June/July 2021 Issue

CPE Monthly: Intermittent Fasting — An Evidence-Based Assessment
By Dana Angelo White, MS, RD, ATC
Today’s Dietitian
Vol. 23, No. 6, P. 46

Suggested CDR Performance Indicators: 8.1.5, 8.3.1, 8.3.6, 9.4.5
CPE Level 1

Take this course and earn 2 CEUs on our Continuing Education Learning Library

Intermittent fasting (IF) is a popular dieting trend, but, unlike many other fads, it’s been the subject of significant investigation to determine its efficacy for mental and physical health.

There are several IF methods, each involving a different pattern of caloric restriction for extended periods of time. Depending on the variation, there may be days of restricted calorie intake, in combination with days during which calories are less restricted.

Continuing to gain traction due to media coverage, IF is promoted as a potential plan for weight loss, increased longevity, improved brain function and mental clarity, and reduced risk of chronic disease. In response to the hype, patients are seeking guidance from RDs about whether they should try IF and whether it might help them meet long-term health and wellness goals.

RDs possess the appropriate skills to answer questions and provide guidance on the various methods of IF. In addition to answering questions about fasting regimens, dietitians can help clients identify potential contraindications to fasting based on their past medical histories, behaviors and attitudes toward food, and preexisting medical conditions.

This continuing education course identifies and examines the basic guidelines for various methods of IF, reviews the scientific literature, and discusses evidence, potential benefits, contraindications, and possible downsides to both short-term and long-term fasting.

What Is IF?
While there are no standardized rules or meal plans for what to eat while practicing IF, it’s often advised that calorie intake on nonfasting days be monitored. Consuming too much or too little on nonfasting days may alter outcomes. In addition to scientific research studies, diet books and franchises, such as the Fast Diet, experiment with various combinations of limited or zero-calorie days. First popularized in the United Kingdom, the Fast Diet suggests users fast two nonconsecutive days per week, with at least one “normal” day of eating in between. On fasting days, calories are limited to approximately 500 kcal for women and 600 kcal for men.

Today, there are many different methods in addition to the Fast Diet approach. Most plans require no food restrictions on nonfasting days, but specifics vary. Calorie consumption on fasting days typically is limited to lean protein, nuts, low–glycemic index produce, and water and other calorie-free beverages.

IF Methods
There are multiple IF styles, the protocols of which may vary in day-to-day practice and the world of fad diets; for research purposes, however, methods must be strictly defined. The common methods of IF explored in the literature include alternate-day fasting (ADF), modified IF, time-restricted feeding (TRF), and religious fasting.

ADF involves fasting days in which little or no energy-containing foods or beverages are consumed, cycled with nonfasting days with unrestricted consumption of food and beverages. Calorie intake on fasting days can vary from 0 kcal to 25% of caloric needs, depending on the protocol.

Complete ADF is an approach that involves a day of zero calorie consumption (calorie-free beverages are allowed) alternated with a day of consuming foods and beverages ad libitum. This cycle repeats so consecutive fasting or nonfasting days don’t occur.1 Some ADF diets allow consumption of 25% energy needs on fasting days.2

Modified IF
Modified IF regimens are similar to the Fast Diet mentioned previously. This fasting protocol involves restricted intake on fasting days followed by a longer series of nonfasting days.

Typical modified fasting regimens allow for nonconsecutive days of complete or partial caloric restriction and normal intake (ie, calories to meet needs) the other days of the week. One of the most popular methods of modified fasting is the 5:2 approach: On two nonconsecutive days, the dieter consumes only 20% to 25% of daily calorie needs, which translates to 500 kcal per day on a 2,000-kcal diet, and for the remaining five days of the week follows normal caloric intake.1

TRF allows for ad libitum energy consumption within a specific time frame.1 One of the most popular types of TRF is the 16/8 method. Dieters meet personal calorie needs within an eight-hour eating window, resulting in a 16-hour fasting period.

