Monday, October 20, 2014

The end of aging

Do naked mole rats have the secret to long, healthy lives?

by Joseph Stromberg on June 16, 2014

Even at young ages, naked mole rats look prematurely old. They're wrinkly and bucktoothed, with gray whiskers and tiny eyes that seem myopic. Their bare skin hangs off their bodies in thick ridges. When he first saw a naked mole rat in 1842, German naturalist and explorer Eduard Rüppell thought he might have found a diseased specimen because it lacked fur.

But there's something special about naked mole rats that Rüppell couldn't have seen. Similarly-sized rodents, under ideal conditions, can live for five years or less. The life span of a naked mole rat is about six times as long. Even into their twenties, they barely seem to age, retaining strong heartbeats, dense bones, and remaining fertile. Scientists have dosed them with all sorts of carcinogenic chemicals and radiation, but unlike every other mammal, a naked mole rat has never once been observed to develop cancer.

Until recently, what let the naked mole rats conquer cancer and live so long was a total mystery. But over the past few years, a handful of researchers around the world have uncovered strange mechanisms inside their cells that seem to be the basis for the animals' uncommon longevity. The scientists' ambition is lofty, but not surprising: they want to harness these discoveries to one day vanquish cancer and battle aging in humans too.

The goal of anti-aging research isn't to raise life expectancy from 80 years to 90 — but to slow aging down, so a 60-year-old can feel like she's 50

Modern medicine's greatest success has been defeating a wide variety of deadly infectious diseases, from smallpox to polio. But eliminating or reducing the risk of one disease has increased the risk of another one that hits people later on. "In the 20th century, we added about 30 years to life expectancy," says Jay Olshanksy, a public health researcher at the University of Illinois at Chicago who studies aging. "We've allowed people to live into their 60s, 70s, and beyond. But what we got in return was heart disease, cancer, stroke, and Alzheimer's. As a byproduct of our success, we got aging."

To some scientists, this suggests another strategy is necessary. "If aging is a risk factor for everything, why not go after aging itself?" he asks. The idea isn't simply to extend life, but to somehow extend healthy life by slowing the process of aging. For a perfect model of this, you could look to the naked mole rats: well into their eighties (in terms of their human age equivalent), they stay fit and sharp, with strong muscles, hearts, and cognitive functioning. They somehow compress all their aging into the last few years of life.

Many people are troubled by the battle against aging, and are especially concerned about the possibility that success in the field could lead to catastrophic overpopulation and economic collapse as people live ever longer. But Olshansky feels that our whack-a-mole approach to diseases — solving one so that another can bloom, instead of slowing aging itself — is already extending life for many people, but with a hugely negative consequence. "We end up producing the very thing we want least: an extended period of frailty and disability," he says. The goal of anti-aging research isn't to extend this period further — say, by raising life expectancy from 80 years to 90 — but to slow aging down, so a 60-year-old in the future can feel like she's 50.

Studying aging itself, instead of disease, can take a number of different forms. Research can exclusively involve humans: some scientists are looking at the genes of particularly long-lived people, while others are studying people with rare disorders that prevent them from aging normally.


LONG LIFE IS KILLING US

In the 1900s, pneumonia and influenza were the leading causes of death among people in the U.S. As better treatments developed, people began living longer, leading to a rise in age-associated deaths caused by issues such as heart disease.

Heart disease
Tumors, cancer
Pneumonia, influenza
Tuberculosis
Deaths per 100,000 people

Swipe left on the graph to view more years

Sources: Centers for Disease Control, American Lung Association



But a particularly fruitful pathway might be comparing different animal species — and trying to figure out why some age so much more slowly than others. "Understanding species' differences in aging is crucial to understand the basic process of aging and why we humans age the way we do," says João Pedro de Magalhães, a biologist that's studying aging at the cellular level in a variety of species at the University of Liverpool. "This is one of the greatest mysteries in biology."

Last year, the prestigious journal Science named the naked mole rat its vertebrate of 2013. That unlikely designation was mostly based upon a string of striking discoveries made by the husband-and-wife biologist team Vera Gorbunova and Andrei Seluanov, who have a colony of about 100 of the animals at the University of Rochester. "They're so much more interesting than mice. A mouse sits in a corner and eats," Seluanov says. "These are intensely social, highly intelligent creatures."

In the wild — the grasslands of Kenya, Ethiopia, and Somalia — they live in a society like ants or termites. A single female queen and a few males do all the breeding, while dozens of sterile working animals use their teeth to dig networks of tunnels in complete darkness. Others search for tubers, their main food source. They use certain chambers for defecating and disposing of their dead, and others for nursing. Vast colonies can hide under the surface, only breaching it to expel dirt in a small mound.

