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Tuesday, May 21, 2024

The Long, Strange Life of the World’s Oldest Naked Mole Rat

Joe has looked old since the day he was born, back in 1982. He’s pink and squinty and wrinkly. His teeth are weird: His incisors sit outside his lips to keep the dirt out of his mouth as he digs tunnels for his tube-shaped body.

“He looks remarkably the same,” says Rochelle Buffenstein, a comparative biologist who has studied naked mole rats since the 1980s when she was doing her doctoral work in Cape Town, South Africa. That’s where she met Joe. (He doesn’t have an official name, so we’re going with Joe.) A few years later, Buffenstein was starting her own research on vitamin D metabolism in mole rats because they spend all their time in dark tunnels, away from the sun. She moved to Johannesburg with a few subjects to begin her work, leaving Joe behind. He was eventually shipped off to the Cincinnati Zoo. But he and Buffenstein would soon reunite.

In the late 1990s, Buffenstein noticed something odd: Her mole rats just wouldn’t die.

“They were more than 15 years old, which is by rodent standards extremely long-lived,” Buffenstein says. “So I thought, ‘Wow, they should be only living a maximum of six years; they’re living more than double their maximum life span.’” She pivoted to aging research, knowing that the field was important but understudied. In the early 2000s, Joe’s other half at the zoo passed away, and he needed a new mate. Buffenstein offered to help him start a new colony at her lab in New York and took him in. Since then, he has traveled with Buffenstein to research posts in New York, Texas, and California.

Today, Joe is still a wrinkly rodent with a taste for root veggies. But he’s now Buffenstein’s oldest naked mole rat, the oldest ever recorded—Joe turns 39 this year. That’s nine times older than typical mice live, and five times more than other similarly sized rodents.

When Buffenstein set out to study how naked mole rats age, she wanted a sort of before and after picture of their biology—to determine when their bones, or organs, or even antioxidant levels change. She waited. Then waited some more. “It was very frustrating," Buffenstein says. "Because you want to see this change happen, so that you can then delve down to what's changed.”

Back then, Buffenstein was one of just a few researchers looking at mole rats and aging. Now mole rats are all the rage, and labs around the world are exploring their basic biology with the goal of using those insights to develop drugs that might prevent the ravages of age in people. Because humans and gorillas get hypertension. Mice and zebrafish get cancer. Kangaroos and dogs get arthritis. An endless list of diseases of aging plague an endless list of animals. The “and”s are so prevalent that any “but” makes scientists’ eyes spring open. Joe is a “but.” Mole rats enjoy incredibly long and healthy lives before they expire.

“The naked mole rat says it's not inevitable,” says Buffenstein, who now works for Google’s biotech spinoff, Calico Labs, which does R&D to combat aging and associated diseases. "They clearly have a blueprint to stave off aging.”

But what is that blueprint? It could be that their cells are teeming with protective molecules; that a large set of genes are unexpectedly switched on or off; or that the very makeup of their immune system, organs, or cell membranes are radically different. (Perhaps even too radically different.) Mole rat researchers haven’t yet managed to harness these shrively fountains of youth. Maybe their unique anti-aging tricks are destined to extend human life—or maybe they’re just an inevitable dead end.

Joe barely ages, but you do. As you get older, your cell function deteriorates, making your body more susceptible to disease and—eventually—death. Your DNA accrues damage from oxidizing molecules, which also attack proteins and fats, tearing you apart microscopically from the inside. Old “senescent” cells stop replicating. Reserves of rejuvenating stem cells dry up. Communication between cells breaks down, and inflammation cranks up. There’s no single force that drives cellular aging; it’s a network of feedback loops. Enzymes read genes like a grocery list of different proteins to prepare, and those proteins might protect that enzyme, or that gene, or some body-wide process. Your body is programmed to tolerate these bumps and bruises. “While we are young, that repair actually works almost flawlessly,” says Vera Gorbunova, a biogerontologist who studies mole rats at the University of Rochester. When aging sets in, though, “now damage outpaces repair.” Gene-reading enzymes falter, misfolded proteins gum up the brain, sputtering mitochondria weaken muscles, and cancers bloom.

What begins life as a balanced merry-go-round of mistakes and repairs, devolves into a creaky wooden roller coaster—thrown off keel by rusted machinery and lackluster repair jobs; more susceptible to gusts of wind, and a brutal hell on your spine.

As the damage from aging accumulates, it also accelerates. Your body observes something called the Gompertz mortality law, a mathematical model that quantifies how the intrinsic risk of death increases exponentially as an animal gets older. Although life spans vary for different species, the shape of the Gompertz curve is canon. A lab mouse’s risk of dying doubles every three months or so. For a dog it’s about every three years. Once a human turns 25, their risk of dying doubles every eight years. Naked mole rats don’t play by these rules.

In 2018, Buffenstein and her colleagues at Calico published a paper showing that naked mole rats defy the Gompertz mortality law. Even at 35, Joe hadn’t statistically doubled his risk of dying compared to when he was 2. Naked mole rats still die, of course, but the risk stays nearly flat. “They haven't read the textbooks,” Buffenstein says. “They don't know how they’re meant to behave.”

