Intermittent Fasting Benefits: Exploring Emerging Research and Clinical Applications

by Sara Gottfried, MD and Kari Hamrick, PhD, RD

Did you grow up with parents who told you that breakfast is the most important meal of the day?  The word “breakfast” comes from breaking the overnight fasting period, and replenishing the body with a supply of glucose and other nutrients. It implies a period of metabolic rest that we know from ancestral health is beneficial, but in recent time, that period has shortened. While physicians and dietitians have touted the advantages of eating in the morning– including lower BMI, better memory and attention through the day, along with improved cardiovascular benefits¹—now, a growing body of research demonstrates that the hermetic stress of fasting triggers a cascade of adaptive responses that may prove that intermittent fasting benefits health and slows the aging process.  Intermittent fasting is a method of dieting that restricts the amount of time you are allowed to eat.  The intermittent fasting benefits appeal to many dieters since there is no need to count calories or eat certain foods.  This increasingly popular dietary approach² is the subject of many self-help books that claim that intermittent fasting benefits weight loss, reduces ill health, and promotes longevity, with even Silicone Valley getting in on the craze with biohackers self-experimenting with different types of fasting and recording their results on social media.

The attraction of intermittent fasting above standard calorie restriction approaches is the assertion that intermittent fasting can exert beneficial health effects when weight and total energy intake are maintained. These beneficial effects are claimed for normal-weight as well as overweight individuals. Although most of these claims are deduced from pre-clinical studies in animals,³ the practice of intermittent fasting for therapeutic purposes is increasing, and health care practitioners are likely to encounter questions regarding its safety and efficacy.⁴ The question we aim to address in this article is whether intermittent fasting is a passing fad that only focuses on short term weight loss and health benefits, or if there are sustainable beneficial effects on metabolic and disease markers that make it a viable tool for promoting widespread public health.

A brief history

An appreciation of the history of fasting is helpful to the understanding of evolution of therapeutic dietary interventions and the effect of food deprivation in various diseases.  In every written source of all cultures, religions and geography there is mention of fasting.⁵  Fasting has been used for health and spirituality and is one of the most ancient and widespread healing traditions in the world.⁶ Hippocrates, the father of modern medicine, prescribed and championed the practice of fasting. He wrote, “To eat when you are sick, is to feed your illness”.⁶ The ancient Greek writer and historian Plutarch (cAD46 – c AD 120) also echoed these sentiments. He wrote, “Instead of using medicine, better fast today”. Ancient Greek thinkers Plato and his student Aristotle were also staunch supporters of fasting.⁶

Fasting has played a key role in all the world’s major religions.⁷  Judaism has several annual fast days including Yom Kippur, the Day of Atonements; in Islam, Muslims fast during the holy month of Ramadan, while Roman Catholics and Eastern orthodox observe a 40 day fast during Lent, the period when Christ fasted 40 days in the desert.⁶

For the treatment of disease, the ancient Greeks noticed that periods of fasting would cause seizures in epileptics to become less frequent and less severe.⁸ The first modern use of fasting as a treatment for epilepsy was recorded by Gulep and Marie in 1911,⁹ during which they observed less severe seizures in 20 children and adults with epilepsy during fasting therapy. Fasting became standard treatment for epilepsy until anticonvulsant drugs appeared in the 1950s. In the mid-1800’s, B. H. Dewey, MD, in his book The True Science of Living, wrote, “every disease that afflicts mankind [develops from] more or less habitual eating in excess of the supply of gastric juices.”¹⁰ Upton Sinclair, better known for other literary works, wrote extensively on the health benefits of fasting.¹¹

What’s new in fasting literature?

Intermittent fasting is nothing new, but what is new is that clinical research on the benefits of intermittent fasting for health and longevity is beginning to tell an interesting story.  Hormesis has been defined as an adaptive response of cells and/or organisms to a moderate, usually intermittent stress, and the agents which bring about the process of hormesis are called hormetins.¹² An intermittent energy deficit via dietary restriction can be considered a hermetic stimulus and may lead to improved health outcomes.

