Biological Origami and Naked Mole Rats

Seeking the secrets of longevity in misfolded proteins
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Viviana Perez, an assistant professor in the Department of Biochemistry and Biophysics at Oregon State, grew up in Santiago, Chile. After earning her Ph.D. at the University of Chile in 2004, she worked as a post-doctoral researcher at the Barshop Institute for Longevity and Aging Studies at the University of Texas Health Science Center. With funding from the Ellison Medical Foundation, her research seeks to generate new insights into human aging through the study of protein homeostasis, dietary restriction and an immunosuppressant drug called rapamycin.

A half-ounce flying mammal, a tiny marsupial that glides from tree limb to tree limb, and a hairless, burrowing rodent with supersize front teeth all share a trait that makes them intriguing to researcher Viviana Perez: exceptional longevity.

The little brown bat (Myotis lucifungus), common across North America, has been known to live more than 30 years. So has the naked mole rat (Heterocephalus glaber) from East Africa. The sugar glider (Petaurus brevicepts), native to Australia, can live 15 years. In contrast, most similarly sized mammals, such as mice and “lab opossums,” have a lifespan of only three or four years.

Uncovering the secrets to these animals’ remarkable staying power could point the way to healthier aging for humans, says Perez, a biochemist in Oregon State’s Linus Pauling Institute. She is investigating the animals’ “cellular surveillance” abilities — that is, how well their bodies can find and repair damaged proteins before they cause harm.

You might imagine that she would need colonies of mole rats, bats and sugar gliders for her experiments. But maintaining such species in labs — especially the finicky mole rat, which demands ample space for burrowing plus a daily diet of fresh fruits and veggies — is too expensive and labor intensive, she says. To prove her point, she reports that only two labs in the United States maintain colonies of naked mole rats.

So instead of using live animals, she works with live cells. These she obtains from her collaborators at the University of Texas Health Science Center in San Antonio, which maintains a cell bank representing at least 30 animal species. When she views those cells under her microscope, she’s looking for aggregations of malformed proteins and the mechanisms that resist, repair or recycle the damage.

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Naked mole rats are native to East Africa where they live in underground warrens.

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A type of possum from Australia, the sugar glider dines on insects in tree canopies.

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Little brown bats are vulnerable to a disease known as white nose syndrome.

Scientists call such protein malformation “misfolding.” You can think of protein formation as a kind of biological origami, in which a coil or strand of amino acids “folds” itself into a 3-D structure to become functional. Sometimes, helper molecules called “protein chaperones” assist in the folding and refolding. When the malformed proteins can’t be repaired, a properly functioning system will send in enzymes to break them down and carry them away. But if something goes wrong and the bad proteins don’t get cleaned up, they stick together to form aggregates that can lead to neurodegenerative diseases like Alzheimer’s, Parkinson’s and other chronic illnesses associated with aging.

Naked mole rats hold special interest in aging research. While they live to ripe old ages eating tubers in their lightless warrens, the wrinkly rodents never develop cancer. Bats, too, rarely get cancer. Perez thinks these long-lived species may be more resistant to protein misfolding and aggregation because evolution has equipped them with better protein equilibrium or “homeostasis.” Her earlier studies with bats and mole rats have suggested that, compared with mice, “proteins from long-lived species are structurally more stable.” Her current study will test this hypothesis by comparing the three long-lived species against three short-lived species of rodent, bat and marsupial (lab mouse, evening bat and lab opossum). She adds a fluorescent protein associated with Huntington’s disease to the animal cells and then follows it to see whether it forms clumps.

“If all three of the long-lived species show better quality control for proteins,” she says, “my study would show for the first time that protein homeostasis might be an important mechanism in how species have evolved to have long lifespans.”

Known for their exceptional longevity, these three mammalian species — the little brown bat, the naked mole rat and the sugar glider — may hold clues to healthy human aging.

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