Mole rats like Joe certainly exhibit weird behaviors that are (presumably) unrelated to aging. For one thing, they’re eusocial, a rarity among mammals. That means that one queen rules over the entire colony. She mates with up to three males and remains fertile even 30 years after puberty. (For a human that would equate to having babies at 300 years old.) Joe, as it happens, is a rare breeding male. His late mother, like every mole rat's mother, was a queen, and she kept other females reproductively repressed with acts of dominance—pushing and shoving that may sometimes look aggressive, depending on the despot.

Joe has seen dynasties rise and fall. He and his colony mates have spent their years cleaning the nest, caring for the queen, and guarding against intruders as designated workers or xenophobic soldiers. Most of them live relatively healthy lives. And because they live in deep desert burrows, mole rats have few natural predators.

So what does kill a naked mole rat? “They beat each other up,” says Martha Delaney, a veterinary pathologist at the University of Illinois. Naked mole rats are extreme xenophobes. They’ll attack outsiders, push and bite each other, and banish colony members as outcasts.

“They’re lovely, lovely animals,” Melissa Holmes says with great sincerity. Holmes is a behavioral neuroscientist at the University of Toronto who works with more than 1,000 naked mole rats. The inner workings of mole rats’ odd eusocial structure earns them a reputation for aggression. “But for animals that live in such large groups, they are remarkably stable,” she says.

Holmes has had her colonies for 12 years. “And in some of my colonies, we’ve never had an injury, ever,” she says. “That's amazing—that animals live together for years with that lack of aggression.”

It’s not that naked mole rats never age or get sick. They do. But their bodies somehow slow those processes down. While typical mammals’ bones get more brittle and thin over the years, mole rat bones keep the same mineral content and remain just as solid. People tend to tack on more fat with age. Naked mole rats? Nope.

“But the most striking system,” says Buffenstein, “is cardiovascular.” Human veins and arteries normally stiffen with time. The more rigid those walls get, the harder the heart has to pump. Blood pressure goes up. Risk of death goes up. Naked mole rat blood vessels stay springy throughout life. “Every measure that we've looked at in heart function is unchanged from six months to 24 years,” she says.

In humans, heart disease is the leading cause of death. Cancer is second. About 40 percent of people in the US develop cancer in their lifetimes. For naked mole rats, the probability is well below 1 percent. In a 2008 study, Buffenstein reported no cancers at all in a group of 800 mole rats. As of 2021, Buffenstein says she’s only found five cancers in over 3,000 necropsies.

“They do age very well,” says Delaney “They’re very well adapted, just kind of like a physiological marvel.” Delaney primarily studies naked mole rats in zoos, scanning biopsies and tissue slices to tease out how they died. She has found a couple cancers in two naked mole rats (“after evaluating hundreds and hundreds,” she says). Neither cancer was fatal. Naked mole rats do develop kidney and brain lesions with age, but those rarely turn into disease.

This unexpected resilience means there may be something about their biology that we can capture in pill form—or possibly one day as gene therapy—for humans. “And that's why I think they're so popular now,” says Delaney, “As research models for not just cancer, but age related diseases.” But popular or not, the true payoff remains elusive.

Scientists want to sort out what to tweak in our biology to mimic the mole rat’s longevity. Take cancer. Mole rats are so great at avoiding cancer that researchers think their cells might be hardwired with protective molecules that stop mutated cells before they take over. For example, naked mole rat cells amass large amounts of a protein called p53, which is known to suppress tumors. Last year, Buffenstein reported that they show 10 times more of it in their connective tissue than in humans and mice—and it’s more stable.

And remember how human aging is linked to DNA and other cellular odds and ends falling apart? A protein called NRF2, or nuclear factor erythroid 2-related factor 2, may protect against that descent into disorder. It’s a transcription factor, meaning it sticks to DNA and activates certain genes that protect the cell. NRF2 works as a sort of crossing guard for antioxidants, detoxicants, and proteins that keep other proteins from misfolding. “Every time I look, it seems to be regulating something else that's equally important for aging and longevity,” says Buffenstein. Heart disease, diabetes, depression, she continues, “just about every disease that you can think of seems to have an accompanying low level of NRF2.”

All mammals, including people, naturally make this protein, but Buffenstein recently found that the naked mole rat version is more active, either because it’s more abundant or better at binding. Drug developers have also noticed that NRF2 is involved in medications approved to treat specific diseases. For example, metformin, a diabetes drug, also activates NRF2 and is being studied for anti-aging. Rapamycin, an immunosuppressant prescribed after organ transplants, activates NRF2 and extends life span by about 25 percent in male and female mice. Clinical trials are underway to test it against human aging. Perhaps NRF2 helps mole rats escape the onset of multiple aging-related diseases simultaneously.

