Live, Fast, Die Old 

A growing body of evidence suggests that eating less, way less, could thwart disease and delay old age.

Page 4 of 6

If calorie restriction works by tripping "longevity" genes, it may be possible to develop a drug that mimics its effects without the harsh diet regimen. While it would be hard to sell the FDA on claims of human life extension, Lin says, a drug mimicking calorie restriction could have enormous potential as a treatment for diabetes or cancer. Kenyon, meanwhile, is cofounder of Elixir Pharmaceuticals, a company that aims to pinpoint the control mechanisms of aging and metabolism and develop drugs that affect the process. "We're not talking about genetic engineering here -- it's a pill, kind of like a vitamin that would make you live longer," Kenyon speculates. "That's not to say we know how to do that. We don't."

Since this wonder pill is still entirely theoretical, and most people would find a lifetime of fasting unpleasant, might there be an easier way to trick your body into extending life?

Perhaps. In 2003, Mattson had a brilliant revelation. As a matter of course, the test animals in most published calorie-restriction studies were fed every other day, presumably because it made life easier for graduate students. But what if that intermittent feeding pattern, not the severe diet, was triggering the results? Mattson promptly devised a study wherein rats had access to all they could eat on every other day, and nothing during the intervening days. The striking result: The rodents behaved much like their calorie-restricted counterparts in prior studies. Their glucose metabolism improved -- blood sugar and insulin levels dropped -- and so did their stress response. This, Mattson surmised, signaled diminished free-radical production and an enhanced ability to deal with stress, both keys to longevity and disease prevention. (Low blood sugar thwarts diabetes, while the ability of the heart, blood vessels, and brain to resist stress protects against heart disease and strokes.)

Hellerstein and Hsieh went on to show that intermittent feeding may have a similar effect in thwarting cancer. They fed mice on alternating days, with one group getting just short of the standard lab diet, while the other mice ate 33 percent less. Remarkably, the well-fed mice showed nearly the same slowdown in cell proliferation as the severely restricted group. The researchers concluded that the biological trigger had to be the intermittent fasting, not the overall food intake. "That was stunning to me," Hsieh says.

And yet it rings true, Hellerstein says. In the wild, nobody is guaranteed a daily meal. Carnivores in particular have a built-in schedule: hunt, pig out, sleep it off, fast, repeat. Humans are no different, Mattson agrees. "Our genetics are geared towards going for extended times without food," he says. "Our ancestors never had a refrigerator in their house -- they had to go out and find food, and depending on the season of the year they might have had trouble."

Instead of starving, Hellerstein and Hsieh say, perhaps a partial fast on alternating days will prove enough to trip the self-preservation response in humans. "We had been thinking about it as kind of a preserve-your-body-in-the-most-crude-way response: Don't die now," Hellerstein says. "Unknowingly, we stumbled upon the fact that you can exploit this starvation response for therapeutic benefit because it's so potent and so brilliantly conceived. We evolved to be so excellent at this that you can maybe even exploit it intermittently."

Reducing food intake every other day, of course, is a gentler proposition than full-blown calorie restriction, and it's something cancer or diabetes patients might be willing to try as a therapy if it's shown to limit human cell growth and insulin production. Indeed, several studies of alternate-day fasting are under way, and Hellerstein is proposing a collaborative project to measure cell proliferation rates in alternate-day fasters. The only research published to date, however, suggests that some refinement may yet be in order to make the diet more palatable. The authors noted that going without food on every other day is medically feasible in the short term, but participants reported being crabby and hungry all the time, and lost weight even if they didn't intend to. The researchers concluded that people might be happier if they could eat one small meal on their fasting days.

Some people are already trying the latter variation. Since he published his rat study in 2003, Mattson says he's gotten e-mails from around fifty people claiming to have tried it with positive results. One is Dr. Donald Laub, now retired from his post as chief of plastic and reconstructive surgery at Stanford University Medical Center. Laub has always been an adventurer -- he helped pioneer sex-change operations and later founded Interplast, which sends surgeon volunteers to operate on poor children with congenital deformities. Now 71, and having survived a battle with lymphoma, he has decided to devote what he calls his "second life" to healthier living. After reading Mattson's article, he made himself an independent guinea pig for the every-other-day diet.

Laub had previously tried straight calorie restriction, but quickly dropped it. "You get ornery," he says. For the past year, he has alternated days where he eats as much as he likes with 500-calorie days. As a physician, he's aware of both the benefits and drawbacks, and readily admits it's not easy. To overcome hunger, Laub says he relies on a variety of psychological tricks. For example, he keeps a package of instant shake mix nearby that he knows he can eat in an emergency -- when he feels a hunger pang, he tries to "postpone" it by ten minutes in the hope that it will pass. He deals with going to bed hungry by making lists of what he'll eat the next day. "I'll think, 'Tomorrow morning I'm going to eat sausage, cheese, fried eggs, and bacon,'" he says. "That helps me get over it. The next morning I wake up and I don't want to eat anything."

Nevertheless, he's convinced his diet is much more feasible than daily calorie restriction, and intends to do it for the rest of his life. Laub has dropped forty pounds and says he's gained a great deal of energy, particularly on fasting days. "After you go through five or ten down days, you relish them. On the down day you have much more energy, you have an obsessive-compulsive tendency to do obsessive-compulsive things like clean the desk drawers and get the files in order," he says. "You have actually more stamina and more energy. These characteristics are also in anorexic patients, I must admit."

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