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  We know that exercise sharply increases oxidative stress, at least in the short term. For a long time, scientists puzzled over this fact, concluding that exercise is healthy despite the higher levels of ROS that it produces. And indeed, it’s possible to exercise to excess, to the point where we cause actual damage; if we go lift weights one day after doing nothing for a month, we’ll be sore afterward thanks in part to oxidative damage, or so it was thought. So for decades, athletes have been taking antioxidant supplements, thinking they would mitigate the soreness caused by their training.

  Ristow’s findings turned the oxidative stress theory upside down. He subjected his young, hopefully well-paid volunteers to excruciating muscle biopsies both before and after the training period. Both groups showed evidence of oxidative stress in their muscles after training, as expected, but he found that the subjects who had taken the supplements—harmless-seeming vitamins—had actually benefited far less from their exercise program than the ones on the placebo. If anything, the antioxidants seemed to have wiped out the benefits of training. All of which led Ristow to suggest, in a subsequent letter to the editor, that antioxidant supplements are “worse than useless.”

  He thinks so, and here’s why: Normally, our bodies produce their own antioxidants, powerful enzymes with superheroesque names like superoxide dismutase and catalase, which soak up the excess free radicals that exercise produces. The supplements seemed to be blocking these enzymes. “If you take antioxidants, you preclude your own antioxidant systems from being activated,” Ristow explains. “Not only antioxidants, but other repair enzymes.”

  In other words, by taking supplements we allow our native antioxidant defenses to grow weak and lazy, leaving us more vulnerable to damage from ROS. Adding a little bit of stress, like exercise, helps keep our own antioxidant defenses in tune. We adapt to the stress, and come out stronger (not to mention live longer). “This is why the benefits of exercise last so much longer than the exercise itself,” he explains. The same goes for caloric restriction, he feels.

  The supplements were blunting this hormesis response. The good news here is that we’ll all be saving a lot of money in the vitamin aisle at Whole Foods—just like Todd Becker, the Hormesis Guy, who disdains pretty much all supplements, even things like fish oil and omega-3 fatty acids. As for things like pomegranates and blueberries, which have become celebrated as “superfoods” because of their antioxidant properties, Ristow says, “They are healthy despite the fact that they also happen to contain antioxidants.”

  Ristow’s work also pointed to a completely new understanding of oxidative stress itself: Not only was it not harmful, but he suspected it was beneficial, and perhaps even essential to life. In studies, he and others had found that increased levels of oxidative stress actually lengthened lifespan in worms. Even spritzing them with low doses of the herbicide paraquat, which incites major oxidative stress because it’s a poison, ended up making the little buggers live longer. Arsenic did the same. (Again: Don’t try this at home.) Others had observed similar results: Even mice that had had their antioxidant enzymes completely whacked out of them (via genetic manipulation) suffered no reduction in lifespan or health. It got stranger. In other experiments, Ristow found that antioxidants also wiped out the benefits of calorically restricting his worms, which would normally extend their lifespan.

  In English: Antioxidants appeared to be irrelevant to aging. And it didn’t matter whether they are produced by our own bodies, or swallowed in pill form. Ristow went so far as to suggest that free radicals are far from the dangerous toxins that Denham Harman imagined; in reality, they are essential signaling molecules, produced by the mitochondria specifically in order to trigger beneficial stress responses in other parts of the cell. Or to simplify, ROS are our intracellular Paul Reveres. Exercise and lack of food—which in evolutionary terms means we are hunting or undergoing a famine—actually shift our mitochondria into a different state altogether, which he terms mitohormesis, in which they produce more free radicals, which in turn trigger our bodies’ own health-promoting responses to stress, like DNA repair, glucose scavenging, even killing potential cancer cells.

  A little bit of stress, then, is good for us. But what about a lot of stress? To answer that, I traveled to Texas in search of the world’s most stressed-out animal, and also one of the ugliest.