Some of the benefits of intermittent fasting in animals and humans include:

• Reduced insulin resistance and improved glucose homeostasis^13-16
• Reduced blood lipids (including triglycerides and LDL)^17-19
• Reduced blood pressure^16,17,20
• Reduced markers of inflammation (including CRP, IL-6, TNF, DBNF)²¹
• Reduced oxidative stress (including markers of protein, lipid and DNA damage)^22,23
• Reduced risk of cancer²⁴
• Increased cellular turnover and repair²⁵
• Increased fat burning^26,27
• Increased growth hormone release²⁸
• Increased metabolic rate²⁹
• Improved memory and cognitive function^30-32

Although the list of benefits appear compelling, and there is a heightened scientific and lay interest in fasting, it is important to consider the limitations of the scientific evidence for the health benefits of intermittent fasting in humans. Animal models have been used for a great deal of the research, and the human research is often based on observational data on religious fasting (particularly Ramadan), derived from experimental studies with modest sample sizes, or compares intermittent fasting with a “normal” diet, which is typically not balanced and calorically equivalent.  Therefore, determining the benefits of intermittent fasting versus eating fewer and healthier calories can be challenging.

The most studied intermittent fasting approaches are alternate days of energy restriction, with either a total fast or 25% of estimated requirements on alternate days, two non-consecutive days of energy restriction per week (5:2 approach), or time restricted feeding (TRF) in which individuals fast for 16,18 or 20 hours per day. All of these models have been called “intermittent fasting” in the literature, which can confound the results. Differentiating a true intermittent fast from other intermittent energy restriction (IER) regimens, which allow some food on restricted days, is important since complete non-caloric intermittent fasting may create greater metabolic fluctuations and stress in individuals and may be associated with binge eating during non-restricted days.³³  Therefore, in this article we will use the term IER to cover all of these approaches.

Choosing a fasting protocol

Considering all the benefits, it is easy to understand why so many people are interested in giving fasting a try.  But what IER protocol is best?  Unfortunately, head-to-head studies of different IER and continuous energy restriction protocols are lacking.  However, it is possible to differentiate between protocols based on emerging clinical applications as well as individual practical lifestyle aspects.

Alternate day fasting (ADF)

The first-line therapy prescribed to obese patients for weight loss is daily calorie restriction (CR).¹ However, many patients find it difficult to adhere to a conventional weight-loss diet because food intake must be limited every day.²  Studies have observed that adherence to daily CR decreases after 1 month and continues to decline thereafter.^3–5 In light of this limitation, another approach called alternate day fasting (ADF) was developed that requires individuals to restrict calories only every other day.⁶   This strategy is perhaps the most restrictive of the IER protocols and is a true intermittent fast.  The plan alternates fast days (no caloric intake, unlimited non-calorie beverages) with feast days allowing habitual dietary intake.¹²

Animal studies of ADF find lower diabetes incidence and lower fasting glucose and insulin concentrations, effects that are comparable to those of daily caloric restriction (CR).³⁴ In terms of cardiovascular disease risk, animal ADF data show lower total cholesterol and triacylglycerol concentrations, blood pressure, heart rate, along with improved cardiac response to myocardial infarction.³⁴ There is no human evidence to date relating fasting to cancer risk; however, animal studies found decreases in lymphoma incidence, longer survival after tumor inoculation, and lower rates of proliferation of several cell types.³⁴ The findings in animals suggest that ADF may effectively prevent chronic disease development by tempering several clinical risk factors to an extent similar to that of CR.³⁴

ADF intervention studies in humans are limited by small sample sizes and short durations, although the data suggest some positive impacts on metabolic markers and modest weight loss.³⁵  ADF was not well tolerated with participants expressing dissatisfaction with no calorie consumption on fast days and feeling uncomfortably hungry and irritable.²⁷

Modified ADF

To improve compliance to ADF, a modified ADF was developed which involves fast days where individuals consume 25% of their usual intake (approximately 500 kcal for women and 600 kcal for men), alternated with a feast days where individuals are permitted to consume food ad libitum. Findings from a phased human study among 16 obese participants resulted in a 5.6 +/- 1.0 kg weight loss, as well as improvements in lipid profiles and systolic blood pressure, after 8 weeks of controlled and self-selected modified ADF.³⁶

The first long-term randomized clinical trial (RCT) comparing modified ADF, CR, and no-intervention control was conducted in 2017.  Researchers found that mean weight loss, fat mass, lean mass and visceral fat mass were not significantly different at 6 or 12 months between ADF and CR.³⁷ There was significant patient dropout across the study. In the alternate day fasting group, 38% of those enrolled dropped out, and around one-third of those were due to dissatisfaction with the diet. In the restricted calorie and control groups, 29% and 26% of participants dropped out respectively.³⁷ Interestingly, the study investigators found that over time people in the fasting group ate more than prescribed on fasting days and less on feasting days. In contrast, those prescribed caloric restriction achieved closer adherence to their prescribed calories. So basically by the end of the study the modified ADF group were eating similarly to the CR group.³⁷