Because one of the main appeals of IF is to avoid the need for calorie counting, individuals should be hyperaware of hunger levels. Dieters might eat between 8 AM and 4 PM, or 12 PM and 8 PM, allowing for much of the fasting to take place overnight. The times may vary for those who prefer to skip breakfast or dinner.

This might be a more realistic method of IF because some people may instinctively be eating in a similar pattern already.3 Because the allowable window for food intake is limited, there’s a chance that TRF can help promote weight loss.4 However, as many dietitians have seen, these types of limitations also may put dieters at risk of falling short of their nutrient needs.

Religious Fasting
Researchers are investigating outcomes of a variety of fasting regimens for religious or spiritual purposes. However, current research is almost entirely observational. IF may have originated from fasting practices that accompany religious holidays such as Ramadan, which involves fasting from sunrise to sunset during the holy month.1 The most common method is to eat a large meal after sunset and then a light meal before dawn, thus creating a fasting period of about 12 hours.

Fasts also are practiced within other religions. The Church of Jesus Christ of Latter-Day Saints observes Fast Sundays, typically the first Sunday of every month. According to their principles, members skip two consecutive meals while they pray for forgiveness from sins and for those less fortunate.

Seventh-day Adventists also practice religious fasting, in some cases daily.1 For example, they may practice fasting as a “beneficial spiritual discipline” on the first Sabbath of each quarter. Fasting or modified fasting lasts from six to 24 hours.5

Calorie Restriction vs IF
Traditional dieting calls for daily caloric restriction for extended periods of time. Modified IF may have better compliance than caloric restriction. One study showed that IF was as effective as caloric restriction and may be useful for individuals who find caloric restriction too difficult to maintain.1 The authors of this study suggested that modified IF requires the individual to focus on eating fewer calories only on certain days of the week, which may be more feasible than restricting calories every day.1,6

Caloric restriction often is used for control or comparison purposes in research studies. In these cases, calorie allotments are set below needs but executed daily instead of following any of the previously mentioned formatted fasting regimens.2,7 Caloric restriction regimens are valuable for comparison against IF protocols to help determine the roles timing of intake and length of fasting have on the outcomes being measured.

In the Comprehensive Assessment of Long Term Effects of Reducing Intake of Energy (CALERIE) two-year randomized clinical trial, Ravussin and colleagues evaluated caloric restriction independently and determined that restriction to 25% less than baseline needs was feasible to promote adherence and weight loss in subjects without obesity aged 21 to 50 for two years. Researchers also observed improved quality of life and reduction in weight, fat, and cholesterol levels.8 Additional examples of the effects of caloric restriction will be discussed later in this article.

Current Research
Much of the research on IF comprises animal studies, but some findings with human subjects in the last 10 years have increased interest for additional studies. Studies have highlighted associations between IF and weight loss, fat loss, improved cognitive function, increased longevity, and effects on diseases such as diabetes and certain types of cancer.

Weight Loss and Fat Loss
Dating back to the early 1980s, IF protocols have demonstrated evidence of reduced body weight. Studies with small numbers of subjects revealed reductions in insulin production and loss of 1% to 2.5% of body weight.8,9 In a review published in 2017, Mattson and colleagues cited that TRF for four or eight hours per day for an eight-week period in young and physically fit adult male subjects demonstrated efficacy for weight loss and lean body mass retention, but more research is needed with larger subject populations.9

A study compared ADF at 25% of calorie requirements on fasting days and 125% of calorie needs on “feast days” compared with subjects on a flat daily caloric restriction of 75% of needs. After one year, both the caloric restriction and ADF groups lost weight but ADF wasn’t superior for weight loss, weight maintenance, or cardioprotection. Both groups displayed similar weight loss results at six and 12 months compared with the control group. It’s also worth noting that the ADF group had the poorest compliance and the highest dropout rate; subjects reported they had difficulty adhering to the diet.10

