By mid-2016, Calico was bustling along. It had 98 employees, with more in the pipeline. The research labs inside of its growing South San Francisco office were strewn with names like the Lily Pond, Northwest Territory, and Middle Earth. Walls of glass were covered with handwritten graphs and computations: the aggregated thoughts and insights of Calico’s growing roster of lab cats. And everywhere, researchers were hunkered down, working out the ways to bring death to a halt: some in the microscopy section and others in cell biology or computational science.
Soon Calico was developing arrangements with Ancestry.com to investigate centenarians who seemed, inexplicably, to live so long; the oddities of yeast and the ways they might explain long life; and, perhaps most interesting of all, animals in the biological hinterlands that lived extremely long. The Calico team had found some pretty fascinating examples.
It was obvious that if you compared, say, an elephant and a dung beetle, their life spans would differ. But what if you looked at two very similar animals and found that one survived much longer than its cousins? That was the case of a fish named Hoplostethus atlanticus, the orange roughy, which, not long ago, was a popular entrée on menus worldwide.
Orange roughy is very similar to the common pirate perch, which lives in freshwater streams and lakes. Like most fish, they swim around for a few years and then move on to that great pond in the sky. Orange roughy, meanwhile, swim the world’s oceans, in cold water, hauling around pretty much the same genes as their perch colleagues. But how long do they live? The record is 149 years.
When Levinson, who was an avid consumer of seafood, got that news, he stopped ordering orange roughy on the spot. It made him wonder how many times he had gulped down some poor Hoplostethus atlanticus in its youth, robbing it of a century of good times trolling the reefs off the Kamchatka Peninsula or Scotland’s North Sea.
But the larger point was that one fish, the perch, was dead and gone in four years; the other stuck around for a century and a half. How did you explain that? This was another example of evolution finding a way to bend beta. And Art Levinson was bound and determined to get to the bottom of it.
It turns out that nature has created all kinds of intriguing examples of this sort. Another was the naked mole rat, an underground-burrowing rodent also known as a hystricomorph that lives in East Africa. It’s just about the ugliest creature anyone ever laid eyes on: a mouse-size, pigeon-toed alien with beady, lifeless eyes, clawed feet, and yellow skin so pale and bloodless you’d think it had been sheared off a corpse and draped over its sepulchral body by some amateur taxidermist. At the end of its snout protrude two buck teeth that seem to have been randomly hammered in by some sadistic scientist.
Yet some researchers adore the little beasts, partly because no other rodent lives as long as it does. The hystricomorph record was a male that a physiologist named Shelley Buffenstein brought to the United States from Africa back in 1980, when the little animal was only two years old. After a while, Buffenstein started calling the critter Old Man because he just went on and on. He finally died in 2010, but was still an alpha male in the nest, having a grand old time mating with the queen mole rat right to the end.
Mole rats routinely lived 25 years. Your average mouse might manage to exist three, and your everyday lab rat’s life rarely ran to four. And yet those shorter-lived rodents shared a lot of the same genes as the mole rat. So why the big difference in life span?
If anyone knew the answer, it would be Buffenstein. She had been running the largest mole rat colony in the scientific world for years: 2,000 of the brutes at the Barshop Institute for Longevity and Aging Studies in San Antonio. In 2015, she brought her brood to Calico.
Once settled, Buffenstein continued to compare her tribe with a whole herd of other rodents of the lab rat variety: hamsters, the Cactus mouse, the white-footed mouse, gerbils—even other types of blind mole rats. Some of the other mole rats lived up to 20 years, but none lived 30 like the Old Man.
Buffenstein’s comparisons, once she had delved into the genetic noise, revealed that mole rats like Old Man enjoyed the benefits of a powerful protein known as Nrf2, which balances the damage oxidation does to cells, including free radicals. It exists in lots of mammals, including humans. Nrf2 in mole rat cells seemed to help improve the way they handled all sorts of perfidious assaults: oxidation, various poisons, inflammation, heat, deteriorating brain cells—pretty much anything that broke the body down.
