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  Yet these studies were basically ignored until a plastic surgeon from Mississippi named Jim Johnson stumbled upon them while searching around in an online database. Johnson had battled with his own weight for years, and he was looking for a diet technique that would help him lose it once and for all. “I’m a backsliding fat person,” he admits. He also happens to be fluent in Spanish, and when he read the old nursing-home study (which was published only in Spanish), he got excited and wondered if short-term fasting or alternate feeding might have more wide-ranging effects on human health. But there was still next to no recent “literature” on it.

  Johnson eventually found his way to an NIA scientist named Mark Mattson, who had been looking at the effect of fasting on mice. In 2007, he persuaded Mattson to collaborate with him on a small study in actual humans. Johnson recruited a dozen overweight and obese volunteers, all of whom had some degree of asthma, a complaint with its roots in inflammation. The volunteers ate normally every other day, but on the days in between they subsisted on a meal-replacement shake that provided only 20 percent of their usual calories.

  They lost weight, which wasn’t that surprising, but their asthma symptoms also cleared up, perhaps because the fasting had reduced the level of inflammation in their bodies. Clearly, fasting was doing something good for these patients, beyond simply reducing their body fat. Studies of Muslims during Ramadan have found a similar effect, and even Muslim athletes seem to perform better during the month of daytime fasting. Speaking of athletes, the pro football running back Herschel Walker was famous for not eating at all before game days—a complete flouting of the conventional wisdom. It didn’t seem to hold him back from winning the Heisman Trophy and playing in the NFL for fifteen years. Even into his late forties, Walker was competing as a mixed-martial-arts fighter, thrashing guys half his age. (He’s since retired from that, which was probably wise.)

  To the rest of us, the idea of going without food sounds torturous, something that only the religiously devoted might attempt. But Mattson points out that actually, our bodies are hardwired to survive without food. “If you look at evolutionary history, we didn’t used to have three meals a day, plus snacks,” Mattson points out. “Our ancestors, even pre-human ancestors, would have to go extended periods of time without food, so the individuals that survived were the ones that were able to cope with this situation.”

  Intrigued by these preliminary results, Mattson began pursuing it and found that not only do short periods without food improve physical health, in the same ways that caloric restriction does, but it also actually seems to be good for the brain. He found that mice (and later humans) that ate on an alternating schedule were found to have higher levels of brain-derived neurotrophic factor, or BDNF, which promotes the health and connectivity of neurons. Also produced when we exercise, BDNF helps preserve long-term memory and staves off degenerative conditions like Alzheimer’s and Parkinson’s.

  “When you’re hungry, your mind better be active and figuring out how to find food, how to compete and avoid hazards to get enough food to survive,” Mattson says. In other words, when we’re hungry we want to kill something. That’s evolution at work. Unfortunately, evolution did not endow us with strong willpower when it comes to food; in fact, quite the opposite. So not many people have the discipline required to cut their food intake by 25 percent, day after day. (Hell, most of us can’t even manage to floss regularly.) There’s a reason why Luigi Fontana’s caloric-restriction study had just a few dozen participants. Sure, they had great cholesterol numbers, but who would trade places with them?

  Fasting, on the other hand, has a finish line; there is relief on the horizon, in a day or two. Fasting for brief periods appears to provide many of the same benefits of caloric restriction, and is more achievable than a lifelong commitment to austerity. “Only 10 percent of people can do caloric restriction,” says Valter Longo. “With fasting, it’s maybe 40 percent.”

  One reason may be that, as Mattson and others have shown, intermittent fasting—or if you prefer, intermittent eating—has greater benefits than caloric restriction, and those benefits seem to be independent of how many calories you eat. In other words, you can eat just as much as you did before, you just can’t keep eating all the time. Sounds easy, right?

  The corollary to this is that there’s no one “right way” to do intermittent fasting. Other researchers have found weight-loss and other benefits from all kinds of eating schedules: from every-other-day fasting (which sounds rough), to twice-a-week fasting, to simple meal skipping; so many books on fasting have come out in the last few years that it’s safe to say intermittent fasting is trendy. But unlike many trendy diets, there’s solid science behind it.