For the past five years, Gorbunova and Seluanov have tended a colony at Rochester's Hutchinson Hall, inside a room kept at 90°F and sealed by a thick metal door. The hairless rats scurry back and forth, squeezing past each other in a network of plastic tubes that look like an elaborate home gerbil habitat. They occasionally fight for social dominance, and at times even kill each other. But these wounds account for nearly every adult death that's occurred in the colony — old age hasn't killed any of them so far.

Gorbunova and Seluanov, who were both born in Russia and met during high school, have studied the biology of aging in human cells, mice, and other species, but first got interested in naked mole rats in 2005. At the time, virtually all animal-based aging research involved mice or rats, which live three to five years. "Everybody studies animals that are short-lived for longevity, because it's more convenient," Gorbunova says. You can tinker with the animals' biology — say, by altering a particular gene — and see the effect pretty quickly.

Rsz_2013-08-26_naked_mole_rat_121

This is what a naked mole rat looks like (Andrei Seluanov and Vera Gorbunova, University of Rochester)

But when she and Seluanov compared the genetics of 30 different rodent species, they were struck by the huge range of lifespans within the group. In both rodents and other animals, size is usually a rough predictor of lifespan. Chipmunks, for instance, can live up to ten years. Chinchillas can last 17 years, while squirrels and porcupines can live for 24 or so. But the small, blind naked mole rats can live the longest — up to three decades.

So Gorbunova and Seluanov, along with a few graduate students, began growing naked mole rat cells in petri dishes, using samples sent over from labs where the animals were used in neurological research. They immediately noticed something weird. "The naked mole rat cells didn't grow in the same way as most animal cells," Gorbunova says. "Usually, if you culture cells, they fill up the plate. But the naked mole rat cells kept stopping when there was still lots of room left."

All healthy cells have a tendency to stop growing when conditions get too packed, a property called contact inhibition. Normally, in a petri dish, they'll grow to form a sheet before they stop growing, but won't grow on top of each other. But the naked mole rat cells didn't even form a full sheet — they seemed to be hypersensitive to getting crammed in. This was intriguing, because in humans and other animals, contact inhibition can prevent the uncontrolled growth of cancerous tumors: clusters of cancer cells will stop growing when conditions get too tight.

So Seluanov and Gorbunova tested this resistance, dosing the naked mole rat cells with chemicals that reliably triggered the formation of tumors in mouse and human cells. Nothing happened.

To probe the animals more deeply, the biologists established a colony of live ones in 2009. They found a supply of the exotic animals at Vanderbilt University, from a neuroscience researcher who was now wrapping up his project. Because the animals are so sensitive to cold, their graduate students had to drive them up to Rochester mid-summer in a van with the air conditioning shut off. "About an hour away from Rochester, they got pulled over by the police for speeding," Gorbunova remembers, "and they'd taken their shirts off to stay cool."

As they continued to investigate why the animals' cells wouldn't grow tumors, they saw something else weird in the petri dishes. "We noticed that there was a very viscous goo building up between the cells," Seluanov says. "I got obsessed with figuring out what the goo was doing."

Eventually, they identified the goo as a sugar called hyaluronan. Human cells also secrete hyaluronan — it acts as a lubricant and structural protein between cells — but the naked mole rats' hyaluronan molecule was different, about five times longer. To test whether the hyaluronan was involved in the cells' resistance to growing closely together, the researchers added an enzyme to the petri dishes that cut it down to normal length.

"All of a sudden, the cells could grow quite densely, just like normal cells," Seluanov says. Later, when the researchers altered the DNA of the cells — turning on genes that are known to trigger tumor formation in other species, and turning off genes that led to the production of hyaluronan, and implanting the cells in live mice — tumors formed. These were the first cancers they'd ever induced in naked mole rat tissue.

As detailed in a Nature study last year, they ultimately found that two short genetic mutations in the animals were responsible for the long form hyaluronan. It seems that receptors on the surface of the naked mole rat cells register its presence — and when they come too near each other, it sticks to the cells, signaling for them to stop growing and preventing tumors from forming.


The oldest cat ever was 38 years old. The oldest horse was 62. The oldest dog was 29, and the oldest human was 122.

"Evolution has generated a great deal of variation in how long species live. We know that a mouse, on average, lives about three years, and a whale — another mammal — can live 210 years," says Olshansky, the aging researcher. "How does this happen?"

For most species, the answer is straightforward: the more vulnerable an animal is, the shorter its lifespan. Species that are likely to be eaten, like mice, have to mature and reproduce within their first few years, because they can perish anytime.