But here’s the thing about putting drugs to new uses: More isn’t always better. NRF2 levels that are too low or too high can lead to cancerous growths. The same is true for p53. “We've always got to be careful, because so many disease states have hijacked the same proteins to make them work in their favor, too,” says Buffenstein. “It's that very fine line of figuring out how this will help you, versus how this could be used to kill you.”

It’s unlikely mole rats have only one unique mechanism that mitigates a disease as diffuse as cancer, much less aging. The naked mole rat likely gets its longevity from more than just one gene that protects against DNA damage, or one enzyme that keeps misfolded proteins from gumming up the brain—it emerges from multiple adaptations, each working in tandem to keep the body alive.

And many labs are looking into where those adaptations are hiding. A treatment for humans may come from any distinct process they uncover, or even many separate ones. “It's not a single solution,” says Gorbunova. “We have to really study from multiple angles."

So mole rats are unquestionably weird, and that might well be useful, but they might also turn out to be too weird. Their isolated, predator-free, underground existence, says Rich Miller, a University of Michigan biogerontologist, might be too unique to translate. “It's not a safe bet,” he says. Miller doesn't study naked mole rats, but he has studied animal aging for over 50 years and is an expert in testing interventions like rapamycin and metformin, leading one of three labs of the National Institute on Aging’s Interventional Testing Program for almost two decades. "They are so weird and, in many ways, so different from the other kinds of slow-aging mammals," he says. For example, levels of one particular antioxidant called thioredoxin reductase 2 are elevated among the long-lived rodents, primates, and birds Miller has studied. But it’s not in naked mole rats.

To be sure, they’re still mammals. (“We are fairly similar to rodents,” Gorbunova says. “It's not like they're some kind of sea sponge.”) But while a Tesla is a car, its spare parts won’t fix your cousin’s Ford Pinto. Maybe the really good stuff is built differently—and is irreconcilably untranslatable.

Naked mole rats may be full of such "idiosyncrasies," says Steve Austad, a biogerontologist at the University of Alabama Birmingham who has studied aging in animals since the 1980s. But Austad doesn’t dismiss unique lessons as untranslatable. Rather than just focusing on this one species, he suggests that studying a diverse array of long-lived mammals, like bowhead whales and Brandt’s bats, will point out important overlaps. “It could be that there are certain tricks that nature has invented time and time and time again,” he says. “I'd say it's probably something that's more likely to be relevant to humans.”

And Gorbunova, who has studied tissue from dozens of species in her lab, says interest in unconventional animal subjects is growing. Now, she says, “people believe in it.”

The drugs aren't here yet, but the biotech tools to decode animal secrets have gotten supercharged. Genome analysis is faster and more reliable than ever. Buffenstein's team is reexamining the naked mole rat genome—the published version isn’t adequate for finding new genes, she says. “You don't know if you're not seeing something because it's really lost or because the genome is of poor quality.” Annotating the sequence from scratch will help trace which genes are critically present, and which are critically unusual or absent. Better tech is also giving researchers an intimate look at the mole rat epigenome—the set of molecular ride-alongs that stick to DNA throughout their lives.

As biotech tools have gotten more refined, the search for mole rat secrets has split off in every imaginable direction. Gorbunova, the biologist from Rochester, has spent years focused on a starch-like molecule called hyaluronan. Naked mole rat cells churn out tons of the stuff, and her lab has connected it to their sturdiness against osteoarthritis and cancer. Ewan St. John Smith, a neurophysiologist at the University of Cambridge, identified the gene variation and protein that keeps Joe and his conspecifics from feeling stinging pain from acid. Other labs are analyzing the animals’ gut microbiome or tinkering with reprogrammed mole rat stem cells. Their mitochondria churn out tons of a peptide that correlates with long human health span, and their mole rat brains seem impervious to high levels of another that correlates with Alzheimer’s. Their bodies are exceptional at dismantling dysfunctional proteins, and surprisingly tolerant of others. Their taste for living in crowded, low-oxygen burrows makes them less prone to seizures and may have adapted their pain receptors.

And on lab benches not far from where Joe’s friends sleep and squeak, Buffenstein has also pinpointed surprising weirdness in their immune systems. Since they fend off disease so well, she expected to find a festival of natural killer cells—the quick-moving hit squad that zaps cancerous cells and pathogens in humans before they can turn into bigger problems. “Again, these little critters drove me crazy,” she says. “We couldn't find natural killer cells at all.” More lethal T cells may pick up the slack, Buffenstein says. They’ve also got a much higher proportion of macrophages and neutrophils—the invader-eating white blood cells that turn into pus. That front line is “ready to pounce on anything that's foreign and destroy it almost instantly,” Buffenstein says. For mole rat (and human) health, there are still many more questions than answers.

“I sort of like the fact that the animals are winning,” Buffenstein says, “and we haven't quite got there yet.”

Buffenstein and her team will celebrate Joe’s 40th next year. As far as we can tell, he’ll just want a few nibbles of sweet potato, some quality time with his queen, and maybe a little wrinkle cream. He’ll be the first to live so shockingly long. And, perhaps, not the last.

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