The Salty Secrets of Extreme Longevity

Black Rockfish Shutterstock / Mariusz S. Jurgielewicz

Rockfish, clams, tortoises, and other underwater Methuselahs harbor adaptations that could provide clues to unlocking our own longevity.

Spearfishing is a sport you can do in almost any ocean, barring marine reserves. But it is not the same sport in every ocean. In warm, tropical waters with high visibility, fish dart about, wary of the slightest movement. In colder oceans, especially when the visibility is poor, fish tend to be more curious and less cautious. Chalk it up, perhaps, to less experience with a diver carrying a deadly weapon, but fish in colder climates can be comically curious at times, even swimming right up to the point of a spear. 

Still, don’t count these slower swimmers as less intelligent than their tropical relatives. Marine species—fish and otherwise—that live in colder climates might seem a bit sluggish. But cooler waters can mean longer lifespans, too. Scientists are still unraveling the mechanism behind this, but a spate of ocean species have shown promise for unlocking the secrets of extreme longevity. Now, aging experts are hoping to harness the genetic, metabolic, and other cellular differences that protect these creatures from the usual drivers of aging, including a breakdown of cellular processes, cancer, and other stressors.

The mechanisms behind species-specific evolutionary patterns are often unique, though not always. Sometimes very different species develop the same evolutionary adaptation to a common problem. The challenge for scientists is that these evolutionary “fixes” often happened so long ago that we can’t be sure what drove them. 

“We can’t know the direction of causation. All we know is that these two things happened together,” says Vincent Lynch, an evolutionary developmental biologist at the University of Buffalo in New York. “It could be that what happened first was these genetic changes reduced their probability of getting cancer and other aging-associated diseases and that allowed them to evolve long lifespans. Or it could be that there was a reason for them to evolve long lifespans. And because of that need to evolve a long lifespan, they had to acquire these genetic changes.”

But as research progresses, people increasingly want to know not only how evolution happened, but how we can harness its secrets to improve human lifespans, too. 

The impact of genetics on aging increases as we age, says João Pedro de Magalhães, an expert in the genomics of aging at the University of Liverpool in England. “If you want to be a healthy 78 or 80-year-old, you have to watch your lifestyle,” he said in a 2015 TEDx talk. “If you want to be a centenarian and live 120 years, then it’s really down to your genes.” For most of us, that means a double-digit lifespan. But for many of our relatives in the animal kingdom, life can last decades, even centuries longer.

Deep-sea clams do it by avoiding free radicals

Not too many clams become famous enough to make headlines. But in 2013, an ocean quahog called Ming did. Named for the long-gone Chinese dynasty that reigned at the time of its birth, the 507-year-old bivalve was collected from an underwater Icelandic shelf along with many other ocean quahogs. Ming died when it (no sex was recorded) was flash frozen along with the other clams for preservation purposes, raising international ire, though researchers later told National Geographic that it’s likely there are many ocean quahogs of Ming’s age, including those killed by people fishing. Ming was simply the first of its age to be measured and recorded. 

Since Ming, ocean quahogs have garnered interest from longevity researchers like Enrique Rodriguez, who has studied how mitochondrial “supercomplexes” can help these clams live for such a long time. Mitochondria are the membrane-bound energy generators in cells. In ocean quahogs, antioxidant pathways are more resistant to oxidative stress than those in closely related bivalve species. In practice, this means they’re able to resist hypoxia, or low oxygen levels, found in deeper levels of the ocean. Ocean quahogs can keep their shells closed for a long time, shutting out predators and oxygen from the ocean. Unlike other mollusk species, they can avoid producing a flood of damaging free radicals when oxygen is newly available.

The two halves of Ming the quahog.
Ming the quahog. Wanamaker / Bangor University / Science Source

Rodriguez compares the effect of free radicals to a car that rusts with age or “like pollution as a consequence of traffic jams, damaging the road and the environment.” A car on the road, then, might represent electrons that become jammed in the electron transport system, an electrochemical gradient that drives the production of cellular energy. A more organized system—mitochondria’s so-called supercomplexes—is like an efficient superhighway system that makes a whole city (or cell) function more smoothly. Smoother function means a longer lifespan. Could the same be true for humans?

