Intermittent Fasting: The Risks and Rewards

Laird Harrison


September 25, 2018

Slim down. Cure your cancer. Reverse your multiple sclerosis. Prevent heart attacks. Live longer. Reports that intermittent fasting could help with the biggest health concerns facing people in developed countries have inspired millions to take it up.

In one survey, 10% of Americans aged 16-34 said they fast intermittently, making it the most popular style of diet for that age group.[1]

"It has, to a certain extent, become one of the fad diets of the time right now," says Benjamin Horne, PhD, MPH, director of cardiovascular and genetic epidemiology at Intermountain Healthcare in Salt Lake City, Utah, who is researching the health effects.

As with so many health fads, though, the evidence for intermittent fasting—in which participants drastically restrict energy intake for some part of a day, a week, or a month—lags behind the enthusiasm of the participants. Careful clinical trials have so far shown that intermittent fasting can help people lose weight, but not necessarily better than more conventional diets.

More dramatic findings—including effects on cancer and cardiovascular and neurologic health—come mostly from studies in animals, with only a few tantalizing results in humans so far reported.

And although careful fasting regimens appear to be safe for most people, there may be some risks. "A lot of people are going to get hurt," predicts Valter Longo, PhD, director of the Longevity Institute at the University of Southern California.

The Data on Calorie Restriction

The notion that some form of fasting might have health benefits is nothing new, but it has gained currency in recent decades because of research showing that calorie restriction can dramatically extend the lifespans of many life forms. If you put baker's yeast in plain water, for example, it will live several times longer than if you put in on a gel with sugar.

Experiments with calorie restriction have lengthened the lives of bacteria, worms, mice, rats, and monkeys.[2] Research suggests that fasting activates genes responsible for protecting DNA from oxidation, and reducing production of toxic molecules.[2]

Studies in humans are more difficult, but a 2-year trial suggested that reducing calorie consumption by 12% might improve lifespan and overall health because it improved such biomarkers as body mass index, lipid profile, glucose tolerance, insulin action, and inflammation that are indicative of reduced risk for chronic disease.[3]

However, the trial also illustrated the difficulty of simple calorie restriction. Participants failed to achieve the 25% calorie reduction that the investigators set as their goal. And even that 25% is short of the 30%-50% that has achieved the most dramatic effects in animals.[4]

More severe calorie restriction may cause health problems as well, such as reduced lean body mass and bone mineral density,[4] and an increased risk for anemia and gallstones.[5]

In addition, Longo warns, there is the possibility that metabolism will slow down in people who restrict their calories for a long period. "It may take years to recover that metabolism," he says. If they then revert to their previous diets, calorie restrictors could put on more weight than they lost. And staying on a diet that reduces calorie intake by as much as 40% is challenging for anyone.

Consequently, researchers, including Longo and Horne, have been looking for ways to reap the benefits of calorie restriction without the problems. That led them to intermittent fasting. "People were tinkering around with regimens of calorie restriction and found that in animals, there was more benefit if it's done over a longer time, but only periodically," Horne says. Also, "with calorie restriction, you have this constant gnawing hunger. With intermittent fasting, you don't have that. So potentially it's more tolerable."

Researchers are experimenting with a range of protocols. Longo is looking at severe calorie restriction 5 days per month. Horne is studying a water-only fast day per week. Krista Varady, PhD, an associate professor of nutrition at the University of Illinois in Chicago, has done a trial of a regimen of alternating fast days and feast days.

Others still have advocated a restriction by hours of each day: for example, 8 hours of eating and 16 hours of fasting. Despite concerns that participants would gorge themselves on feast days, the studies generally show participants losing weight on intermittent fasting, and many show improvements in biomarkers for disease risks.

In one of the more careful randomized controlled trials, Wei and colleagues[6] randomly divided 100 people into two groups. Forty-eight consumed a "fasting-mimicking diet" that was low in calories, sugars and protein but high in unsaturated fats for 5 days a month. The diet provided about 1100 kcal for day 1 and 700 kcal for days 2-5. The dieters ate whatever they wanted for the rest of the month. The other 52 participants ate whatever they wanted throughout the month as a control group.