  One researcher, Satchin Panda at the Scripps Research Institute in San Diego, put mice on an eight-hour limited feeding “window” and found that they did not gain any weight, even though they ate a high-fat diet. For humans, that translates into skipping breakfast each day; or better yet, dinner. Perish the thought. But I actually tried this one for a while, and once I got used to it (nice latte in the morning, then nothing until 1 p.m.), I kind of liked it; at least I could do it, and I did seem to lose weight and feel sharper in the morning.

  As one woman who has practiced intermittent fasting for weight loss for years advised me, “I learned to embrace a little bit of hunger.”

  Which is a useful thing to tell oneself, next time you’re stuck on a long plane flight with no decent food. Embrace the hunger. It’s good stress, after all. We’re evolutionarily hardwired for it. And as Longo eventually discovered, the benefits of hunger go all the way down to the cellular level.

  Back in his lab, Longo was trying to figure out why his starved yeast were living longer, and what that might mean for us. Digging down into the molecular biology of it all—long story short—he ended up unlocking a series of metabolic pathways that appear to regulate longevity. At the deep cellular level, metabolism and longevity are so closely intertwined they are basically inseparable.

  These metabolic pathways all radiate from an important cellular complex called TOR, which is perhaps best thought of as like the main circuit breaker in a large factory. When the breaker is switched on, the factory (that is, the cell) goes humming along, forging amino acids into the proteins that are the building blocks, messengers, and currency of life. It’s busy and messy, like Christmas season in Santa’s workshop. When the breaker is off, the cell goes into more of a maintenance mode, “recycling” old damaged proteins and, by cranking up autophagy, cleaning up the junk that accumulates in our cells over time—like January in Santa’s shop.

  In an influential paper published in Science in 2001, Longo found that blocking the TOR pathway caused his yeast to live three times longer. This led him to believe that many of the effects of caloric restriction come about because the lack of nutrients and shuts down TOR—an effect observed not only in yeast, but also in more complex critters like worms, flies, and mice. (Like the sirtuins, TOR is “conserved,” meaning it appears up and down the tree of life.)

  Turning down TOR also inhibits many of the growth pathways that appear to be connected with aging. With the TOR breaker switched off, protein manufacturing is shut down, and cells don’t divide as rapidly, so the animal does not grow. Instead, its cells become “cleaner” and healthier. They also resist stress better, and use fuel more efficiently—and thus are less susceptible to damage. It’s a classic example of beneficial stress response, or hormesis. And it makes sense evolutionarily: When food is scarce, there is no point in wasting energy on growth.

  But after his experience in Roy Walford’s lab, Longo wasn’t so interested in dietary restriction, which he considers to be “gradual, chronic suffering.” But just as chronic, long-term stress is bad, short-term and acute stress can be good. Temporary, limited fasting qualified as short-term stress—and if anything, it appeared to shut down TOR more completely than a partial cutback in calories. So its effects were more intense. “Fasting is much more
powerful than calorie restriction,” Longo says. “It’s like the strongest cocktail of medicine.”

  But medicine for what?

  That’s where the story gets really interesting.

  One day about ten years ago, Longo heard from a friend of his named Lizzia Raffaghello, who was a cancer researcher at Los Angeles Children’s Hospital. She had a young patient, a six- or seven-year-old Italian girl who suffered from a rare type of brain tumor called a neuroblastoma. She wondered whether Longo could help the girl somehow. He said he couldn’t—he studied aging, not cancer—and the little girl passed away soon after.

  Her death prompted Longo to do some soul searching about his choice of career. “Lizzia and I got into a lot of discussions about whether it was right to focus on extending the human lifespan when a seven-year-old can die of cancer and there is nothing we know how to do to help her,” he recalls. He was not an MD; he studied yeast. But he realized that his yeast might actually have yielded an insight about the nature of cancer.