The mechanism behind this, according to Rodriguez’s latest research, seems to be these highly organized electron transport system supercomplexes, which are structures formed from protein complexes within the mitochondria. As we age, mitochondria are less able to manage free radicals in the body, which means the electron transport system gets worse at regulating free radical production, resulting in an increased rate of cellular damage. But as ocean quahogs age, supercomplexes within the mitochondria remain tightly organized, helping stave off that damage. When scientists compared ocean quahogs with related clams that had less organized electron transport systems, they found a link between extreme longevity and the ability of mitochondria to maintain these supercomplexes.

“While it is true that bivalves are distant to humans, mitochondria are remarkably well conserved genetically among species, and are at the nexus of metabolism,” Rodriguez says. Mitochondria are also adaptable, so understanding their age-defying functions in one species—or, hopefully, finding common age-defying functions across multiple species—could help scientists figure out how to encourage positive adaptations in human mitochondria, too. “One thing we know is that nutrition and genes are at the core of a healthy, long lifespan, and mitochondria are at the very basis of both, dealing with the molecular sub-products of what we eat, and they carry their own genome,” Rodriguez says. Testing diets and even new drug compounds for potential mitochondrial boosters is one possible outcome of this research. Rodriguez is currently studying these possibilities in fruit flies.

A photograph of a Galápagos Tortoise.
The Galápagos tortoise. Shutterstock /

Galápagos giant tortoises do it by being genetically tidy

Ocean quahogs aren’t the only species that have benefited from staying organized. Galápagos giant tortoises have evolved a unique resistance to cancer that, like ocean quahogs, has something to do with their ability to keep a clean house, on a cellular level. However, their secret has to do with genetics, not mitochondria. In many species, cells with genetic errors will self destruct, a kind of cellular suicide that helps stave off harmful mutations that can lead to cancer. The Galápagos tortoise just happens to be better at it than most turtles and many other organisms as well. 

Using cell lines propagated from Galápagos samples, scientists led by Vincent Lynch measured how the tortoise cells reacted to stressors such as chemicals that caused oxidation. Like many tortoises, the Galápagos cells were highly resistant. But scientists also noted an unusual response to a process associated with cancer and aging known as endoplasmic reticulum stress. The endoplasmic reticulum produces cellular proteins and ensures they have the right shape and, thus, function. 

“If you stress that out, the Galápagos tortoise cells die, whereas other cells don’t,” Lynch says. “The cells kill themselves.” These tortoises have duplicate genes responsible for sensing irregular proteins. And while more is not always better, in terms of genetic function, Lynch says, in this case, the additional genes do have an additive effect, making the Galápagos super efficient at sussing out irregular proteins before they can develop into cancerous cells.

And while we hardly want to start duplicating genes in humans, identifying such a specific genetic function may help scientists develop new medications for people in the future. A new pharmaceutical might replicate some of the functions of those genes, without requiring a person to actually have copies of the gene itself.

“Evolution is simultaneously very creative, and also very lazy when it comes to solving problems.”

It’s a process made more complicated by the spate of genes that govern all biological processes. As important as the genetic bonuses he uncovered, Lynch says, is realizing that these are not the sole mechanisms behind cancer resistance in the Galápagos tortoise. In fact, given that larger members of the same species often have a higher cancer risk (due, simply, to having more cells), it’s even more astonishing that massive Galápagos tortoises outlive their relatives. One captive Galápagos tortoise lived to 177 years old.

“These changes that we identified can’t be the only ones that are responsible. There have to be lots of other ones that all contribute,” says Lynch. “So these changes contribute some of the effect of protection against cancer, from the deleterious effects of aging, but there’s going to be lots of other genetic changes associated with those things.”

Rockfish do it by phenotype 

When it comes to sussing out genetic changes and adaptations, it’s often hard to tell cause from effect and to accurately map the result of evolutionary pressures over millions of years. But one recent study managed to narrow it down, thanks to the plethora of rockfish species that have co-evolved a wide range of lifespans.

