Mattson thinks that intermittent fasting acts in part as a form of mild stress that continually revs up cellular defenses against molecular damage. For instance, occasional fasting increases the levels of “chaperone proteins,” which prevent the incorrect assembly of other molecules in the cell. Additionally, fasting mice have higher levels of brain-derived neurotrophic factor (BDNF), a protein that prevents stressed neurons from dying. Low levels of BDNF have been linked to everything from depression to Alzheimer's, although it is still unclear whether these findings reflect cause and effect. Fasting also ramps up autophagy, a kind of garbage-disposal system in cells that gets rid of damaged molecules, including ones that have been previously tied to Alzheimer's, Parkinson's and other neurological diseases.
One of intermittent fasting's main effects seems to be increasing the body's responsiveness to insulin, the hormone that regulates blood sugar. Decreased sensitivity to insulin often accompanies obesity and has been linked to diabetes and heart failure; long-lived animals and people tend to have unusually low insulin, presumably because their cells are more sensitive to the hormone and therefore need less of it. A recent study at the Salk Institute for Biological Studies in La Jolla, Calif., showed that mice that feasted on fatty foods for eight hours a day and subsequently fasted for the rest of each day did not become obese or show dangerously high insulin levels.
The idea that periodic fasting may offer some of the same health benefits as continuous calorie restriction—and allows for some feasting while slimming down—has convinced an increasing number of people to try it, says Steve Mount, a University of Maryland genetics professor who has moderated a Yahoo discussion group on intermittent fasting for more than seven years. Intermittent fasting “isn't a panacea—it's always hard to lose weight,” adds Mount, who has fasted three days a week since 2004. “But the theory [that it activates the same signaling pathways in cells as calorie restriction] makes sense.”
On Thin Ground
Despite the growing enthusiasm for intermittent fasting, researchers have conducted few robust clinical trials, and its long-term effects in people remain uncertain. Still, a 1956 Spanish study sheds some light, says Louisiana-based physician James B. Johnson, who co-authored a 2006 analysis of the study's results. In the Spanish study, 60 elderly men and women fasted and feasted on alternate days for three years. The 60 participants spent 123 days in the infirmary, and six died. Meanwhile 60 nonfasting seniors racked up 219 infirmary days, and 13 died.
In 2007 Johnson, Mattson and their colleagues published a clinical study showing a rapid, significant alleviation of asthma symptoms and various signs of inflammation in nine overweight asthmatics who near-fasted every other day for two months.
Detracting from these promising results, however, the literature on intermittent fasting also includes several red flags. A 2011 Brazilian study in rats suggests that long-term intermittent fasting increases blood glucose and tissue levels of oxidizing compounds that could damage cells. Moreover, in a 2010 study co-authored by Mattson, periodically fasting rats mysteriously developed stiff heart tissue, which in turn impeded the organ's ability to pump blood.
And some weight-loss experts are skeptical about fasting, citing its hunger pangs and the possible dangers of compensatory gorging. Indeed, the most recent primate study on calorie restriction—the one that failed to extend life span—underscores the need for caution when radically altering the way people eat.
Still, from an evolutionary perspective, three meals a day is a strange modern invention. Volatility in our ancient ancestors' food supplies most likely brought on frequent fasting—not to mention malnutrition and starvation. Yet Mattson believes that such evolutionary pressures selected for genes that strengthened brain areas involved in learning and memory, which increased the odds of finding food and surviving. If he is right, intermittent fasting may be both a smart and smartening way to live.