  When he starved the yeast, they not only lived longer, but they became immensely resistant to stress of all kinds, like oxidative stress caused by free radicals, and exposure to toxins. Meanwhile, although tumor cells seemed invincible, he knew that they actually were not. The reason is that cancer cells must eat constantly, gorging themselves like André the Giant at a cruise-ship buffet. One way doctors locate tumors is by injecting them with glucose that carries a chemical tag. The tumors hog all the glucose, so they light up with the tag. Longo saw that this made them potentially vulnerable. Because the tumor cells were always eating, always growing, their TOR was turned up to eleven—which actually reduced their stress resistance. In the lab, he showed that subjecting cancer cells to added stress, by taking away their food, really did weaken them.

  He proposed a radical experiment to Raffaghello and her colleagues: Take mice with cancer, and starve some of them for as long as they could stand it, and then blitz them with huge doses of chemotherapy drugs, which are (obviously) highly toxic to all cells. “I still remember when I presented the idea to one of her MD collaborators in Italy,” he says. “He looked at me shaking his head, and thinking that was the dumbest idea he had ever heard.”

  But the results surprised everyone: In some of the experiments, all the pre-starved animals survived the chemo, while all the normally fed ones died. The short-term fasting appeared to have switched the animals’ normal cells into a protected state, while the tumor cells remained more vulnerable to the chemotherapy agents. This “differential stress resistance,” as they termed it, could make the drugs more effective by targeting them at the cancer cells themselves; the cancer cells would be unable to adapt, while the noncancerous cells were in a protected state because of the fasting. So they would suffer less collateral damage.

  Trying it out in human patients was not easy. Chronic calorie restriction had long been known to protect mammals against cancer—as it had done for the monkeys—but the severe weight loss it entails would seem to rule it out for use by actual cancer patients, who were already fighting to keep their weight. The oncologists were skeptical, and many were not willing to subject their already-suffering patients to yet more suffering. The patients weren’t thrilled at first, either. “Nobody wants to fast, especially people with cancer,” he says. “They’re like, What? You’re telling me not to eat? It just seems weird to people.”

  Doctors resisted it, too. But Longo and an MD in his lab named Fernando Safdie ultimately found ten late-stage cancer patients who were willing to give it a try on a voluntary basis. They fasted for between two and five days (!) in conjunction with a cycle of chemo, and surprisingly, all ten reported less severe side effects from the treatment after fasting. In some patients, the chemo also appeared to be more effective. It was only a tiny pilot study, but the results were intriguing enough that there are now five larger clinical trials going on, trying short-term fasting in conjunction with chemotherapy in about one hundred patients each, at USC, the Mayo Clinic and in Leiden, the Netherlands, and other locations. Early results have been promising.

  “The key mechanism, we think, is really what I call death by confusion,” Longo explains. “The idea is that normal cells have evolved to understand all kinds of environments, and cancer cells have de-evolved in some sense: They’re very good at doing a few things but are just generally bad at adapting to different environments, especially if they’re extreme.”

  Cancer cells are dumb, then; and when we fast, our healthy cells get smarter, or at least more adaptable to stress. And we wouldn’t know any of it, if tourists had not discovered Easter Island.

  A remote outpost in the Pacific, two thousand miles west of Chile, Easter Island is of course famous for its huge, mysterious statues of giant heads. In the 1960s, as the Chilean government was preparing to expand the airport in order to bring in more tourists, a Canadian expedition visited the island to take soil and plant samples before the isolated ecosystem was disturbed by outsiders.

  In one of the samples, the scientists found a unique bacterium called Streptomyces hygroscopicus, which sounds like something you might catch from a bus-station drinking fountain but is in fact fairly benign—to humans, at least. In the dark subworld of the soil, however, a chemical war is being waged between bacteria on one side, and fungi on the other. Penicillin, for example, is produced by mold to kill bacteria—hence its antibiotic properties. Bacteria fight back with their own poisons. The Canadian scientists, from the Ayerst drug company in Montreal, found that Streptomyces hygroscopicus secretes an especially intriguing fungus-fighting compound that they named rapamycin, after Easter Island’s native name, Rapa Nui.