Nrf2’s molecular interactions were incredibly complex: thousands and thousands of bubbling, bouncing, invisible discombobulations across billions of molecules. But in a nutshell, the naked mole rat seemed particularly good at sensing and regulating oxidation in general, and free radicals in particular. If this oxidative stress isn’t cleaned up in any living thing, it accumulates a lot of damage. Thus, not unlike Kenyon’s mutated Daf-2 genes, Nrf2 sets in motion a whole domino effect of benefits with nothing more than a single protein that shields the little beasts so well that they live five to six times longer than nearly every other known rodent. One more example of evolution flipping a master switch and stopping the clock!
The more scientists inspected the genomes of the animal world, the stranger their discoveries became. Another was an immense creature that the indigenous Inupiat people haul out of the Arctic Ocean onto the packed, hardtack beach of Barrow, Alaska, every fall and spring. Barrow (now known as Utqiaġvik) is the northernmost city in the United States: the last slip of the planet that North America has to offer before giving up nothing more than wind, snow, and the harsh gale-swept waters of the Beaufort Sea.
When John “Craig” George arrived in Barrow in 1977 to take up work as a young lab assistant and wildlife biologist for the Naval Arctic Research Laboratory (NARL), he told his boss he wasn’t sure he would last very long. It wasn’t that he minded shoveling animal dung, or keeping track of elk and bear and walrus out on the tundra. But where was the stately beauty of Alaska? Certainly not here!
Barrow, you see, was a little like the mole rat of Alaska. Even today, the place looks like some wind-whipped, gold rush settlement out of a 1950s B movie, an architect’s nightmare pocked with World War II-era Quonset huts and their drab descendants: ramshackle, prefab metal and pressed-wood buildings with an occasional geodesic dome here or there, each sitting on pylons hammered into the ice-hard permafrost to keep it from listing into the tundra when summer briefly makes its way to what the locals call “the top of the world.” Here, the streets don’t even require paving; they stay that cold.
Nevertheless, 40 years after George’s arrival, he had grown to love the place, and was still living there when he made a remarkable discovery about life span inside the body of the great creature in question: a bowhead whale.
Although most whaling has been outlawed worldwide, under a special relationship with the federal government and the Alaska Eskimo Whaling Commission (AEWC), the Inupiat people of Utqiaġvik are allowed to harvest bowheads for a few weeks a year. The deal was arranged because the whales are central to the native culture in the way buffalo once were for the tribes of the American Plains and West. Only so many whales can be harvested, and their meat, under the agreement, must be freely distributed to the natives of the village. Nothing can be sold either at a restaurant or store.
George was a great fan of bowheads, and knew just about everything about them. They were immense, among the largest animals on Earth, often as long as an 18-wheeler and weighing 45 to 65 tons. Largely because of their gargantuan dimensions, they had been revered by the Inupiats for more than 2,500 years. During the vast majority of those years, Inupiat whalers hunted the immense animals using long wooden harpoons, hafted with broad, flint blades. But beginning around 1890, those harpoons were replaced when Yankee whalers from New England started heading north. The Inupiat worked with the white whalers and took up the new technology that came with them: metal harpoons called Temple toggles, which were catapulted from a kind of cannon on deck.
One spring day in 1992, George arrived with one of his colleagues, Billy Adams, just as one of the whales was being hauled on shore. The whale was mature: 50, maybe 60 years old. Everyone figured he was getting pretty long in the tooth, because the consensus then was that all whales lived about the same length of time: no more than 75 years.
As the two biologists were looking the whale over, Adams noticed a divot in its back. It appeared strange enough that George asked if he could see that section of the whale as they were preparing to butcher and distribute it to the villagers. That was part of George’s job at NARL, keeping tabs on all animals in the region.