Systematic reviews comparing ADF to daily CR have concluded that both are equivalent in terms of short-term and long-term weight loss; however, it has been noted that interpretation of the ADF literature has been limited by small sample sizes.³⁸

5:2 protocol

This pattern of eating is the basis for the bestselling book by Mosley and Spencer called The Fast Diet.³⁹  The 5:2 plan involves eating normally for five days of the week and cutting calories to about 25% of normal intake on two nonconsecutive days of the week.  Fast day calories should be spent on high protein foods and fruits and vegetables with low glycemic loads.  On the five days with no fasting, there is no calorie cap and no food is off-limits.

The benefits of the 5:2 plan is that there are very few rules to keep track of and you are only dieting two days per week.  It can be helpful for individuals that are struggling with a consistent caloric restriction for weight loss and need support with restrained eating. The variable schedule allows individuals to restrict calories on certain days, which is conducive for maintaining social gatherings associated with food. As with all fasting protocols, this is not an appropriate diet for pregnant or underweight individuals, elderly, kids/teens or if there is a history of eating disorders.

To investigate the short term effects on cardiometabolic markers in individuals with central obesity irrespective of weight loss, a RCT assessed 43 non-smoking men and women (35-75 y), following 4-week IER (48 h 600 kcal/d followed by 5-day healthy eating recommendation) or CR diet (-500 kcal/d healthy eating recommendation). No between-diet differences occurred for most markers of cardiometabolic risk; however, fasting plasma non-esterified fatty acid concentrations were lower after IER compared to CR (mean difference CER-IER 0.15 mmol/L (0.06, 0.24), P < 0.005), suggesting some adaptive metabolism changes occurred as a result of IER.⁴⁰  The outcomes of this study are limited by its small sample size and absence of data on compliance and adherence to diet protocols.

Sundfor et al. compared the effects of longer-term intermittent versus continuous energy restriction on weight loss, maintenance and cardiometabolic risk factors in adults with abdominal obesity.²⁰ During the 12 month study, 112 participants (men [50%] and women [50%]) aged 21-70 years with BMI 30-45 kg/m² (mean 35.2 [SD 3.7]) were randomly assigned to intermittent (5:2 protocol) or continuous energy restriction. Both groups had improvements in waist circumference, blood pressure, triglycerides and HDL-cholesterol and were not significantly different. In addition, both groups resulted in similar weight loss, maintenance, weight regain and cardiovascular risk factors after one year. Once again, however, feelings of hunger were more pronounced during intermittent energy restriction.²⁰

Overall, intervention trials of 5:2 diet protocol suggest weight loss with modest and mixed effects on glucoregulatory markers, lipids and inflammatory markers.  There is little evidence to suggest that this approach produces superior weight loss or metabolic changes in comparison to standard energy restriction diets.

Time restricted feeding (TRF)

The TRF protocol suggests consuming meals within a 6-8 hour eating window each day and allowing at least 16 hours of fasting.  If you think about it, all of us “fast” every day while we are sleeping.  The idea behind TRF is to simply extend that time frame.  The timing of the 6-8 hours window is flexible, with some choosing an early TRF where breakfast is consumed and eating is halted around 2-3 pm.  Another approach is to skip traditional breakfast and have the first meal at noon and complete food intake by 8pm.  This approach may be best for individuals that need support with overall calorie intake each day. It is easily integrated with other caloric restricted protocols, especially the ketogenic dietary pattern which produces a greater satiety response.

Sutton at al. conducted the first supervised controlled feeding trial to test whether early TRF has cardiometabolic health benefits in humans independent of food intake and weight loss.  Prediabetic men following an early TRF improved their insulin sensitivity and beta cell function, lowered blood pressure, and decreased oxidative stress levels without losing weight.¹⁶  Additionally, the early TRF lowered the desire to eat in the evening, which could facilitate compliance and weight loss.

