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Harvey S. Hahn, MD, FACC, Cardiovascular Fellowship Training Program and Co-Director, KPN CV Quality, Kettering Medical Center; Associate Professor of Clinical Medicine, Wright State University/Boonshoft School of Medicine, Kettering, OH, and Loma Linda University, Loma Linda, CA
Joyce Yoo, MD, Centerville, OH
Mark P. Mattson, PhD, Adjunct Professor of Neuroscience, Johns Hopkins University School of Medicine, The Solomon H. Snyder Department of Neuroscience, Baltimore
Intermittent fasting is a nutritional concept that has been gaining scientific credibility. In addition to weight-loss purposes, other advantages include favorable body composition changes, improvement in lipid and glucose metabolism, and enhanced cellular survival. Unlike most diets, intermittent fasting is free, simple, requires no extensive food choice changes, and may be more sustainable long term.
Intermittent fasting, which once was strictly in the purview of religion and health fads, has undergone a rapid increase in scientific interest. Studies now demonstrate the positive impact that various methods of intermittent fasting can have on overall health. These changes in health are not limited to weight loss, which is probably the most common reason people become interested in fasting, but include increased cell survival, change in body composition (fat loss), improved cognition, and improved lipid and glucose metabolism. Intermittent fasting also is an easily deployable method that doctors can teach their patients to aid them in becoming healthier. Finally, intermittent fasting is one of the few health “techniques” that bridge the often-arbitrary divides placed between eating, sleeping, and exercising, all of which are critical components to overall health.
There has been a dramatic increase in the scientific interest in intermittent fasting over the past several years, culminating in a New England Journal of Medicine review article in December 2019.1 Initially, intermittent fasting typically was thought of only as a religious practice or as a new health fad, but recent scientific studies have demonstrated its impact on multiple health parameters. Furthermore, its attractiveness is its ease of implementation. Intermittent fasting is arguably the least “restrictive” of any weight loss plan, since it does not mandate the elimination of large groups of foods like the vegan or ketogenic programs. Thus, it may be easier to maintain long term. In a study of intermittent fasting vs. daily caloric restriction, intermittent fasting was well tolerated. Of 142 obese women who were screened for enrollment, only 12% could not tolerate the two-day trial period.2 At the end of the trial, at four months, only 2.7% of the intermittent fasting group withdrew as a result of problems adhering to the diet, while 7.5% of the daily caloric group withdrew.
Although weight loss is important because of the worldwide obesity epidemic, intermittent fasting offers more advantages than just strict weight loss.3 There are favorable body composition changes (i.e., fat loss).4 Similar to exercise, there is an increase in brain-derived neurotrophic factor (BDNF) secretion and cognitive improvement.5 (See Table 1 for abbreviations and definitions related to intermittent fasting.) Furthermore, lipid and glucose metabolism both are improved.6 Finally, the low-level periodic stress that intermittent fasting affords actually improves cellular stress resistance.4,5 (See Table 2.)
Intermittent fasting also interacts with and bridges three of the most commonly targeted areas of health: food, exercise, and sleep. This review will discuss how employing a strategy of intermittent fasting can enhance all three of these areas.
Intermittent fasting is a program of restricting calories based on time. Fasting does not mean a total lack of food; it can mean a reduction of food/calories taken in over a certain length of time. Also, water and coffee typically are not counted in most fasting programs. The terms “fasting” or “time-restricted feeding” can be used interchangeably, depending on the provider’s preference.
Part of the challenge of studying intermittent fasting is that there are almost unlimited ways to accomplish some degree of fasting. The most commonly studied approaches are:
As in any program, and in parallel to exercise, it probably would be prudent to slowly build up to the goals listed here. (See Table 3 for some examples of how to prescribe this program to your patients. Also see patient handout.) An example for alternate day fasting would be to fast one day per week for several weeks before adding a second day. For the 5:2 plan, calorie restriction could begin at 1,500 calories on fasting days for several weeks, then reduce to 1,000 calories, and finally to the target goal of 500-600 calories, depending on gender. Finally, for the time-restricted programs, an example would be to start off fasting for 12 hours per day for several weeks and then decrease the feeding time by two hours until reaching the goal of 16 hours of fasting every day.
There is a wealth of data showing that calorie restriction (CR) is a potent means to prolong life.1,4 This should come as no surprise, with the plateauing of American lifespan coinciding with the aforementioned increase in obesity.3,7 Reducing caloric intake is a mainstay of weight loss.
In the well-done, randomized CALORIE trial, a 12% reduction in caloric intake was associated with almost all the health benefits already listed for intermittent fasting.8 This calls into question whether CR alone is enough, or whether the periods of intermittent stress add further benefit.