  In a windowless basement room, somewhere beyond the outskirts of San Antonio, the strangest animal I have ever seen is crawling up my arm. She is bigger than a mouse but smaller than a hamster, and really weird-looking: pale pink, with delicate wrinkly skin and two pairs of enormous beaver-teeth. I email a pic to my girlfriend, who replies that it resembles “a penis with fangs.”

  Quite.

  But the two most interesting facts about this critter, a naked mole rat whom I’ve dubbed Queeny, are these: She is thirty years old, six times as old as the oldest laboratory mouse ever known. And, two, she is pregnant. Very, very pregnant. So pregnant that I can see the outlines of her next litter, little dark lumps bulging beneath her nearly translucent skin. So, in human terms, I am holding in my hand the equivalent of an eight-hundred-year-old pregnant woman. Naked mole rats, it seems, have conquered menopause.

  That’s not all that’s fascinating about Queeny: She and her brothers and sisters (and parents and children and uncles and cousins, all of whom are living together in this sealed Habitrail-like enclosure) endure massive amounts of oxidative stress in their bodies, levels that would scorch the fur off virtually any other animal on the planet. Yet it doesn’t seem to bother them one bit. “From a very young age they have high levels of oxidative damage,” says my guide, Shelley Buffenstein, “and yet they live twenty-eight more years.”

  More than three decades ago, as an undergraduate, Buffenstein had helped collect Queeny’s parents and about a hundred of their friends and relatives from a colony that was living beneath a dirt road in Tsavo National Park in Kenya. At the time, not much was known about the naked mole rat, beyond the fact that they are really strange animals. Because they live underground, they had rarely ever even been seen. Unlike most rodents, mole rats are “eusocial,” meaning they live in colonies dominated by a single breeding female, like many kinds of ants or bees. They are the only mammal to live this way. And they rarely if ever see the sun, which explains their delicate pink skin, not to mention the fact that they are blind. They “see” with their whiskers, Buffenstein informs me, in her lilting Afrikaner accent.

  Buffenstein grew up on a farm in what was then white-ruled Rhodesia, and international sanctions had forced her to pay her own way through school in Kenya. So she took a job as an undergraduate lab assistant for a biologist named Jenny Jarvis, who was the first to study the naked mole rat. Jarvis kept a few mole rats in cages in her office, and when she embarked on an expedition to study them in the wild, Buffenstein went along. The result was that Queeny’s ancestors were uprooted from their cozy underground nest, and when Buffenstein eventually immigrated to America, she brought the mole rat colony along with her. Here in the basement of her lab, they live in a rather large and complex Habitrail kind of system. One chamber is reserved as the communal toilet, just as in their underground nest. The air is quite pungent.

  Originally, Buffenstein set out to study the animals’ endocrine biology—hormones, basically—but as the years passed she noticed something odd about her already-strange charges: They seemingly refused to die. “When they turned ten, I thought, Wow, they live a long time!” she says. “I said, We should start studying aging and figure out how they live so long.”

  Easier said than done. Everything about the “nakeds” (as she called them) seemed like a piece to a different puzzle, starting with their off-the-charts levels of oxidative damage; their tiny little bodies carried around more “rust” than a Russian roller coaster. Yet they kept on ticking for decades, long after the oxidative stress theory would insist that they should have died.

  Their survival is all the more puzzling to Buffenstein, w
ho believes that these extreme levels of oxidation are actually a function of their life in captivity. In the wild, deep in their underground burrows, the nakeds survive on much less oxygen than we surface dwellers enjoy; they rarely if ever see the sun, or breathe surface air. So they have much less oxidative stress. “Imagine sharing a burrow two meters deep with three hundred of your closest friends,” she says wryly.

  But in their lab cages, the naked mole rats are exposed to much higher levels of oxygen than they experience in the wild, which should poison them. “And yet they tolerate it!” she marvels. “They live in captivity for thirty years with all this oxidative damage.”