Since a large amount of earlier research had been conducted only in rodents, a 2014 review examined the effects of IF on humans vs rodents. Researchers found that rodents undergoing TRF displayed significant decreases in weight, cholesterol, and glucose levels, with improved insulin sensitivity. Human subjects following the same protocol displayed lower concentrations of triglycerides and blood glucose. LDL cholesterol decreased and HDL cholesterol increased, but weight reduction in humans was inconsistent. The timing of fasting regimens also appears to play a role. TRF windows of both three to four hours and eight to nine hours showed consistent decreases in body weight in animals, while a 12-hour window was associated with favorable results in human subjects.11

Studies also have examined whether synching IF with circadian clocks and normal day and night eating patterns is beneficial. A study conducted at the University of Alabama suggests that eating in alignment with the body’s circadian clock may positively influence health in several ways. According to researchers, metabolism functions at its optimum capacity in the earlier hours of the day, which suggests that eating in an earlier morning window would produce better weight loss outcomes.12

This controlled feeding trial found that early TRF, which was defined as eating only between the hours of 8 AM and 2 PM, followed by an 18-hour fasting period, could limit hunger during the day and increase the amount of fat burned at night, as measured by a respiratory chamber and serum and urine values. Hunger levels on the TRF regimen were better controlled throughout the day when compared with eating between 8 AM and 8 PM. The TRF model of eating also was found to raise metabolic flexibility, which enables the body to shift between burning carbohydrates and burning fat.12

Increased nighttime fasting may be beneficial and more realistic since it’s in line with normal eating and sleeping patterns and the way in which most people typically eat meals.3 Even when independent from fasting, reducing nighttime eating can benefit health, as research has determined that nighttime eating, defined as calories consumed between 5 PM and midnight, can lead to overconsumption of calories as well as increased markers of inflammation.13 Since the dietary evaluation in the latter study was conducted via 24-hour recall, more research is needed to determine whether the nutrient density and calorie content of foods consumed during nighttime eating would yield different outcomes.

Another small study examined eight men and eight women who fasted every other day for 22 days. It was found that three weeks of ADF led to weight loss and fat loss in subjects without obesity (BMI of 20 to 26). Researchers also found that subjects lost approximately 2.5% of their initial body weight and 4% of their initial fat mass. However, ADF may not be realistic long term due to extreme hunger on fasting days. Some subjects reported constipation and light-headedness over the course of the trial, as well as irritability and hunger on fasting days. Researchers hypothesized that subjects would be less likely to continue this type of diet for extended periods due to these findings.14

Physically active subjects may see benefits from IF. A study was conducted to examine whether ADF combined with exercise more significantly alters body composition and plasma lipid levels than ADF without exercise. While this was a small study (n=64), researchers found that in the exercise group, fat mass and waist circumference decreased, lean mass was retained, LDL decreased, and HDL increased. Researchers gave subjects food on fasting days and asked them to keep a separate log if they ate more than indicated. Subjects reviewed logs with researchers each week, which determined whether they adhered to the protocol. Diet adherence was about 81% on fasting days across all groups.15

In a study by Moro and colleagues, 34 resistance-trained males followed eight weeks of a 16/8 TRF model, eating meals at 1 PM, 4 PM, and 8 PM daily, and were compared with a control group who followed a diet consisting of a morning, midday, and evening meal daily at 8 AM, 1 PM, and 8 PM, respectively; calorie intake and macronutrient distribution was consistent across both. The TRF group presented with decreases in fat mass compared with the nondiet group but also demonstrated decreases in testosterone and insulinlike growth factor. However, fat-free mass and maximal strength were maintained in both the experimental and control groups. There were no significant changes in resting energy expenditure.16

IF also may impact hunger levels, which in turn influence efficacy of long-term weight loss. It’s hypothesized that creating regular periods of fasting not only lowers total calorie intake but also elicits a hormonal response that may further influence health by eliciting weight loss.3

Hormones such as leptin, which decreases appetite, and ghrelin, which increases appetite, have been measured and compared in a systematic review. Eight studies assessed changes in leptin levels associated with IF interventions. Of these studies, three determined a statistically significant impact of a decrease in leptin levels among subjects practicing IF. For two of these three studies, subjects followed an ADF protocol. In the remaining study, subjects followed one day of TRF.3 This suggests that various types of fasting protocols—and even very short-term interventions—can influence hormones that drive hunger. It’s unclear what this means for long-term weight loss success.