Another study comparing early and late TRF found that when food intake and meal frequency are matched, eating earlier in the daytime to align with circadian rhythms in metabolism enhanced weight loss.⁴¹ The early TRF did not affect 24-hour energy expenditure but did decrease mean ghrelin levels by 32 ± 10 pg/mL (P = 0.006), made hunger more even-keeled (P = 0.006), and tended to increase fullness (P = 0.06-0.10) and decrease the desire to eat (P = 0.08).⁴¹

Connection with circadian clock

Many metabolic and hormonal rhythms peak in the morning and are downregulated in the evening, implicating the morning as optimal for food intake.⁴²  The circadian system, or internal biological clock, may explain why the effects of TRF appear to depend on the time of day. Glucose, lipid, and energy metabolism are all regulated by the circadian system, which upregulates them at some times of day and downregulates them at others.⁴²  Therefore, fasting protocols may need to consider that food consumption that is not synchronized with natural circadian rhythms may at best be unsustainable, and at worst may exert adverse health effects and increase disease risk in the long-term.

A regular meal pattern including breakfast consumption, consuming a higher proportion of energy early in the day, reduced meal frequency (i.e., 2-3 meals/day), and regular fasting periods may provide physiological benefits such as reduced inflammation, improved circadian rhythmicity, increased autophagy and stress resistance, and modulation of the gut microbiota.⁴³

Sustainability of fasting as a lifestyle

While weight and fat mass decreased in most IER studies, it is important to consider protocol adherence and dropout rates with the different interventions. The dropout rates have been as high as 40% indicating that IER is difficult to follow in real-world settings and suggests that the clinical significance and practicality of sustaining an IER regimen are questionable.⁴⁴

In addition, many believe that eating three meals each day is healthy and that skipping meals can be detrimental. In an online survey, participants (N = 312) with experience of intermittent fasting reported their beliefs about healthy meal and snack frequency, as well as their non-fasting-day and fasting-day eating patterns. They also reported their level of concern with fasting-day meal patterns and their concern to generate fullness when selecting foods. Both current and former intermittent fasting dieters participated in the survey. Former intermittent fasting dieters were more likely to believe that it is healthy to eat three meals a day plus snacks, and were more likely to be concerned about the negative consequences of missing a meal. In addition former intermittent fasting dieters were also more likely to eat in anticipation of future hunger, and to prioritize fullness over taste when selecting foods. These findings reveal how beliefs about a healthy eating style can play an important role in shaping dietary patterns. Interventions aimed at modifying beliefs about healthy meal patterns may promote adherence to fasting protocols.⁴⁵

Conclusions

Due to the increasing prevalence of overweight and obesity, Americans are searching for effective weight loss methods. Despite the recent popularity of intermittent fasting and associated weight loss claims, the supporting evidence base in humans remains small. Animal models and human trials suggest that IER protocols are as beneficial as standard caloric restriction on weight, body composition, cardiovascular biomarkers, and aging. At the cellular level, IER may also increase resistance against oxidative stress, decrease inflammation, and promote longevity.

At this time, evidence is not strong enough to suggest that healthcare professionals should prescribe IER as a reliable method for successful long-term weight loss and maintenance.  It is still unknown which individuals would most benefits from IER and which form of IER is most effective.⁴⁴  It is important to consider lifestyle matching and desired outcomes when choosing an IER to increase patient compliance and promote long-term success. Should IER become a part of standard practice, a multidisciplinary approach including physicians, registered dietitians and other essential healthcare providers will ensure safety of the patient and decrease the possibility of adverse effects such as rapid weight regain, depression and binge eating disorder.⁴⁴

 

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Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management.

Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet, and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger.

Kari Hamrick, PhD, RD is a registered dietitian with over 25 years of experience in nutrition and wellness and is the founder of Navigate Nutrition and Wellness, a private practice nutrition counseling center located in Gig Harbor, WA. Dr. Hamrick earned her PhD in nutritional sciences from Texas Woman’s University and received Adult Weight and Lifestyle Management certification from the Commission on Dietetic Registration. Kari has special training and experience in Mindfulness Based Eating Awareness Training (MB-EAT), women’s health issues, and the nutritional management of heart disease, eating disorders, and digestive health. Dr. Hamrick is currently completing a medical communication fellowship at Metagenics. Dr. Hamrick’s passion is helping individuals meet their nutrition and health goals with respect, open communication, and a sense of humor. She is also a yoga and dance instructor and enjoys learning and performing aerial acrobatic arts.