowhere near the extent that you could, by looking at species that have already over a multimillion year evolutionary process, modified their biology and have features that enable them to live 10 times longer than a mouse. And that's where I think the naked mole rats are an important model.”

“The real answer is we don't really know what it is that kills them. We just know what doesn't kill them are the common diseases that kill mice and rodents.”

“Every time we've tried to induce some kind of stress, we see a very abrogated or attenuated inflammatory response. They don't seem to activate their inflammatory pathways to the same extent as other animals.”

“Unlike mice, which have predominantly lymphoid cells, T cells and B cells, naked mole rats tend to rely much more on the innate immune system, on the myeloid cells.”

“Both humans and more rats have about 40% of their immune cells being the slow responding adaptive immune cells.”

“Any female in the colony can breed, but most of them are stuck in the suspended prepubescent state. When a female becomes the dominant breeding female, she continues to breed throughout her life. There's no sign of menopause.”

“In most species, fertility declines as you get older. It's true of mice, and it's true of humans. And yet mole rats are showing the exact opposite pattern where the number of offspring produced in a litter increases with increasing age.”

“The naked mole rat can survive 18 minutes in an oxygen-free environment without damaging its brain in any way. Whereas humans and mice after three minutes are brain dead.”

“I think many of the effects that we see that pertain to their extreme longevity are byproducts of having to cope with such a harsh and hostile environment.”

“The biology of the naked mole rat provides a proof of concept that it contains a blueprint for how to stave off many of the adverse effects of aging. The real problems with trying to figure out what that blueprint is.”

“To me, the next steps are trying to successfully make transgenic naked mole rats, and being able to manipulate certain genes both in them, and giving their unique genetic makeup to mice to see if we can extend their longevity, or at least their health span in a significant kind of way.”

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