  She believes the mole rats pretty much disprove the oxidative stress theory of aging, at least in its simplest form. More interesting to her, though, is the idea that they could be undergoing a kind of stress response—our friend hormesis—that keeps them alive for decades longer than most other rodents. She thinks this stress response helps condition them for the stress of living in the colony, where a social hierarchy is rigidly enforced. “The queen is a bully,” she explains, and within the colony there are power struggles worthy of Shakespeare, even over whose job it is to tidy up the brood’s “toilet.” The queen, being the queen, gets to poop right in the doorway. And as she is the beneficiary of all the others’ work and protection, it is perhaps not surprising that she lives an astonishingly long time.

  But then, so do the lowly workers who can last twenty years themselves. The fact that they live underground, where it’s hard for predators to pluck them out (although snakes and spoonbill ibises certainly try), has earned them the luxury of evolving really long lifespans. Their bodies are simply better designed for growing old—which means they are better designed to handle stress, which they do by “up-regulating” their cells’ own internal protective mechanisms.

  For example, the mole rats’ proteasome, the cellular garbage disposal, operates at a much higher rate than that of a normal mouse, which in turn helps it get rid of all those oxidatively damaged proteins and cell components. So where most lab mice die from cancer, and the rest die with it, the mole rats are completely cancer-free; Buffenstein’s team has yet to find even a tumor in a dead mole rat. Their cells just don’t become cancerous. Even when the mole rats were slathered with a highly potent carcinogen called DMBA, which induces pretty much instant cancer in mice, they remained healthy; it might as well have been suntan lotion.

  “We think the naked mole rat cells have better surveillance mechanisms to say, Wait a second, there’s something not kosher, there’s a change in my genome, and I’m not proliferating with it,” she says.

  The naked mole rats are unusual, but by no means unique in nature. There are other animals that tolerate extreme levels of oxidative damage without dying. One of these hardy critters, a kind of cave-dwelling salamander called the olm, is found only in caves in Slovenia and northern Italy; ghostly pale, blind, and no more than ten inches long, the olm lives nearly seventy years—which is an insanely long lifespan for a salamander. It lives nearly as long as the average Slovenian male, which is why it’s locally nicknamed “the human fish.”

  Indeed, the olms and the naked mole rats reminded me in some ways of Nir Barzilai’s centenarians, like Irving Kahn; and not only because they were so small and wrinkly. They are hardly the world’s most robust creatures, yet they both possess an inner resilience, a quality that author Nicholas Taleb dubs antifragility, that enables them to live for an extremely long time. Irving Kahn had escaped the heart disease and cancer that claim more than half of aging Americans—and this despite the fact that he had smoked for decades—because he is antifragile. Like the mole rats, he must be uniquely resistant to oxidative damage, and his proteasome probably kicks butt, too. Like the naked mole rats, his cells go to the Jaguar mechanics, not the Jiffy Lube guys.

  But there’s also a key difference between naked mole rats and centenarians, one that is perhaps the most important of all. Human lifespan, as we’ve seen, tops out around 120. Nobody really knows how long a naked mole rat can live—or an olm, for that matter, although there are very few of them in captivity to begin with. With the mole rats, it’s not even entirely clear that they age, at least not the way other living things do; their mortality rates do not climb with age, the way ours do (according to Gompertz’s law, which we talked about earlier). Nor do the mole rats go through anything resembling menopause, or reproductive aging—as Queeny rather amply demonstrated, shortly after my visit, when she gave birth to a litter of more than a dozen wriggling pups. Do they age at all?

  In an effort to find out, a team including Buffenstein worked to sequence the naked mole rat genome. They reported in Nature that in terms of gene expression—which genes are switched on, and which shut off, a crucial barometer of aging status—a twenty-year-old naked mole rat was essentially the same as a four-year-old, young adult naked mole rat. This is decidedly not the case in humans, where patterns of gene expression and DNA methylation are increasingly considered to be like biological “clocks” for aging. And it meant that, in essence, the naked mole rats were not aging—or were doing so very slowly. Very, very slowly.

  More than any other mammal, even more so than forty-year-old bats or two-hundred-year-old bowhead whales, the naked mole rats had achieved what gerontologists called negligible senescence. That is, they hardly aged. Which must be nice.