Evolution provides powerful incentives for surviving those few years and reproducing: animals that do so pass on their genes. But after reproduction, survival doesn't matter — in evolutionary terms — so these species don't develop mechanisms that might allow them to live a long time. One analogy is a car: if you bought a junker that you knew would break down in 10,000 miles, it wouldn't make sense to invest in a high-end stereo.

But for animals that are protected from predators, the evolutionary logic works somewhat differently. "When an animal can survive for longer, there's a selection for genes that provide longevity, because they can provide a real advantage," Olshansky says. A creature that won't get eaten — whether because of size (like an elephant) or armor (like a tortoise or porcupine) — is likely to live longer, so can reproduce for many years. Each additional year of life increases the chance of passing on its genes, so there's a strong incentive to evolve mechanisms that allow for longevity. It's like buying a brand-new car that might last 200,000 miles — in which case it makes sense to invest in quality parts and accessories.

The blind naked mole rats might not seem to have much protection. But theirs comes from lifestyle. Sometime around 25 million years ago, a colony of ancient rodents began digging their way underground, literally carving out a new niche as they left their cousins on the surface. In their vast, intricate tunnel networks, they had to deal with total darkness, no light, very little oxygen — but had virtually no chance of being eaten by a predator.

In this context, the naked mole rat cells’ cancer-resistance makes a lot of sense. "If you can live long, keeping cancer in check suddenly becomes important," Gorbunova says.

This evolutionary history also suggests the naked mole rats have many other adaptations that allow them to live uncommonly long. Gorbunova's cancer discovery, though striking, falls into the older strategy of combating one disease at a time — but other research, both at her lab in elsewhere, has begun uncovering the basic mechanisms inside naked mole rat cells that cause them to age so slowly in the first place.

One of the most surprising discoveries came as a result of difficulties Seluanov and Gorbunova had trying to analyze the animals' DNA. Normally, one of the first steps in doing it is sorting a cell's DNA pieces by length. Apart from the long strands of DNA that make up an animal's chromosomes, sorting usually reveals two distinct pieces of shorter RNA (a genetic material similar to DNA) that make up the two components of the cell's ribosomes — small machines that churn out proteins, based on the instructions written in genes.

"If you can live long, keeping cancer in check suddenly becomes important"

But there was a problem. "Instead of two bands of RNA, we kept seeing three," Seluanov recalls. "For the longest time, we kept thinking there was a mixup."

Further study, though, showed there was no mixup: unlike virtually every other known animal species, naked mole rats have strange ribosomes made up of three subunits, instead of two.

Ribosomes play a central role in the functioning of your cells. As part of a process called translation, they convert instructions present in your genes into the production of specific proteins that allow your body to operate. But all ribosomes make some mistakes, leading to incorrectly-formatted proteins. It's been suspected that some age-related diseases, such as Alzheimer's, are the result of defective proteins accumulating in tissue over time.

So the naked mole rats' weird ribosomes led to a hypothesis: that they might promote longevity by making proteins more accurately.

To test it, the researchers inserted a gene into the cells of both mice and naked mole rats that instructed their ribosomes to make a protein that fireflies use to produce bioluminescence. They'd tampered with the genetic instructions, though, so the protein didn't light up. But if the ribosomes made an error, the proteins would light up as usual. This way, after allowing the different species' ribosomes to operate for a while, the level of bioluminescence the cells produced would reflect the number of errors each ribosome made.

The results were definitive. The naked mole rat ribosomes worked just as quickly as the mouse ribosomes, but shone only about ten percent as brightly — meaning that they made about ten percent as many errors.

It's still hard to say for sure that this slows aging in the naked mole rats. But other research, by scientists at the University of Texas, further suggests that the elimination of malformed proteins is involved.

That work is led by Rochelle Buffenstein, a biologist who's worked with the animals since the 1970s, when she was an undergraduate at the University of Cape Town in South Africa and collected a few dozen from the wild in Kenya. "At the time, no one had any idea how long they lived," she says. "One book I found said they lived eight years."

Buffenstein has spent the years since uncovering the many strange physiological adaptations that allow the animals to live underground — where the air has very little oxygen and levels of carbon dioxide hundreds of times higher than the surface. In response to these conditions, she's found, the naked mole rats have evolved to consume very little oxygen and painlessly tolerate corrosive acids, including one that forms from excess carbon dioxide. Part of the way they save on oxygen is by slowing down their metabolism, and by not needing to regulate their body temperature the way that virtually every other mammal species does, due to the tunnels' uniform warmth.

Most recently, her lab's research has turned to the question of the animals' longevity. One of the most promising things they've found involves another class of malformed proteins: not ones that result not from errors in fabrication, but once-pristine proteins that were later damaged by naturally-occuring chemicals in cells called free radicals.

