Look to large bodies to understand long life spans
Larger animals live longer, but tiny dogs outlive big ones. What's the deal?
The tiny nematode known as Caenorhabditis elegans lives its entire life in about three weeks. The worm’s fleeting existence is just a fraction of the time allotted to centipedes or rats. These animals are in turn left in the dust by a horde of other creatures, from badgers to lions to chimpanzees. Even more impressive is the bowhead whale, whose 200-year life span is the longest of any mammal.
There are a few extreme outliers, animals whose lives stretch well beyond their closest relatives. One quahog clam reached 500 years of age—a life span that is about 8500 times longer than that of the humble nematode, says Matt Kaeberlein, a molecular biologist at the University of Washington in Seattle. The ancient clam could have fit on a dinner plate. Generally speaking, though, large animals like whales and elephants live a great deal longer than smaller ones like mice.
But how do they do it?
“My guess is there’s not going to be one answer,” Kaeberlein says. There seem to be a wide range of strategies that animals use to protect their DNA and tissues from the ravages of aging and outlive their peers. Scientists are determined to discover what they are in order to stave off age-related maladies like cancer, dementia, and heart disease in people.
The good news is we already have a pretty good idea why large animals often live longer than small ones. It has to do with the fact that tiny animals are more likely to be gobbled up by predators. These animals tend to have babies early and age quickly. “If you’re a mouse, there’s no selection pressure really there to solve problems relating to cancer or older age, because in all probability you’re dead by then, you never get to that stage,” says Kevin Healy, a macroecologist at the University of St Andrews in Scotland.
Bulky animals can afford to take a long time to grow up and reproduce. “If you’re an elephant, you’re not going to get eaten by a hyena, for instance, so being big has intrinsic advantages,” says João Pedro de Magalhães, a biologist who studies aging at the University of Liverpool in the United Kingdom. So when an animal has a low risk of being killed by outside circumstances like food shortages or predators, it has a chance to evolve a longer life span.
Some groups of animals live a lot longer than their body size alone would suggest, including many birds and bats. Healy and his colleagues have examined how different lifestyles like flying or burrowing might explain why this is. They found that the ability to fly was key to whether an animal would have a long life span. “It’s kind of like being really, really big,” Healy says. “If you fly you can evade your predators, you can move to new areas quite easily, if there’s a drought in one area you can move somewhere else.”
Animals that burrow far out of reach of predators might also have an advantage. However, there aren’t that many species that live underground, Healy says. The most noteworthy specimen—the naked mole rat, which can live over 30 years and barely seems to age or get cancer—might also have evolved its super-long life span for other reasons.
The naked mole rat behaves more like ants or termites than a typical rodent, Healy says. They live in colonies of workers presided over by a single queen who births all the pups. “They’re protecting the queen, so that no predators get near the queen, if there’s a food shortage it’s the queen that gets the food first, and so basically creating an environment that’s really protective and allows them to live much longer,” he says.
Primates tend to enjoy lengthy lives too, de Magalhães says. Chimpanzees live about twice as long as you’d expect based on their body size. And going by size alone, human beings ought to have a maximum life span of about 27 years. But the oldest person we know of lived to more than four times that; a French woman, Jeanne Louise Calment was 122 years and 164 days old when she died in 1997.
Comparing chimps to people isn’t entirely fair, de Magalhães says. Our maximum possible life span is probably skewed because we have access to medicine and by the fact that there are just so many more of us than other primates. Still, part of our ridiculously long life spans comes from our superior intellect; skills like being able to build and use tools probably gave us a survival edge, allowing us to evolve longer life spans over time.
“The evolutionary perspective of why larger animals live longer is well understood,” de Magalhães says. “What are the mechanistic bases of that? I think that’s less clear.”
Live fast, die young?
Scientists used to think that the main reason big animals live so much longer than smaller ones is that they have slower metabolisms.
“When you’re tiny like a mouse you have a lot of surface area per unit of volume and that means you’re radiating heat like crazy,” says Richard Miller, a biogerontologist at the University of Michigan in Ann Arbor. A big animal like an elephant needs to burn relatively less of its energy to stay warm. This means that animals with long life spans will also tend to have low metabolic rates. Scientists assumed that this put less wear and tear on their cells.
