June 2

The mysterious life of the world’s oldest mole rat: Challenging death, about to eat his birthday at an age 9 times older than his fellow humans

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Scientists around the world are hungry to find out the secret to the longevity of the very special naked mole rat.

Joe looks noticeably older, compared to the day he was born, in 1982. He now looks ruddy, cross-eyed, and lined with wrinkles. Its teeth have also become strange, with incisors located on the outside of its lips to push dirt out of its mouth when it needs to dig tunnels to accommodate its tubular body.

Rochelle Buffenstein, a biologist, met Joe when he began studying naked mole rats in the 1980s, during her PhD in Cape Town, South Africa. Her research concerns the metabolism of vitamin D in mole rats, as they spend all their time in dark tunnels, far from the sun. But then she moved to another city, Johannesburg to start her job, leaving Joe behind. The mole Joe was later transferred to the Cincinnati Zoo. No one thought that the two would reunite anytime soon.

In the late 1990s, Buffenstein noticed something strange. The mole rats she had studied were not dead yet.

“They’re over 15 years old, which by rodent standards is a very long life,” Buffenstein said. “So I thought, ‘Well, they should only live a maximum of six years.’ And now it’s living more than double its maximum lifespan.”

She then turned to the study of aging, knowing that the area was important but understudied. In the early 2000s, Joe’s “other half” at the zoo passed away and this “guy” needed a new mate. Buffenstein offers to help it start a new life at his lab in New York. Since then, this naked mole rat has joined Buffenstein in research papers everywhere.

Today, Joe is still a rodent with wrinkled skin and a taste for vegetables. But it is currently Buffenstein’s oldest naked mole rat, as well as the oldest mouse ever recorded. This year, Joe turns 39 years old. It is at an age 9 times longer than normal mice and 5 times longer than other similarly sized rodents.

When Buffenstein began studying the age of naked mole rats, she wanted to take a sort of before-and-after image of their biology, to determine when bones, organs or even levels. Their antioxidant properties change. But she kept waiting, and waiting, and then waiting again because nothing happened.

“It’s very frustrating. Because you want to see this change happen, so you can dig into what’s changed,” Buffenstein said.

Back then, Buffenstein was one of the few researchers who took moles and the aging process seriously. And now, mole rats are taking over all the halo, and laboratories around the world are working to uncover their underlying biology, with the goal of using those insights to develop new drugs. A drug that can stop the ravages of aging in humans.

Because humans and gorillas have high blood pressure. Rats and seahorses have cancer. Kangaroos and dogs have arthritis again. An endless list of diseases caused by aging, an endless list of animals. That “and” is so common that any “but” makes scientists frown. Joe is a prominent “but” among them. This mole is enjoying an incredibly long and healthy life.

“Naked moles seem to say that aging is not inevitable,” said Buffenstein, who now works for Google’s biotech division, Calico Labs, which specializes in research and development. solution to fight aging and related diseases said. “But they clearly have a blueprint for stopping the aging process.”

But what is that plan? It may be that their cells are filled with protective molecules, or that a large set of genes are turned on or off unexpectedly, or that the structure of their immune systems, organs or cell membranes is complete. totally different. Naked mole rat researchers have yet to uncover the secret behind this amazing age. Maybe their unique anti-aging tricks will help prolong people’s lives – or maybe everything is just an inevitable dead end.

Joe is aging, but at a super slow aging rate.

Joe is getting old, so are people. As you age, cellular function declines, leaving the body vulnerable to disease and eventually death. Your DNA accumulates damage due to oxidizing molecules, which also attack proteins and fats, ripping you apart from the inside. Cells that “get older” stop reproducing. The reserve of rejuvenating stem cells is gradually depleted. Communication between cells is disrupted and inflammation increases. There is no single driving force behind cellular aging, because it is a network of feedback loops. Enzymes read genes like a grocery list, of different proteins to prepare, and those proteins can protect that enzyme, that gene, or some process throughout the body. Your body is programmed to tolerate bumps and bruises.

