Nutritional research publications can be maddening. Their sheer volume is overwhelming, but once the poorly done studies are filtered out, once you eliminate the ones that may have some statistical but no clinical significance, get rid of the ones that make grandiose claims about health effects based on food questionnaires administered on a single occasion, purge the ones that over-interpret results based on too few subjects, exclude those that imply long term effects based on short term trials, and disregard studies that unrealistically extrapolate animal data to people, you don’t have much left to chew on. But let’s nibble away at the studies that explore the current hot topic in “wellness,” which is “time-restricted eating.” The proposition is that when it comes to health status, it is not only what we eat that is important, but also when we eat.
While there certainly is controversy about details, there is a general consensus about the “what.” A diet should be based mostly on vegetables, fruits and whole grains, with minimal processed foods, especially ones high in sugar and salt. Fish is preferred over other flesh foods, and extra-virgin olive oil over refined seed oils. Saturated fats, such as in butter and in red meat should be limited, as well as foods charred by high heat. Alcohol no more often than a couple of times a week, and soft drinks as close to never as possible. With that out of the way, let’s get down to the “when.”
It was back in 1935 that Cornell University nutritionist Dr. Clive McCay discovered that mice fed a diet that reduced calorie intake by 30% were physically more active and far less prone to diseases of advanced age than their free-grazing laboratory mates. Furthermore, they lived about 40% longer! At the time, the interpretation was that the benefits were due to a reduced production of tissue-damaging “reactive oxygen species (ROS)” that are by-products of the reaction between glucose and oxygen, the reaction that produces the energy needed to fuel the life processes in cells. Chemically speaking, ROS are “free radicals,” electron-deficient species that are ready to steal electrons from any molecule they may encounter. Since electrons are the “glue” that bind atoms together in molecules, their loss results in bond breakage. Should the molecules affected be proteins or nucleic acids, the consequence can be disease or accelerated aging. But if there is less food to metabolize, goes the argument, fewer free radicals are produced with the result being enhanced longevity.
Since McCay’s original observation, numerous studies using fruit flies, mice, dogs, and monkeys have demonstrated that caloric restriction increases longevity. However, reduced free radical formation may not be the only factor involved. Not recognized in the early rodent experiments was the fact that the animals consumed their restricted food allotment within a few hours of it being provided, meaning that they had long periods of fasting.
In a normal state, cells “burn” glucose, provided by the diet, to produce the energy needed to sustain life. In a fasting state, with no glucose being provided, a back-up system is engaged. Cells, instead of “burning” glucose, switch to metabolizing stored fats. This involves the breakdown of fats to yield acetone, acetoacetate, and beta-hydroxybutyrate, the so-called “ketone bodies” that serve as an alternate fuel for energy production. But “ketosis,” as this fat-burning process is called, is also a signal to the body that there is no food coming in, a crisis situation. The “metabolic switch” to burning ketones instead of glucose then triggers a number of cellular responses aimed at survival. Cells begin to crank out various molecules that repair DNA, reduce inflammation, regulate glucose sensitivity and break down damaged cells (autophagy). All these processes can benefit health.
This brings up the question of whether the benefits of a calorie-restricted diet seen in animals may be a function not only of the reduced calorie content, but also of the time frame during which no food is consumed. Is there an optimal way, researchers wondered, to incorporate fasting into a dietary regimen? What if instead of just cutting down on calories, attention were paid to when the meals that make up that restricted calorie diet are eaten? Thus was born the concept of “time-restricted eating,” or its alternative designation, “intermittent fasting.”
Several regimens have been proposed. Eating a regular diet on 5 days and cutting calories down to 500-700 on two days a week (5:2 fast), doing the same on alternate days of the week (4:3 fast), or fasting for 14-16 hours a day (daily time-restricted eating) have all been tried. In the latter case, no restrictions are placed on calories during the 8-10 hours when food is consumed, but experiments have shown that this automatically results in a reduction of calories because night-time snacking is eliminated. While most of the trials involving these regimens have resulted in weight loss, the benefits such as improvement in glucose regulation, blood pressure, inflammation, and loss of abdominal fat, go beyond what would be expected for weight reduction. For example, in one study, women were assigned either to a 5:2 intermittent-fasting regimen, or a daily 25% reduced calorie diet. Over 6 months, both groups lost the same amount of weight, but the 5:2 group had improved insulin sensitivity and a larger reduction in waist circumference.