Low-level stressors activate our cellular survival systems, priming them for when they are challenged again. Two examples help to explain this concept. One is the adage that “whatever doesn’t kill you will make you stronger.” If you can survive a stressor, you will know what to expect and be better prepared, mentally and physically, for it next time.
The other example is exercise. Exercise is a low-level stressor that allows us to tolerate and better withstand a similar stressor the next time we are challenged by it. The best-known examples of intermittent stress that have been studied are intermittent fasting, exercise, and cold exposure.
The intermittent nature of the stressor is important. If the stressor is not relieved, then untoward effects will ensue. If the fasting period continues unabated, then starvation will occur. If exercise is not followed by rest and recovery, overtraining syndrome or injury typically follows. Finally, if a person has prolonged cold exposure, this will lead to frostbite and tissue damage, which is the exact opposite of the therapeutic target sought. (See Table 4.)
Further supporting this concept are several studies that have demonstrated that other low-level chronic stressors are associated with impaired physiologic responses and increased adverse outcomes. These include, but are not limited to, unhappy marriages,9,10 work stress,11 and small particulate air pollution.12,13 The intermittent nature, in comparison to even low levels of chronic stress, appear to be important.
This pattern of low-level intermittent stress has been elegantly termed “metabolic switching.”4 Metabolic switching occurs when the body switches, or flips, from glucose metabolism to free fatty acid and ketone metabolism. In the case of CR, this usually does not occur, but typically happens with intermittent fasting. In comparison to simple CR, intermittent fasting (16:8), in an eight-week trial of healthy resistance-training males, led to a significantly lower respiratory ratio and decreased fat mass, while preserving lean muscle mass and muscle strength.14 In comparison, straight CR, without causing a metabolic switch, did result in weight loss and fat loss, but also lean muscle loss over time.15 That being said, CR is an essential and necessary part of intermittent fasting. Two well-done studies have demonstrated that isocaloric diets, even restricted by time, did not lead to favorable biometric or physiologic changes. While there was fat loss in both studies, blood pressure and low-density lipoprotein (LDL) cholesterol both rose in one study, and glucose tolerance worsened in another study testing a single large isocaloric meal.16,17
An excellent study of intermittent fasting was published in January 2020 by Wilkinson et al.6 The researchers studied a group of patients diagnosed with metabolic syndrome and who already were taking pharmacologic blood pressure and cholesterol treatments. The intervention was to allow feeding for only 10 hours per day (or to fast for 14 hours per day). The subjects could pick the times of the day to not eat, as long as it was continuous. In three months, the subjects lost weight (an average of 7.3 pounds) and fat; decreased waist circumference; lowered blood pressure, LDL cholesterol, and hemoglobin A1c levels; and slightly increased sleep duration. What is most impressive about this study is that subjects did not alter the quality of their diets — they were asked to keep eating the same things they typically ate. They also were not started on any new exercise program; the only difference was when they ate. This study is exciting, not only for the results, but for the ease with which those results were achieved. On average, the participants’ level of CR was only 8.6%. This was estimated by taking photographs of everything they ate and having the pictures analyzed by the research staff. This is important, since there have been significant criticisms of memory recall data used in dietary studies.18 In fact, an entire issue of the Annals of Internal Medicine was devoted to critically examining the data on meat intake and outcomes, concluding that published data were of low scientific quality and, thus, leading to the reversal of previous recommendations to reduce red and processed meat intake.19 Debating those findings and recommendations is outside the scope of this review.
The study by Wilkinson et al shows how easy intermittent fasting can be, but there is another way to make it even more accessible and successful for patients who are not getting enough sleep — increase sleep time.6 The easiest way to fast is to sleep. Even when we sleep, calories still are being consumed as a result of our resting metabolic rate. The more you sleep, the longer you are fasting, and the more calories that are being consumed. One-third of Americans do not get enough sleep, with an optimal sleep duration of between six and nine hours.20 Both less sleep than this amount and more sleep are associated with increased cardiovascular events and death.21 Every hour less than ideal amount of sleep was associated with a 20% increase in the risk of myocardial infarction (MI). Every hour of sleep more than the ideal range was even more harmful, with a 34% relative risk increase in MI. Even when compared to traditional risk factors, sleep duration continued to be an independent risk factor for cardiovascular events.22
There is a notion that staying awake longer is superior to sleep in caloric output and weight loss. Although this may be true regarding basal metabolic rate, behaviorally it most likely is incorrect. In a well-done study, participants were subjected to total sleep deprivation for one night.23 Their food intake was cataloged during that night and the next day. Also, they underwent functional magnetic resonance imaging (MRI). The researchers discovered several key findings. The sleep-deprived subjects consumed, on average, about 1,000 calories while they were sleep-deprived. They also had their reward centers activated on their functional MRI scans. Furthermore, the following day they consumed more calories than the control group, and typically sought out more fatty foods (thought to be related to the activation of the reward centers in their brains). Thus, overall there was more calorie intake and poor calorie quality associated with a lack of sleep. Although not directly measured in this study, beyond reward activation (“I deserve it”), there most likely would be reduced willpower and resistance to poor food choices with poor sleep. Another factor that was not measured was exercise the day after sleep deprivation. It stands to reason that many people would be too tired to engage in exercise after poor sleep, thus further affecting their health adversely.