“While we’re young, that repair actually works almost flawlessly,” said Vera Gorbunova, a pre-biologist who studies moles at the University of Rochester. “However, as the aging process begins to occur, repair becomes problematic. Gene-reading enzymes falter, proteins are misfolded, radioactive mitochondria weaken muscles and cancer development”.

What begins life as a balanced cycle of mistakes and corrections, turns into a rickety wooden roller coaster – hurled by rusty machinery and makeshift repair processes – prone to being jerked off and up the road to hell. As damage from aging builds up, things accelerate.

There’s something called Gompertz’s law of mortality, a mathematical model that quantifies how the intrinsic risk of death increases exponentially as an animal ages. Although life expectancy varies for different species, the shape of the Gompertz curve is normative. A lab rat’s risk of dying doubles every three months or so. For a dog, that’s about every three years. Once a person turns 25, their risk of death doubles every eight years. But naked mole rats don’t “play” by these rules.

Graph showing Gompertz’s law of death.

In 2018, Buffenstein and her colleagues at Calico published a paper showing naked mole rats defying Gompertz’s law of death. Even at the age of 35, Joe still does not have statistics showing that his risk of death has been twice as high as when he was… at 2 years old. Of course, naked mole rats still die, but the risk is very low.

No one knows if the behavior of the mole rats hides a secret related to the aging process. For one thing, they are highly social, a rarity among mammals. That means that in a colonial area there will be one queen in charge of the entire infection. It will mate with up to three males and remain fertile even 30 years after puberty. For a human, that is the equivalent of giving birth at the age of 300.

Joe has witnessed the ups and downs of moles. It and its colony mates have spent years cleaning the nest, tending to the queen, and defending against strange intruders. But most of the time they lead a relatively healthy life, in part because they live in deep burrows in the desert, where there are few natural predators.

So what can kill a naked mole rat? “They beat each other up,” said Martha Delaney, a veterinary pathologist at the University of Illinois. Naked moles are extremists. They will attack strangers, jostling and biting each other. and banished the members as outcasts.”

Scientists are looking for ways to uncover the “eternal” secret of this rodent.

Melissa Holmes thinks they are adorable animals. Holmes is a behavioral neuroscientist at the University of Toronto who has worked with more than 1,000 naked mole rats. Working within the odd social structure of moles has earned them a reputation for aggression, but according to her, for animals that live in large groups, moles are generally very stable and peaceful. Holmes also had a group of moles of his own to follow over the course of 12 years. And some of them have never been injured in a fight.

And it’s not that the naked mole rat never gets old or sick. But their bodies somehow slow down these processes. Whereas the bones of typical mammals become brittle and thinner over the years, mole bones retain their mineral content and remain as solid. People tend to gain more fat with age. The naked mole rat is not.

“But the most prominent system,” says Buffenstein, “is the cardiovascular system.”

Human veins and arteries often harden over time. The stiffer those vessel walls, the harder the heart has to pump. It leads to increased blood pressure. There is also an increased risk of death. The blood vessels of the naked mole rat remain active throughout life. “Every measure that we looked at of heart function was the same from when they were six months to 24 years later,” she said.

In humans, heart disease is the leading cause of death. Cancer ranks second. About 40% of Americans develop cancer in their lifetime. For naked mole rats, this probability is less than 1%. In a 2008 study, Buffenstein reported that there was no cancer in a group of 800 mole rats. As of 2021, Buffenstein says she has found only five cancers in more than 3,000 deaths.

“They’re very well-adapted, like a physiological wonder,” says researcher Delaney.

Delaney mainly studies naked mole rats in zoos, scanning biopsies and tissue slices to find out how they died. She found a few cancers in two moles, after assessing “hundreds and hundreds of individuals”. But neither of these cancers is the main cause of death. Naked mole rats also develop kidney and brain damage with age, but they rarely turn into disease.