The idea that free radicals contribute to aging is a popular one among scientists. Just as oxygen slowly rusts metal in air, these oxygen-based chemicals gradually destroy DNA, proteins, and fat molecules inside your cells over the years. This is called oxidative stress — which is why the chemicals that may protect against it, which you've likely heard of, are called antioxidants. Over time, enough oxidative stress can cause cancer, heart disease, Parkinson's, Alzheimer's, strokes, and heart attacks. In other words, modern old age.


Why naked mole rats live so long:

THEIR UNIQUE RIBOSOMES

Ribosomes are tiny organelles inside each of your cells.

They use instructions written in genes to create the proteins your body needs to operate.

All ribosomes inevitably make occasional mistakes and create incorrectly-formatted proteins.

Naked mole rats’ ribosomes are strange in that they have three subunits, instead of two.

Experiments show these ribosomes make 10 percent as many errors as normal ones.

The accumulation of defective proteins may cause age-related diseases, so these ribosomes may help keep the rodents young.


You might imagine that naked mole rats produce lower amounts of free radicals. But when Kaitlyn Lewis, a graduate student in Buffenstein's lab, looked inside the animals' cells, she found that even at young ages, they have levels of free radicals that are just as high as other species. When Lewis and other scientists searched for possible defenses that might neutralize free radicals, they found nothing, and ultimately determined that the animals suffer even more damage from free radicals than other rodents. "If anything, they were worse than mice," Buffenstein says. "We weren't very happy about the findings."

But what they ultimately found was even more interesting. It involves the naked mole rats' proteasomes: organelles that, in a sense, are the opposite of ribosomes. Instead of fabricating proteins, they identify and rip apart unneeded or malformed proteins that accumulate inside the cell. Buffenstein compares them to garbage disposals.

All animals have proteasomes, but Buffeinstein's lab has found naked mole rats have unusually high levels of proteasomes in their liver, the organ responsible for eliminating toxins. Tests show that these proteasomes also work more effectively in clearing out damaged proteins. "And even more interestingly, they themselves are resistant to oxidative damage," Buffenstein says. Some other mix of chemicals inside the naked mole rats' cells seems to crucially protect these garbage disposals — but the scientists still aren't sure what they are.

The picture isn't complete, but it's starting to come together. One way naked mole rats manage to age so slowly is that their cells are better at making proteins correctly. But another is that they're uncommonly good at eliminating the incorrect proteins that inevitably form.


Upon hearing about these discoveries, most people ask the same reasonable question: can they be applied to cure cancer and slow aging in humans?

The answer, like many in science, is complicated. It's one thing to discover a rodent has marvelous adaptations that allow it to live a really long time. It's another entirely to put them in another species.

Gorbunova and Seluanov feel that of the most promising avenues is the possibility of using the naked mole rats' extra-long version of hyaluronan in treating cancer. Our bodies naturally produce the shorter form hyaluronan, and supplementary doses of it have already been used in all sorts of medical applications (speeding healing after surgery, treating arthritis, and reducing wrinkles), making it more feasible to envision it as a possible cancer therapy. But at the same time, some research in other species suggests the shorter version of the sugar might actually promote tumor formation and made them more likely to metastasize. The long version seems to have the opposite effect in naked mole rats, but this needs to be replicated in other animals before it can be tested as a drug.

Slowing the process of aging is the ultimate goal. And it's even further away. We certainly can't substitute all of our own ribosomes with naked mole rats' extra-accurate ones, though it's conceivable we might be able to put to use what we're learning about their garbage-disposing proteasomes. But what these findings really do is underscore just how harmful the accumulation of malformed proteins is in causing us to age. If we want to retain well-tuned cardiovascular systems and sharp cognitive functioning into our eighties, like the naked mole rats, it seems that focusing on strategies for preventing defective protein buildup might be an answer.

So an increasing number of labs around the world are pressing on to learn more about how the naked mole rats do it. João Pedro de Magalhães, the Liverpool biologist, is continuing the partially completed project of sequencing of naked mole rat DNA, to allow scientists to search for genes involved in aging. The Rochester group is currently studying their stem cells, because of their role in tissue repair. Buffenstein's lab is continuing research into several of the unusual adaptations the animals have evolved to live underground.

Still, at the moment, the blind, hairless rats remain something of a mystery. "They've lived underground since the early Miocene — we're talking 20 or 25 million years," Buffenstein says. "During all that time, they evolved a radically different way of living, and we're still scratching the surface of it."


Editor: Eleanor Barkhorn
Designers: Uy Tieu, Adam Baumgartner
Illustrator: Dylan Lathrop
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