Although there were no adverse events more serious than weakness, fatigue, and headache, after 3 months, 13 people withdrew from the fasting-mimicking group, compared with five from the control group. The fasting mimickers lost an average of 2.6 kg (in a combination of lean and fat body mass), whereas the people in the control group maintained their weights. The fasting mimickers also had a decrease in insulin-like growth factor 1 concentrations (a marker of cancer risk) and systolic and diastolic blood pressure. But fasting glucose, triglycerides, low-density lipoprotein cholesterol, and C-reactive protein (a marker of inflammation) did not differ between the groups.[6]

After 3 months, the control group joined the other participants on the intermittent diet, and a total of 71 participants completed three month-long cycles of the regimen. Those whose biomarkers put them at highest risk for cardiovascular disease or metabolic syndrome achieved the most significant improvements in these biomarkers.[6]

Such findings have pointed to a way that physicians can now prescribe intermittent fasting, says Longo. "We can recommend it for predisease conditions," he said. "It's fair for doctors to say, 'Let's do a couple of cycles. Let's see how you respond. If you don't respond well, we'll think about drugs.'"

Treating Disease Through Diet

Longo has equity interest in L-Nutra, a Los Angeles company marketing the diet as ProLon, but says he donates the income to charity. He is working on research to explore whether the diet could be used to treat active diseases. For example, some studies suggest that healthy cells become more resistant to chemotherapy during intermittent fasting, whereas cancer cells do not.

In a pilot study, he and his colleagues got promising results in a study of 60 patients with relapsing-remitting multiple sclerosis. They assigned 20 each to a 6-month ketogenic diet; a combined 7 days of fasting-mimicking diet and 6-month Mediterranean diet; and a control diet.[7]

Both the ketogenic and the fasting/Mediterranean groups reported improvements on health-related quality-of-life scales. The finding supported the results in mice with experimental autoimmune encephalomyelitis; fasting mimicking suppressed their autoimmunity and caused remyelination.[8] Experiments are under way in Alzheimer disease as well.[9]

On the other hand, some people with advanced chronic diseases may not be able to tolerate fasting, Horne says. People with diabetes may get benefits, but fasting is contraindicated with certain diabetes medications, he warns.

And researchers are far from figuring out whether one intermittent fasting regimen works better than another, or even showing that fasting-mimicking works better than calorie restriction. In what they believe to be the only trial that pitted intermittent fasting against conventional calorie restriction, Varady and her colleagues recruited 100 obese, metabolically healthy adults (86 women and 14 men).[10]

They randomly assigned 34 participants to alternate-day fasting (25% of energy needs on fast days, 125% of energy needs on alternating feast days). They assigned another 35 to conventional calorie restriction (75% of their energy needs every day). The remaining 31 were instructed to maintain their weight and not to change their eating or physical activity habits.[9]

Contrary to the researchers' expectations, more people (38%) dropped out of the study from the alternate-day fasting group than from the daily calorie restriction group (29%). The intermittent fasters also snuck food that was not provided as part of the study, suggesting that eating just 25% of energy needs every other day was too difficult for many of them.[9]

On average, the daily calorie restriction and the alternate-day groups lost the same amount of weight at month 6 (which was followed by a weight-maintenance phase): 6.8% of body weight. Changes in blood pressure, heart rate, triglyceride, fasting glucose, fasting insulin, insulin resistance, C-reactive protein, and homocysteine concentrations at months 6 and 12 were not significantly different between either intervention groups or compared with the control group. The results might have been different if more of the participants had unhealthy levels of these biomarkers at baseline, the researchers noted.[9]

Varady has since pursued research aimed at figuring out whether some categories of people might benefit more from intermittent fasting than others. Traditional calorie restriction might work well for people who are good at counting calories, she says. But "a lot of people get burned out recording their food every day with an app or calorie counter," she says. "Intermittent fasting allows them to eat throughout the day."

Some of the interest in intermittent fasting has come from people who are essentially healthy but hope to prolong their lives. People should avoid intermittent fasting if they are pregnant, lactating, very old, very young, or frail, or if they have solid organ transplants or are otherwise immune-compromised, says Horne.

As for people who are healthy, the evidence for an extreme regimen isn't there yet, Longo says. Instead, for this population, he recommends restricting eating to 12 hours a day. This moderate regimen is not demanding, and because most people keep eating over the course of 15 hours a day, this could be a relatively easy way for them to avoid the overeating so common in developed countries, he says. And it could put them more in synch with circadian rhythms, which some studies have suggested could be beneficial.[2]

"A 12-hour period seems to be keeping up with our [evolutionary] history," he says. "We probably only ate when it was light out for many reasons." On the other hand, confining calorie intake to a shorter period—such as only 8 hours a day—could lead people to skip breakfast, which may be harmful, he says.

Varady demurs, pointing out that the evidence on breakfast is mixed. And some studies of 8-hour time-restricted feeding show benefits for people wanting to lose weight.[10]

"People just need to try out different ones and see what they can stick to," says Varady. "At one point, I felt like we were trying to find the best diet out there," she says. "But now we're realizing that there is no best diet."


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