“Evolution is simultaneously very creative, and also very lazy when it comes to solving problems,” says University of California, Berkeley biologist Juan Manuel Vazquez, who researches the evolution of longevity. Vazquez studies unrelated species, from elephants and whales to bats and tortoises, and he says because of convergent evolution, some species come to solve the same problem the same way, despite genetic differences. That’s why Vazquez was curious to collaborate on a study that explored genetic differences in 88 species of rockfish, which thrive in chilly, Pacific Ocean habitats. Rockfish lifespans range from 11 to 200 years, and two factors help these fish live a long time. Some rockfish are quite large, a hefty advantage in a predator-filled ocean. As a plus, cold Pacific waters boost rockfish lifespans by slowing metabolic rates—and rockfish prefer to spawn along the ocean floor, where temperatures are the lowest. 

Still, scientists were puzzled by the wide range of lifespans. Why does one type of rockfish die after just decades while another type can live for centuries? To find out, researchers sequenced the genome of more than 100 fish from 88 rockfish species, and they identified 137 genes associated with longevity. Longer-lived species tended to have genes that promoted adaptations allowing fish to live in deeper, colder water. But scientists also found more DNA-repair genes and helpful variations in genes that govern insulin regulation and the immune system. In other words, all rockfish had adapted to grow larger in colder environments, to some extent, but the longest-lived species had more DNA repair genes, along with variations that help ward off cancer and infection. Because there are short- and long-lived rockfish species living at each of the various oceanic depths rockfish inhabit, scientists were able to sift out genes associated with size and depth tolerance, and hone in on those specifically linked to longevity.

Certain genes were also evolving faster in the longer-lived species, according to researcher Greg Owens, one of the first authors of the study. This could be because the genes are directly linked to longevity. Or, it could be just the opposite, and a gene could be evolving quickly because it has no outcome on the fish’s lifespan. “Imagine if you had a fish that moved from freshwater to saltwater,” Owens says. “It no longer needs all these saltwater genes, so then those genes might evolve faster just because they’re not constrained anymore.” The outstanding question is whether the genes are evolving faster because they’re causing longer lifespans, or whether they’re evolving rapidly as a consequence of the longer lifespans themselves. For now, there’s no way to know, especially since the rockfish spawn late in life, with so-called BOFFFs, or “big, old, fat, fecund, female fish” often responsible for the thousands of eggs required to ensure a species’ survival. 

Sebastes mystinus, also known as the blue rockfish. Tyson Rininger

Evolution happens over millions of years, so the consequences for humans of figuring this out are still nebulous. No scientist can ethically hope to steer human evolution, and it’s “ethically and technically challenging” to even conceive of gene editing a human to live longer, Owens says. A constellation of changes would likely be required. “It’s not gonna be like, we just got to put the long-lived gene in,” he says. 

But what might be possible, once these genes are better understood, is pharmaceuticals for people that replicate some of their anti-aging effects. This might be ethically simpler than human genome editing, but it’s still murky because of the complex, yet-to-be-understood links between genetics and aging. First, Vazquez points out, it’s difficult to do aging research on, say, flatworms, fruit flies, or mice because their average lifespans are so short. And there can be crucial genetic differences between species that live for a few years and those that tend to survive for decades. On the other hand, using long-lived species for aging research in the lab is potentially even more problematic because caring for animals over the course of years or decades would be exorbitantly expensive (not to mention the problem of getting grad students interested in a research project that would potentially span multiple human lifetimes).

Besides that, it’s not even clear the salty secrets we uncover in ocean animals would be relevant for humans. When we start comparing, say bowhead whales and the Galápagos tortoise or naked mole rats with ocean quahogs (which both have stellar mitochondrial function), comparative evolution doesn’t have all the answers. “There are so many ways of evolving longevity in so many ways to suppress cancer,” Vazquez says. “What are the odds you’re going to find the same target every single time?” And even if we can identify big, common pathways, it’s possible, he adds, that we’ll miss other pathways that could be less toxic to human biology. 

Humanity’s best bet, Vazquez argues, might simply be the twin efforts of using science to unravel the evolutionary oddities we do recognize and embracing oceanic conservation to preserve the long-lived creatures we don’t—those undiscovered saltwater Methuselahs whose cellular adaptations could provide clues to unlocking our own longevity, too.

Editor’s note: This story was updated on April 22, 2022 to reflect the proper spelling of Juan Manuel Vazquez’s surname.

Go Deeper