Considering the results from the literature cited above, it’s possible that IF can be an effective weight loss tool in the short term. During fasting days, overall caloric intake is decreased, thus producing a negative energy balance and promoting weight loss. During the feeding window for all methods of IF, caloric intake may be naturally decreased because people are unlikely to eat as much in one sitting as they might when they spread meals out during the day. Long-term weight loss may be more difficult due to issues regarding hunger and compliance with such a strict dietary routine.

Studies that have examined IF weight loss also have documented favorable improvements in blood lipid profiles, citing decreases in triglycerides and LDL cholesterol levels as well as increased HDL.11,15 In a review by Mattson, IF was found to have a favorable response on cholesterol, blood pressure, and resting heart rate in rats and mice. The human studies in this review article show IF and caloric restriction promote equivalent reductions in blood pressure and triglycerides and that IF is associated with a slightly greater reduction in total cholesterol than caloric restriction.9

Gabel and colleagues found that plasma lipids, blood pressure, and inflammatory markers weren’t preferentially altered in an IF regimen vs caloric restriction when monitored over a 12-month period.2

Inflammation and elevated C-reactive protein levels also have been identified as potential risk factors for CVD, but the influences of IF on these markers specific to CVD risk in human subjects remains unclear.9,13,16,17

Cognitive Function and Alzheimer’s Disease
There’s a relatively limited amount of animal research investigating IF’s effect on prevention and treatment of Alzheimer’s disease and for supporting brain function. A small rodent study published in 2018 linked IF to the prevention of memory loss as well as short-term and age-related memory decline in rats with induced Alzheimer’s disease. However, these rats also displayed decreased bone mineral density and insulin resistance. It should be noted that the animal subjects were induced to be estrogen deficient and in a state of forced menopause, which could make the findings less generalizable to human populations.18

In a rodent study by Zhang and colleagues, an ADF model was followed for Alzheimer’s disease prevention. Subjects underwent fasting days with complete caloric restriction, with ad libitum intake on nonfasting days. Results concluded that ADF protected against deposition of amyloid-beta, a peptide involved in the development of Alzheimer’s disease.19

Studies have investigated IF’s effects on aging and age-related damage on organs other than the brain. ADF in rodents was found to reduce oxidative damage and protect against inflammatory markers and damage to heart tissue that occurs with aging.17

It appears IF also may combat the age-related effects within the central nervous system. A 2015 study determined that IF reduced the risk of age-related deficits and degenerative disorders that occur within the CNS of both young and older rats.20

Several studies have looked at the impact of IF on glucose control, insulin response, and the prevention and treatment of diabetes. A 2016 study found that TRF led to improved insulin resistance and glucose tolerance as well as an increased use of fat for fuel compared with baseline in postmenopausal, obese mice; in addition, the seven-week experimental phase significantly reduced preexisting metabolic disease.21 Shin and colleagues also found a reduction in fat mass and improved glucose tolerance with decreasing food intake.18

A 2017 study in rodents that found an association between IF and weight loss also suggested a lower risk of insulin resistance and CVD compared with control subjects.9

Reduced meal frequency without caloric restriction can have a negative impact on glucose regulation. A human study published in 2007 compared the outcomes of consuming required calories at one large meal vs spread out over three meals per day. Subjects ate one meal per day between 4 PM and 8 PM for eight weeks followed by eight weeks of isocaloric feedings spread over three meals. Subjects received daily calorie limits for weight maintenance through both phases of the study.22

Results indicated that morning glucose tolerance worsened when subjects ate only one meal per day compared with three meals per day.22 Since many IF protocols limit intake in a similar fashion on fasting days, RDs should be aware of the potential effect on glucose tolerance and consider monitoring this closely in patients with diabetes looking to try IF.