  The Ayerst team initially saw rapamycin as a potential antifungal drug (think Dr. Scholl’s athlete’s foot spray), but in the process they discovered that it had even more powerful effects on the human immune system, damping down the body’s response to invaders. Not only that, but there were signs that it could do other things as well. But Ayerst was not interested, and the company soon shut down its Montreal lab and fired most of the staff. The scientist who had discovered rapamycin, Suren Sehgal, moved to Princeton, and he took his precious soil fungus with him; long story short, rapamycin was eventually approved by the FDA in 1999 as a drug to help prevent transplant patients from rejecting their new organs.

  Which made it a useful but somewhat obscure drug. But rapamycin’s impact ultimately went way beyond transplant patients, and led to a completely new understanding of cell biology. Researchers investigating its mechanism of action eventually discovered TOR, the key growth regulator of the cell—TOR actually stands for “target of rapamycin.”

  In other words, this strange chemical, produced by a microscopic organism that lives in the dirt on an island two thousand miles from land, just happens to unlock the master growth switch for nearly all forms of life on this planet. No big deal.

  But that was only the beginning. In a major study published in 2009—the very same day the calorically restricted monkeys made the front page of the New York Times, in fact—a team of NIH-funded researchers found that rapamycin had significantly extended the lifespan of mice. This was huge news, maybe even bigger than the monkey study: No other drug had ever extended maximum lifespan in normal animals before—how long the oldest animals lived. (Resveratrol had only worked on fat mice.) And it confirmed what Longo’s lab had observed a decade earlier, that shutting down TOR also seemed to slow down aging.

  Not only that, but rapamycin had worked even though the mice were already middle-aged when they took it. The study had started late, because the team’s pharmacologist had spent months trying to get the drug into mouse feed in a chemically stable way. By the time he figured it out, the animals were already nearly twenty months old, the mouse equivalent of about sixty human years—too old, according to conventional wisdom, for an anti-aging drug to have any effect. Yet still the stuff had increased both the average and maximum overall lifespan of the animals by 9 percent for males, and 14 percent
for females. Which may not sound like a lot, but given the late start it was the equivalent of giving sixty-five-year-old humans an extra six to eight years of life, or a 52 percent boost in remaining life expectancy.

  Steven Austad was one of the study authors, and he noticed that not only had the mice lived longer, but their tendons were more elastic—just like the long-lived, slowly aging possums he had studied decades ago on Sapelo Island. That was a pretty good sign that rapamycin was actually slowing aging in the mice—everywhere but in their testicles, which suffered from a mysterious degeneration.

  So much for that wonder drug, you’re probably thinking, but researchers seized on rapamycin, and before long, more positive evidence rolled in. Rapamycin appeared to reduce the incidence of cancer and, more interestingly, it seemed to slow the formation of senescent cells. Even more dramatic was the 2013 finding, by Simon Melov and other scientists at the Buck Institute, that rapamycin actually reversed cardiac aging in elderly mice. After three months of rapamycin treatment, their hearts and blood vessels were actually in better shape than when the study started. “Their heart function had improved over baseline, so it had actually gone backward, which was very, very impressive,” says Melov.

  The researchers also found that rapamycin reduced the level of inflammation in the mouse hearts—and that it was perhaps working on aging at a deeper level. “One of the big mysteries of aging is why do we get this pro-inflammatory response with age? Nobody really knows,” says Melov. “We found that the heart is chronically inflamed in old animals, which as far as I know is novel. And rapamycin, lo and behold, reduced that inflammation.”

  It even improved the strength of the animals’ bones. There seemed to be just about nothing that rapamycin couldn’t fix. Here was a drug that appeared to delay many of the effects of aging—even when taken in middle age or later. And it was already approved by the FDA. Why not try it? Yet while several researchers I met admitted taking resveratrol, most notably David Sinclair, nobody copped to using rapamycin—with one exception.