But metabolism is actually a red herring, Miller says. “Kangaroos and opossums have really low metabolism, and so if this idea were correct you’d expect them to have really long life spans. But in fact, they have really short life spans.” And birds and bats have high metabolisms, yet often live even longer than their body size would predict.
De Magalhães and his colleagues have examined whether there is any connection between life span and metabolic rate across mammals and birds. After they accounted for body size, the correlation vanished.
However, it is possible that metabolic rate plays a role in longevity for cold-blooded animals, whose body temperature depends on their environment. Some of the longest-lived creatures live in cold waters. These include the olm, a cave-dwelling salamander that may reach ages of 100 years; the orange roughy, a deep-sea fish, can live 150 years; and the Greenland shark, which lives to the ripe old age of 400 years. “Their metabolic rate is very low because, just like a furnace, if you turn up the heat we burn more energy,” Healy says.
What’s more, cold-blooded animals like nematodes and flies live longer when they are raised in colder temperatures, de Magalhães says. It’s possible that their cells accumulate damage more slowly under these conditions. It’s harder to test whether this might also be true for mammals, since our bodies stick within a much narrower range of temperatures.
“In the case of the very long-lived clams, I think it’s almost certainly the case that cold temperature is part of the story, but it’s not all of it,” Kaeberlein says. Other clams found in the same areas live for decades instead of centuries.
Similarly, some bats have outstripped even their flying peers. Brandt’s bat can live for 40 years despite being the size of a mouse. The best an actual mouse can hope for is 3 or 4 years. A bird the same size could expect to live around 10 years, Healy says.
“While we do see bigger things living longer, flying things living longer…the variation is really, really large,” Healy says. “It isn’t a universal pattern.”
Peeking under the hood
There are a certain markers of aging that show up across the animal kingdom. As we get older, our mitochondria—the tiny power plants that make energy for our cells—don’t work as well. Proteins begin to fold into the wrong shape and can build up in plaques in diseases like Alzheimer’s. Tiny caps called telomeres that protect our DNA get shorter until the cell can’t divide anymore. Mutations build up in our DNA. These and a few other processes seem to account for much of how our cells age over time.
We don’t know how much they explain the enormous differences in longevity among animal species, Kaeberlein says. However, many of these processes do appear to work differently in animals that have particularly impressive life expectancies. There’s evidence that telomeres in some bats—which have the longest life spans of any mammal relative to their body size—do not shrink with age. And long-lived clams and naked mole rats seem to be particularly good at keeping their proteins from misfolding, Kaeberlein says.
However, naked mole rats have plenty of other talents. One is their ability to produce a unique form of a sugar called hyaluronic acid that keeps skin elastic—and also suppresses tumors. The hyaluronic acid naked mole rats produce is five times larger than the version our own cells make. “This at least might be related to the reason why naked mole rats don’t develop cancer at anywhere near the rates that we would expect them to,” Kaeberlein says. “It wasn’t one of the hallmarks of aging that everybody thought about.”
Scientists are particularly enchanted by unusual cases like the naked mole rat. However, there are also a few patterns that seem to show up across long-lived animals.
These animals may be better able to cope with mutations and DNA damage than those with short life spans. Scientists are investigating these abilities in elephants and bowhead whales. “You would expect these animals that have way more cells than we do to have high cancer rates, but if they did so they wouldn’t live so long,” de Magalhães says. “So they must have tumor-suppressing mechanisms that we lack.”
Researchers have shown that elephants have extra copies of a gene involved in tumor suppression called p53. And de Magalhães and his colleagues have found that in long-lived animals—including bats, elephants, people, and other primates—genes that help cells withstand DNA damage seem to be evolving more quickly than in short-lived animals like rats and mice.
Animals with long life spans may also have hardier cells that are more resistant to stress, Miller says. He takes skin cells from different animals and bombards them with cadmium, hydrogen peroxide, and ultraviolet light. If the cells came from a long-lived creature like a porcupine, it takes a lot more of these noxious substances to kill them than if they came from a mouse.