A recent study followed the contestants from season eight of the television show “The Biggest Loser” after they left the ranch.24 The researchers discovered several interesting findings. The average weight loss at the end of the season was 58.3 kg. All of the contestants gained weight after leaving the show; the average gain was 41.0 kg. Only one contestant did not regain significant weight, and that most likely was the result of undergoing gastric bypass surgery. The measured resting metabolic rate decreased by 610 kcal per day by season’s end compared to before the competition started. At six years, the average decrease in resting metabolic rate had decreased further and was, on average, -704 kcal per day lower than at the start of the competition. One person had cut his caloric intake to 800 calories per day and still was gaining weight.
What was the explanation? At the ranch, the contestants had a professional chef cook them a healthy, 1,800-calorie-a-day diet. They had personal trainers help them exercise several hours every day. As they lost weight, they did not need as much energy, so their resting metabolic rate dropped significantly. Also, they had lost mostly fat but had not gained much muscle mass, which is metabolically more active than fat. Finally, they moved back home from the ranch and back to real life with jobs, stress, prepping their own meals, and exercising on their own.
Weight loss leads to the activation of mechanisms to maintain weight and protect against further loss — the well-known process of homeostasis. The body does not need to burn as many calories as before weight loss and further reduces metabolism to save more calories. The same process applies to exercise.
There are two main theories about caloric expenditure with exercise. One is that calories burned are in a linear relationship with exercise time and effort, called the “additive theory.” The other theory is known as the “constrained theory” of exercise energy expenditure.
In one study, researchers using radioactively tagged water to measure metabolism found that after a certain point, calorie burning started to plateau.25 Energy/calories burned does not happen in a linear relationship with exercise time. Similar to what the body does when it faces reduced caloric intake, the body tries to save calories during times of increased caloric expenditure — another example of homeostasis. So, what happens in exercise is that you actually do come face-to-face with the law of diminishing returns regarding weight loss.
Another way the body tries to achieve homeostasis is to release hunger hormones. Not only does the body slow down metabolism and energy expenditure in response to diet and exercise, it also produces hormones that signal the brain to eat. Even after one year of stable weight loss, there was a persistent elevation in the levels of hormones (i.e., ghrelin) that stimulate hunger.26 Subjective hunger, as measured by a survey, was expectedly elevated over one year after weight loss. Obviously, fighting against being hormonally and biochemically hungry and conservation of calories by the body’s homeostatic mechanisms are potential reasons for weight loss plateauing and eventual failure.
Intermittent fasting, in the short term, decreases production of leptin, an anti-hunger hormone that tells the brain that it does not need to eat.14 Interestingly, over time, intermittent fasting increases leptin in a similar fashion as intermittent cold exposure activates brown adipose tissue, both of which increase leptin levels.27 Furthermore, beta-blocker therapy blocks the intracellular signaling cascade that leads to leptin production, thus possibly representing another way these agents contribute to weight gain.28
Simple CR, and even prolonged bouts of exercise, typically are not strong enough stimuli to reduce weight and burn fat. That is why protocols that can “flip the metabolic switch,” such as intermittent fasting, have become increasingly attractive.
CR, intermittent fasting, and exercise often are initiated with a goal of weight loss. What target should be tracked most and is the most important: weight loss, fat loss, and/or lean muscle mass? Which, of any of these, should be the main target? As demonstrated by the “Biggest Loser” study, fat mass loss with little lean muscle mass gain was associated with significant reductions in basal metabolic rates and, thus, increasing difficulty in maintaining weight loss.24 Furthermore, simple CR not only leads to fat loss, but also to lean muscle mass loss.15 Intermittent fasting also resulted in loss of fat, but maintained muscle mass and muscular strength.14
But does body composition influence health beyond weight or body mass index? Studies have shown that muscle mass is more predictive of mortality than fat mass. Grouped by high or low muscle and high or low fat, there was almost a 20% reduction in mortality in the two groups with high muscle mass vs. those with low muscle mass, regardless of percent body fat.29 High muscle mass actually was protective against high fat mass.
