Genetic tricks of the longest-lived animals

Life, for most of us, ends far too soon—hence the effort by biomedical researchers to find ways to delay the aging process and extend our stay on Earth. But there’s a paradox at the heart of the science of aging: The vast majority of research focuses on fruit flies, nematode worms and laboratory mice, because they’re easy to work with and lots of genetic tools are available. And yet, a major reason that geneticists chose these species in the first place is because they have short lifespans. In effect, we’ve been learning about longevity from organisms that are the least successful at the game.

Today, a small number of researchers are taking a different approach and studying unusually long-lived creatures—ones that, for whatever evolutionary reasons, have been imbued with lifespans far longer than other creatures they’re closely related to. The hope is that by exploring and understanding the genes and biochemical pathways that impart long life, researchers may ultimately uncover tricks that can extend our own lifespans, too.

Everyone has a rough idea of what aging is, just from experiencing it as it happens to themselves and others. Our skin sags, our hair goes gray, joints stiffen and creak—all signs that our components—that is, proteins and other biomolecules—aren’t what they used to be. As a result, we’re more prone to chronic diseases such as cancer, Alzheimer’s and diabetes—and the older we get, the more likely we are to die each year. “You live, and by living you produce negative consequences like molecular damage. This damage accumulates over time,” says Vadim Gladyshev, who researches aging at Harvard Medical School. “In essence, this is aging.”

This happens faster for some species than others, though—the clearest pattern is that bigger animals tend to live longer lives than smaller ones. But even after accounting for size, huge differences in longevity remain. A house mouse lives just two or three years, while the naked mole rat, a similar-sized rodent, lives more than 35. Bowhead whales are enormous—the second-largest living mammal—but their 200-year lifespan is at least double what you’d expect given their size. Humans, too, are outliers: We live twice as long as our closest relatives, the chimpanzees.

Bats above average

Perhaps the most remarkable animal Methuselahs are among bats. One individual of Myotis brandtii, a small bat about a third the size of a mouse, was recaptured, still hale and hearty, 41 years after it was initially banded. That is especially amazing for an animal living in the wild, says Emma Teeling, a bat evolutionary biologist at University College Dublin who coauthored a review exploring the value of bats in studying aging in the 2018 Annual Review of Animal Biosciences. “It’s equivalent to about 240 to 280 human years, with little to no sign of aging,” she says. “So bats are extraordinary. The question is, Why?”

There are actually two ways to think about Teeling’s question. First: What are the evolutionary reasons that some species have become long-lived, while others haven’t? And, second: What are the genetic and metabolic tricks that allow them to do that?

Answers to the first question, at least in broad brushstrokes, are becoming fairly clear. The amount of energy that a species should put toward preventing or repairing the damage of living depends on how likely an individual is to survive long enough to benefit from all that cellular maintenance. “You want to invest enough that the body doesn’t fall apart too quickly, but you don’t want to over-invest,” says Tom Kirkwood, a biogerontologist at Newcastle University in the UK. “You want a body that has a good chance of remaining in sound condition for as long as you have a decent statistical probability to survive.”

This implies that a little scurrying rodent like a mouse has little to gain by investing much in maintenance, since it will probably end up as a predator’s lunch within a few months anyway. That low investment means it should age more quickly. In contrast, species such as whales and elephants are less vulnerable to predation or other random strokes of fate and are likely to survive long enough to reap the benefits of better-maintained cellular machinery. It’s also no surprise that groups such as birds and bats—which can escape enemies by flying—tend to live longer than you’d expect given their size, Kirkwood says. The same would apply for naked mole rats, which live their lives in subterranean burrows where they are largely safe from predators.

But the question that researchers most urgently want to answer is the second one: How do long-lived species manage to delay aging? Here, too, the outline of an answer is beginning to emerge as researchers compare species that differ in longevity. Long-lived species, they’ve found, accumulate molecular damage more slowly than shorter-lived ones do. Naked mole rats, for example, have an unusually accurate ribosome, the cellular structure responsible for assembling proteins. It makes only a tenth as many errors as normal ribosomes, according to a study led by Vera Gorbunova, a biologist at the University of Rochester. And it’s not just mole rats: In a follow-up study comparing 17 rodent species of varying longevity, Gorbunova’s team found that the longer-lived species, in general, tended to have more accurate ribosomes.

The proteins of naked mole rats are also more stable than those of other mammals, according to research led by Rochelle Buffenstein, a comparative gerontologist at Calico, a Google spinoff focused on aging research. Cells of this species have greater numbers of a class of molecules called chaperones that help proteins fold properly. They also have more vigorous proteasomes, structures that dispose of defective proteins. Those proteasomes become even more active when faced with oxidative stress, reactive chemicals that can damage proteins and other biomolecules; in contrast, the proteasomes of mice become less efficient, thus allowing damaged proteins to accumulate and impair the cell’s workings.

DNA, too, seems to be maintained better in longer-lived mammals. When Gorbunova’s team compared the efficiency with which 18 rodent species repaired a particular kind of damage (called a double-strand break) in their DNA molecules, they found that species with longer lifespans, such as naked mole rats and beavers, outperformed shorter-lived species such as mice and hamsters. The difference was largely due to a more powerful version of a gene known as Sirt6, which was already known to affect lifespan in mice.