  But what do the naked mole rats—and the Slovenian cave salamanders—really tell us about our own aging? The answer may well be “nothing,” because these animals are so singular. There’s no one factor that we could turn into a drug, no one gene that we could hope to mimic, at least that scientists have found so far. As with much else in aging, the answer is mind-bogglingly complicated (or, as the scientists say, “multifactorial”).

  But there are surprising ways in which we can boost our own stress resistance, and even our resistance to cancer. One is exercise, which we know about. Cold water swimming, well, maybe that, too. But the last one is, yes, hunger—but not the long, slow, grinding, Biosphere-plate-licking kind of hunger. (Been there, done that.) This kind of hunger goes well with a cheesesteak and a beer.

  Chapter 13

  FAST FORWARD

  The belly is an ungrateful wretch, it never remembers past favors, it always wants more tomorrow.

  —Aleksandr Solzhenitsyn, One Day in the Life of Ivan Denisovich

  Among those on hand, when the Biosphere was unsealed in September 1993, was a young graduate student from Italy named Valter Longo. Although he worked in Roy Walford’s lab, Longo had never actually met his boss in person, because when he had arrived at UCLA in 1992, the scientist was already inside “the Bubble,” maintaining contact with his lab by videoconference. As Longo watched Walford and his colleagues step through the portal and into the blinding Arizona sunshine, he was horrified.

  “When people come out of jail, they look okay,” he remembers. “These guys looked like hell. That was when I decided that maybe caloric restriction was not such a good idea.”

  Longo, who bears a passing resemblance to the actor Javier Bardem, had come to the United States intending to become a musician, not a scientist. His plan was to study jazz guitar at the University of North Texas, which has a world-famous music department. To pay for school, he joined the U.S. Army reserves, which seemed like a safe bet until Iraq invaded Kuwait in August of 1990. His tank unit was hours away from shipping out when Operation Desert Storm abruptly ended. Afterward, the school asked him to direct the marching band, a job he considered supremely uncool, so he changed majors to study aging instead, which is how he ended up with Walford at UCLA.

  Longo had started out working with yeast, and early on, he made a breakthrough discovery: One long weekend, he went out of town and neglected to feed his yeast colony. When he returned, he expected to find them all dead from starvation, which would have been no big deal, since they were only yeast. When he got back, he discovered to his surprise that they were not only still alive, but
thriving.

  “Just as a joke,” he says, he tried to do it again as a proper lab experiment: caloric restriction taken to its absurd extreme. He took a dish of yeast, which normally live in a kind of sugar syrup, and instead gave them only water. Again, the starved yeast lived longer. “A lot longer,” says Longo. (Yes, even yeast get old and die.)

  What started as a joke now piqued his interest: Why would this happen? And what did it say about diet and aging? Maybe the important thing about caloric restriction is not how many total calories a creature consumes in a day, he thought, but what happens to it when it is not eating.

  Everyone who has ever skipped a meal knows that we feel different, somehow, when we are fasting—sometimes worse, and sometimes better. In this case, religion has been way ahead of the scientists: Many world faiths incorporate some form of short-term fasting, from the Muslim month of Ramadan to Christ’s forty days in the desert. Scientists took longer to figure out that fasting may have health benefits as well as moral ones. In the 1940s, not long after Clive McCay starved his rats, a scientist named Frederick Hoelzel obtained similar life-extending results by simply feeding his lab animals every other day. But his 1946 paper on the subject received virtually no attention until decades later.

  There was another, even more fascinating study conducted in the 1950s in a Spanish nursing home. The staff doctors divided the patients into two groups of sixty, randomly. One group was fed the usual nursing-home fare, while the other was fed on an alternating schedule: One day, they would eat half the normal ration; the next, they would be fed about 50 percent more. Over the ensuing three years, the doctors found striking differences between the two groups. The normally fed patients had spent nearly twice as many days in the hospital as the on-again/off-again patients, and more than twice as many of them had died: thirteen deaths versus six.