Muscle mass and strength are important factors in health. Although the emphasis typically has been placed on cardiorespiratory fitness (CRF), muscle strength is more predictive of cardiovascular survival.30 A recent study stratified subjects by not only CRF status, but also by muscular strength determined by a pre-set group of resistance exercises. The groups in the highest tertile of muscular strength had ~ 50% lower event rates regardless of their CRF status. In fact, simple measures of strength, such as grip strength testing, have been shown to be predictive as well, even when applied to genetic risk.31 In this study, measured CRF and strength were highly associated with risk modification across all genetic groups, but self-reported levels of physical activity were less strongly associated with risk. Compared with the highest strength tertile to the lowest one, there was ~ 50% risk reduction across all three genetic risk groups. Although fat and weight loss are important, maintenance of lean muscle mass is at least equally important, if not more so.
Intermittent fasting is an easy, reliable, and sustainable way to achieve fat loss with minimal to no effect on muscle mass. Typically, ketosis begins within eight hours of fasting and continues to climb with further fasting, reaching significant levels before 24 hours of fasting.4,32,33 The more prolonged the fast, the greater the degree of ketosis. There have been multiple trials addressing the specific issue of intermittent fasting protocols and their differential effects on both fat loss and lean muscle mass. This was concisely reviewed and, overall, time-restricted fasting (TRF) and alternate day fasting (ADF) both result in fat loss, but TRF was more consistently associated with maintained lean muscle mass.4 ADF protocols were found to demonstrate mixed results, with some studies showing muscle mass loss and others showing none. This should not be taken as conclusive, since only four studies of TRF and 10 studies of ADF on human subjects have been published regarding their effect specifically on lean muscle mass.
Exercise and intermittent fasting initiate many of the same intracellular pathways. Could there be an additive or synergistic effect on fat metabolism?
A meta-analysis of 27 studies looking at aerobic exercise in a fasted or fed state demonstrated significantly favorable metabolic effects. The results demonstrated that exercising in a fasted state results in lower insulin production, decreased glucose levels, and increased fat oxidation compared to exercising in a fed state.34 Specifically, to subtypes of intermittent fasting, ADF was studied with endurance exercise. There were four groups: ADF, exercise, combined ADF with exercise, and the control group. Over a 12-week period, the combined group had greater weight loss, greater fat loss, greater reduction in waist circumference, and greater LDL cholesterol reduction.35
A similar effect was seen with resistance exercise. A group of National Collegiate Athletic Association female athletes exercised either in a fed or 10-hour fasted state and then had their metabolic parameters measured. The fasted group had a lower respiratory exchange ratio consistent with increased fat metabolism.36 Even a single bout of overnight fasting (eight to 12 hours) resulted in short-term changes in fat oxidation during the following exercise session.37
Intermittent fasting has been shown to enhance fat oxidation when combined with both endurance and resistance training. Although not directly related to intermittent fasting, it is worthwhile to briefly discuss the differential effects of various exercise programs on fat oxidation, independent of fasting.
The U.S. Department of Health and Human Services and the American Heart Association both advocate for 150-300 minutes of moderate or 75-150 minutes of vigorous physical activity each week, or a combination of the two.38 Running is one of the most popular types of exercise.39 It is associated with multiple health benefits and an excess longevity of three years compared to non-runners. Running commonly is the first type of exercise done for weight loss.40
Excess post-exercise oxygen consumption (EPOC) is the condition in which a prolonged period of increased caloric expenditure occurs after exercise is completed, typically supported by fat oxidation.41 Typically, this is intensity- and duration-driven. Compared to steady state running, several alterations in exercise programs can cause EPOC, many of which are timesaving as well.
The first potential alteration is an increase in intensity. A single vigorous, 45-minute cycling session not only burns an average of 519 kcal, but increases metabolism (EPOC) for 14 hours afterward.42 This results in an additional 190 kcal consumed. This may not seem significant, but it represents an additional 37% caloric expenditure for the same exercise session. Taken another way, this increases the effectiveness of the exercise time by 37%.
An even more efficient way to induce EPOC is high-intensity interval training (HIIT). HIIT consists of a warm-up period, and then alternating periods of hard and easy exercise (running, biking, cycling, rowing, etc.).