“If you’re growing up as a mouse and very unlikely to live for a full year before you starve to death or get eaten, having metal-resistant cells doesn’t pay off very well,” Miller says. “But if you’re an elephant or a porcupine or a bat…evolved resistance to a vast range of toxic and physical insults is a really good thing.”
He and his team are looking into how cells in long-lived animals might become less sensitive to stress. They’ve identified one enzyme called thioredoxin reductase 2 that protects the mitochondria from damage and is nearly always found in greater amounts in cells from long-lived primates, birds, and rodents. What’s more, mice with a mutation that cause them to live longer than their fellows also produce more of this enzyme.
The researchers have also zeroed in on structures called immunoproteasomes that help cells break down damaged proteins. Long-lived birds, rodents, and primates all seem to share high levels of immunoproteasomes, and their cells are better at clearing out errant proteins those from short-lived animals. “These three groups evolved separately,” Miller says. “That’s a strong sign that you cannot evolve a long-lived species without all these immunoproteasomes.”
It can pay to be small
So if big animals live longer, what’s the deal with dogs? Smaller breeds like Chihuahuas can live beyond twice as long as the towering Great Dane. About 56 percent of the variation in life span among dog breeds can be linked to differences in body size, Miller says.
And it’s not just a purebred problem—the relationship between size and life span is just as strong in mixed-breed dogs, Kaeberlein says. Nor is it confined to dogs. Even though larger species tend to live longer than small ones, taller individuals within the same species will on average have shorter life spans. “The data are pretty compelling that, on average, bigger people tend not to live as long as smaller people, bigger mice tend not to live as long as smaller mice,” Kaeberlein says.
One of the culprits may be a hormone called insulin-like growth factor 1, or IGF-1, which encourages cell growth. In mammals and invertebrates, individuals with higher levels of this hormone grow larger. There’s evidence that mice and people with more IGF-1 also have a higher risk of cancer, Kaeberlein says. Having less IGF-1, on the other hand, is associated with slower aging and a longer life expectancy in worms, flies, and mice.
“We don’t really understand how these hormones go about creating an animal that is either normal or long lived,” Miller says. However, it’s possible that tinkering with IGF-1 or other related hormones could one day extend human life spans.
Because large dogs are so much larger than small dogs, the differences in longevity are especially dramatic. But there is a silver lining. Kaeberlein and his colleagues are testing whether a drug called rapamycin—originally discovered being secreted by soil bacteria on Easter Island—can extend healthy old age. When older mice are treated with the drug, their hearts become stronger and they live up to 60 percent longer. When elderly people are given a derivative of rapamycin, their immune systems respond to flu vaccines more like those of younger people. Kaeberlein and his team have been testing the drug in pet dogs, which suffer from many of the same age-related diseases as people.
“We’re doing this in large dogs for the very reason that large dogs age faster than small dogs,” he says. “We can actually asses whether something like rapamycin can improve heart function or improve cognitive function in a pet dog in a few years, whereas in a human that might take a decade.”
The drug is thought to work by making cells think that there are few nutrients available so they go into survival mode and don’t proliferate as much. This is similar to caloric restriction, another promising anti-aging strategy.
In a small first trial, the team saw that rapamycin seems to have similar cardiovascular benefits for large dogs as those seen in mice. The researchers are now enrolling dogs in a second, longer trial that would examine heart and cognitive health more closely. Their hope is that rapamycin could eventually be used to help your pooch—and you—live longer.
It’s not easy to figure out why a particular gene or facet of an animal’s environment can help it live longer, precisely because these animals tend to grow to unwieldy sizes and stick around for a long time. “A lot of these are still hypotheses, we can’t prove them yet because we can’t make transgenic or mutant elephants or whales,” de Magalhães says. He hopes to create a mouse with genes from these animals and examine how they affected its life span, though.
All of this means that we’re still at the beginning of identifying the secrets behind why large animals and oddballs like the naked mole rat live so long. “There doesn’t seem to be a one-size-fits-all, universal solution to aging,” Healy says. “It’s more likely to be almost jury-rigged, so different mechanisms to kind of patch up all the aging processes that are going on. The more of these we can find, the more possible solutions to diseases related to aging that we can also find and perhaps implement.”