Other studies involving intermittent fasting have shown better running endurance, improvements in the HDL/LDL cholesterol ratio, reduction in free radical activity and reduced markers of systemic inflammation. Some preliminary studies have also shown suppressed tumour growth in a number of cancers. In animal models, alternate day fasting can delay the onset and progression of neurological diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis. There are even suggestions that intermittent fasting can improve memory and cognitive performance.
The evidence of benefits continues to accumulate. In a widely quoted study, one group of mice was given access to food only during a 9-hour period, while those in a control group were able to eat whenever they liked. The two groups actually ended up eating roughly the same amount of food, so at least in this case, whatever results were obtained could not be ascribed to a difference in caloric intake. After 7 weeks, tissue samples were taken from multiple organs and examined for any changes in gene expression. Genes code for the production of proteins, so basically the researchers measured whether the production of various proteins increased or decreased. Genes that code for proteins responsible for inflammation were found to be less active, while genes that produce proteins that repair damage to DNA and ones that inhibit cancer cell survival geared up. But, of course, mice are not men or women.
So, what about men or women? One interesting study examined changes in a number of proteins produced as a result of eating only during a 10-hour period and fasting for 14 hours. The subjects, 8 men and 6 women, were all observers of the Muslim religious month of Ramadan during which no food or drink is consumed between dawn and sunset. They were specifically selected because each one met at least three criteria of “metabolic syndrome,” defined as central obesity, insulin resistance, high blood pressure, high levels of triglycerides, and high cholesterol. These parameters are easily monitored and can provide information about the health effects of fasting in addition to changes in gene expression.
All of the markers of metabolic syndrome shifted in the right direction during the month of the 14-hour fast, as did proteins involved in destroying cancer cells, repairing DNA, and improving immune function. All very interesting, but the experimental group was small and the study period of a month was short. Also, the subjects all had metabolic syndrome, and calorie intake was not considered. Basically, not much can be inferred as far as the general population goes.
That though is not the case for a study that compared the effects of eating an early or late dinner on glucose levels, insulin production, triglyceride levels and fatty acid oxidation which is a measure of ketosis. Subjects ate their dinner either at 6 or 10 PM, and then had their blood chemistry monitored every hour through an intravenous line. The late dinner resulted in greater glucose intolerance and reduced fatty acid oxidation, both of which can promote obesity. Why should this happen? During sleep, metabolism normally winds down since the body needs less energy. Therefore, ingested glucose and fats are not burned for energy, but rather end up being stored as fat. If dinner is eaten earlier, metabolism remains active until sleep time and less fat ends up being stored. This study would seem to corroborate the benefits of the daily time-restricted fast since if no food is eaten after late afternoon, the reduced metabolism associated with sleep is less of an issue because most of the food will have been metabolized in the 5 or 6 hours between the last meal and sleep.
Now, just as I was ready to wrap things up with a final praise of intermittent fasting schemes, I learned of two recently published papers in respected journals. One found that in adults over the age of 40, a time interval of fewer than 4.5 hours between meals, which essentially means time-restricted eating, was associated with earlier death! Yikes! The second study asked participants to use an app to record the timing of their meals and then went on to relate this to their body weight as documented in their medical records over a ten-year period. Weight changes were not associated with the time between the first and last meals, which would seem to argue against trying to lose weight by time-restricted eating.
Where does all this leave us? As is the case with almost every aspect of nutrition there is controversy, and studies can be found to back up each side. Separating the wheat from the chaff is challenging and requires an extensive review of studies to try to get a handle on the preponderance of evidence. At this point, that evidence indicates caloric restriction to be a factor in reducing markers of disease and longevity, but to make recommendations, especially ones that are difficult to institute, we need more than markers. We need long-term human trials, with a significant number of subjects that compare regular diets, reduced calorie diets, and intermittent fasting with end points of disease or death. Such lengthy trials are difficult if not impossible to finance, organize and monitor. In their absence, we are reduced to making educated guesses.
Since none of the calorie-restricted regimens has shown any risk, there seems to be no harm in giving one or another a shot, whether it be for weight loss or just enhanced health and perhaps a longer life. But I suspect most people would not be able to endure calorie restriction over the long term. There is just too much pleasure to be had from eating. However, having an early dinner and then fasting until bedtime may be a challenge that can be met and may be worth a try. At least until the next study comes out telling us that life expectancy in Spain, where dinners are traditionally eaten late at night, is longer than in North America.
Obviously, the field of nutritional research is very fertile and there are many plants to harvest, but we do have to watch out for the weeds.