A recent, large meta-analysis demonstrated that HIIT reduced abdominal, visceral, and overall fat mass significantly, regardless of gender.43 The effects of HIIT can be seen within two weeks.44 Compared to baseline, seven days of HIIT over two weeks led to a 13% increase in VO2 max and increased whole body fax oxidation by 36%. Furthermore, a single session of HIIT can induce EPOC.45 In this study, five cycles of 30 seconds of vigorous cycling were separated by four minutes of recovery. This single protocol did not affect resting metabolic rate but did increase total daily energy expenditure significantly, by 10% (225 kcal). Moreover, EPOC lasted almost 24 hours, with the greatest period three to four hours post-exercise.
As mentioned previously, muscle mass and strength are important determinants of health.29-31 Resistance training is an obvious way to increase lean muscle mass and strength. What generally is not known is the ability of resistance training to induce EPOC and increase fat loss. A 31-minute, four-cycle resistance program of bench press, power cleans, and squats increased oxygen consumption and kept it elevated for more than 38 hours.46 A review of 16 studies examining EPOC post-resistance training found that circuit training may be the superior method to induce and increase EPOC.47
There has been tremendous interest in intermittent fasting not only for all the reasons discussed previously, but in particular for improved performance during endurance exercise, specifically marathon and ultramarathon distances. The notion of becoming “fat adapted” (the state in which the body burns fat, rather than carbohydrates, for fuel) also is a key reason for the popularity of the ketogenic diet in the ultramarathon community.
In a meta-analysis of 46 studies, researchers looked at both metabolism and exercise performance in a fasted state.48 Most studies showed favorable short-term effects in fat metabolism and some chronic adaptations as well, consistent with the aforementioned studies, but the data on performance were mixed.
More than half the studies showed some benefit of exercising in a fasted state, but the differences were not significant overall.
Conversely to the expected outcome, exercise performance in the fasting state was inferior for prolonged exercise sessions lasting more than 60 minutes. Of note, all the studies in this meta-analysis involved acute bouts of fasting before exercise, with the longest fasting period being 44 hours.
In another study, not included in the previously referenced meta-analysis, investigators looked at chronic adaption of fasting and its effect on exercise. This study involved consistent fasting over a six-week period. The researchers were able to demonstrate that subjects who consistently trained in a fasted state had improved performance, which may relate to the time it takes for metabolism to become fat adapted.49 The mechanisms thought to be related to this improved performance were increased fat oxidation (21% increase vs. 6% increase in the fed state compared to baseline) and prevention of glucose concentration reduction during exercise in the chronically fasting group.
A study of mice showed that intermittent fasting can enhance the ability of exercise to induce ketosis and increase the number of mitochondria in muscle cells seen by biopsy.50
Exercise is well described to affect cellular and molecular systems in the brain, causing structural changes, all leading to improvement in behavioral, emotional, and cognitive function.51 The critical messenger for these neurologic benefits is BDNF.52 Blockade of this pathway in animal models either eliminated or significantly blocked the effects of exercise on neurologic function.53,54
Intermittent metabolic switching, by either exercise or intermittent fasting, increases BDNF production.55 BDNF, regardless of how it is transcriptionally activated, is associated with energy homeostasis, cognition, mood, and neuroprotection. Many of the pathways involved in neuroplasticity and neurologic resistance to stress similarly are activated by either exercise or intermittent fasting.5 Unlike with what is known about the combined effects of intermittent fasting with exercise on fat oxidation, it is not clear if this combination has an additive or synergistic effect on neurologic function and health.
Intermittent fasting is relatively simple, sustainable, and typically can be added to other dietary programs. It is a simple way to get the benefit of calorie restriction and weight loss, but further manipulates metabolism in favorable ways. An obvious method to pair with intermittent fasting is increased sleep, which will shorten the awake fasting period.
Intermittent fasting also increases fat metabolism, and when paired with exercise, seems to create an additive or synergistic effect. (See Table 5.)
Finally, intermittent fasting helps to counteract the activated hormonal and biochemical milieu that occurs with dieting and weight loss, thus helping the program be more sustainable and successful.
Financial Disclosure: Gregory R. Wise, MD, FACP (Editor in Chief) reports he is involved with sales for CNS Vital Signs and Clean Sweep. Harvey S. Hahn, MD, FACC (Author), Joyce Yoo, MD (Author), Mark P. Mattson, PhD (Peer Reviewer), Jason Schneider (Editor), Shelly Morrow Mark (Executive Editor), Leslie Coplin (Editorial Group Manager), and Amy Johnson, MSN, RN, CPN (Accreditations Director) report no financial relationships with companies related to the field of study covered by this CME activity.