This unexpected resilience means that there may be something about the biology of this animal that we humans can grasp, in pill form or maybe someday in the form of therapy. genes, according to scientists’ expectations.

“And that’s why I think they’re so popularly studied these days,” says Delaney. “They are now a research model not only for cancer but also for age-related diseases.”

But popular or not, no secret has really been revealed.

What DNA is responsible for the longevity of this particular animal?

The scientists wanted to sort out what needs to be tweaked biologically in the human body to mimic how naked mole rats are preserved. For example to cure cancer. Naked moles have such an excellent ability to ward off cancer that researchers think their cells may be encapsulated with protective molecules that stop the cells from mutating, before being taken over by them. For example, naked mole rat cells accumulate large amounts of a protein called p53, which is known to suppress tumors. Last year, a report by Buffenstein showed that the amount of this substance in their connective tissue is 10 times more than in humans and other rat species, and it is also more stable.

And aging has long been found to involve a protein called NRF2, which can protect against that decline into a disorder. It’s a transcription factor, which means it sticks to DNA and activates certain genes that protect cells. NRF2 acts as a kind of protective barrier to antioxidants, detoxifying agents, and helps keep other proteins from misaligning. And most common diseases like heart disease, diabetes, depression… are related to the accompanying low NRF2 levels.

And while all mammals, including humans, make this protein naturally, Buffenstein recently discovered that in naked mole rats the production of this protein is active. because they are more abundant or better aligned. Perhaps NRF2 helped the mole rat to escape the onslaught of many aging-related diseases.

But that doesn’t mean scientists just need to produce a drug that makes this happen faster, because more is not always better. NRF2 levels that are too low or too high can both lead to cancer development. The same is true for p53.

“We always have to be careful, because so many disease states hijack the same proteins to make them work in our favor,” Buffenstein said.

However, scientists say it is unlikely that naked mole rats have only one mechanism to help reduce contagious diseases such as cancer, or help slow the aging process. And many laboratories are looking for hiding places for those mysteries. They hope a treatment for humans can be found, coming from any of the distinct processes discovered, or even multiple separate processes.

“It’s not a single solution,” says researcher Gorbunova. “We have to really study from many angles.”

No pill has been created yet, but scientists have come a long way thanks to modern biotechnological tools. Buffenstein’s team is surveying the naked mole rat genome for new genes. Gorbunova has spent years focusing on a starch-like molecule, called hyaluronan. Naked mole cells make tons of things, and her lab has connected it to its ability to fight osteoarthritis and cancer.

Ewan St. John Smith, a neurophysiologist at the University of Cambridge, has identified a genetic and protein variation that keeps Joe and other moles from feeling the sting of acid. Other labs are analyzing the animals’ gut microbiota or tinkering with their stem cells.

Joe is expected to live a healthy life for many more years.

And on the lab benches, not far from where Joe’s friends were sleeping and squealing, Buffenstein was still searching for the secret inside their immune systems. Because mole rats are so resistant to disease, she is expecting to find a special group of cells, something like a rapid response team that can quickly destroy cancer cells and pathogens before they can turn into bigger problems.

“Again, these little creatures drive me crazy,” she said. “We couldn’t find anything like it.”

Because in mole rats, they simply have a very high proportion of macrophages and neutrophils. And these white blood cells easily eat the invaders and turn them into pus.

“The front line is ready to attack anything strange and destroy it almost instantly,” Buffenstein said. “I feel it’s a fact that the animals are winning, and we haven’t been able to do that yet.”

Buffenstein and her team will celebrate Joe’s 40th next year. She’ll get some sweet potatoes to nibble on, some alone time with her partner, and maybe some anti-wrinkle cream. It will be the first mole to live that long. And, perhaps, not the last one either.


Tags

longevity secret, naked mole rat, science


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