So George cuts his way into the 18 inches or so of blubber to see if he can get his hand into the divot, and he feels a harpoon. Normally, that wouldn’t be very unusual. Harpoons were sometimes found in the great animals. But when he pulled the harpoon out, the hair on George’s neck stood on end. In his hand, he held a large blade of slate that had been carefully hafted into the end of a long pike of bone or ivory: beautifully crafted and shaved to a razor’s edge in the shape of a triangle five inches long and four inches wide. Stone Age technology. Nothing like it had been created since the Yankee whalers had arrived with their Temple toggles 120 years earlier!
George knew enough about whale craft and history to understand what this meant. Some Inupiat hunter, coming in for the kill, riding in a whaling boat made of wood and sealskin no larger than the whale itself, had stood up in the frigid, open sea and thrust the harpoon into its back more than 120 years ago. That was when Ulysses S. Grant was president, and Jules Verne wrote Around the World in Eighty Days!
It wasn’t until 2015 that scientists got around to sequencing the genome of bowhead whales. The news revealed what everyone had come to expect: Bowheads were by far the longest lived mammals on Earth. It wasn’t unusual for them to survive 215 years! Right now, some of those out there beyond Utqiaġvik might have been swimming the Beaufort Sea when Napoleon was marching to Moscow.
Other animals, like the quahog clam (the one used in clam chowder), were known to live 400 years. And the well-known ancient tortoises of the Galápagos Islands poked along for upwards of 100 years. And in 2016, scientists had confirmed that some Greenland sharks might swim the cold waters of the North Atlantic for 500 years. But those were fish and amphibians and mollusks. Bowhead whales were mammals—large and complex—and they routinely lived almost three times longer than your average, healthy human. Once again, evolution had set a different clock, a different beta. But why? And how?
Over the years, Craig George developed some theories. For one thing, new studies revealed that bowheads didn’t even begin to mate until they were 25 years old. There was a direct correlation between the time a mammal grew sexually active and how long it lived. Another factor was that like humans, bowheads usually had only one calf at a time, and took 14 months to gestate. And like humans, they required a lot of care after birth. So, over time, evolution tended to select bowheads that would live longer: the better to ensure the species’ offspring survived and had time to continue breeding.
And then there was that old issue related to calorie restriction. Bowheads were the only whales in the world that lived in cold water year-round. While all of the world’s other whales swam to warm waters to bear their children, bowheads spent every last minute of their existence among the frigid seas of the Arctic. That made food scarce, which meant evolution would select for bowheads that could survive longer without food.
This, in turn, would slow the rate of reproduction. Research had shown bowheads could go 18 months without eating a single plankton or shrimp, and still go strong. (This was one reason their blubber was, by far, the thickest among all mammals.) The animals simply needed longer life spans and reproductive cycles to survive, and the evolutionary lottery had allowed them to manage it.
Rabbits and rats, on the other hand, are good examples of species that live in a world where they rapidly proliferate in climates where food is plentiful. They have no reason to survive especially long. They can procreate like, well, bunnies, and then pass on to make room for their offspring. In more ways than one, this paralleled the Daf-2 gene mutations in worms, fruit flies, and mice, which also slowed their aging, or the effect of the drug metformin as it changes the insulin pathways in humans. On a molecular/cellular level, all of these actions cause the creatures to react as though they are living in an environment where food is scarce.
George had no particular opinions on that insight, but he knew one thing: Bowheads were astonishingly tough—strong and healthy to the end. The powers of their DNA repair were stunning. Throughout their lives, they seemed to continually repair the huge numbers of cells needed to keep them alive and swimming millions of miles. Never once, after a good thousand of his investigations over the years, had George found evidence of any cancer or dementia in a bowhead.
Whatever was going on, all the evidence indicated that evolution could somehow change key genetic pathways that lengthened the life of a species. And that begged the bigger question: If evolution could find a way to do this, could science do it too?