Another short-term study in humans was conducted to compare and evaluate modified IF with carbohydrate restriction vs caloric restriction. Subjects followed the 5:2 format of fasting at 25% less than calorie needs, plus restricting carbohydrate intake to less than 40 g per day on two nonconsecutive days. Subjects in the caloric restriction group decreased daily caloric intake by 25%. Researchers found that IF with carbohydrate restriction produced significantly greater improvements in insulin sensitivity compared with caloric restriction, but more long-term data are needed.7

A study published in 2019 looked at IF’s role in diabetes prevention. Researchers recruited 100 subjects at risk of developing diabetes and separated them into three groups: ADF, caloric restriction, and control. The 12-month intervention included a six-month weight loss phase followed by a six-month weight maintenance phase.2

The ADF group consumed 25% of needs between 12 PM and 2 PM on fasting days and 125% of calorie needs spread out over three meals on “feast days.” The calorie restriction group limited intake to 75% of daily needs spread out over three meals. Although there was similar weight and fat loss across both ADF and CR groups, the ADF group more effectively decreased insulin resistance.2

Conversely, a 2017 animal study suggested that fasting regimens may produce undesired effects in subjects with overweight and compromised glucose metabolism. The study determined that eight weeks of an IF regimen with 40% of calories from fat exacerbated insulin resistance. Subjects displayed increased insulin resistance, defective hepatic insulin signaling, and compromised glycogen mobilization.23

Cancer prevention is another area believed to be impacted by IF, but evidence is limited. Some rodent studies have supported the potential protection IF can have against cancer.2 Conversely, a review published in 2015 found that of 59 studies, 37.5% reported IF didn’t prevent cancer. Overall, this review determined IF wasn’t significant in preventing cancer. Interestingly, 90.9% of these studies demonstrated that caloric restriction was associated with an anticancer benefit.24 Researchers speculated the role of hormonal changes observed in studies using caloric restriction may have contributed to cancer prevention, but more research is needed.

Fasting may result in a systemic increase in cellular maintenance, an increased ability for the body to manage stress, a decrease in inflammation, and inhibition of the mTOR pathway, which regulates cell turnover and possibly affects the development of certain types of cancer, as cancer often affects cells that overturn rapidly.9

C-reactive protein, a marker of systemic inflammation, can be decreased by reducing evening calorie intake and fasting for longer overnight intervals. Conversely, increased levels of C-reactive protein also were related to a higher risk of heart disease and possibly breast cancer.13

Di Biase and Longo have investigated the impact of fasting-type diets on cancer treatment. While more research is needed, researchers cite the “drastic changes” in plasma levels of nutrients that IF invokes could have a significant impact on cancer cell sensitization by creating restriction in both macro- and micronutrients that cancer cells require.25 However, because these same nutrients are required to help maintain skeletal muscle mass in patients undergoing cancer treatment, more research is needed.

Client Considerations for IF

Side Effects
The effects of any restrictive diet can include symptoms such as hunger, temperature changes, fatigue, headache, low energy, and irritability. Continually alternating between fasting and nonfasting also can result in gastrointestinal issues such as gas, bloating, and constipation. A few studies suggest that proper adherence to IF protocols could affect mental state and behavior, including improving mood, reducing tension and anger, and increasing self-confidence, but subjects also have complained of hunger on fasting days that doesn’t subside over time.1

Feelings and behaviors toward new dietary shifts can vary significantly among individuals; therefore, a patient’s tolerance of newly initiated IF interventions needs to be monitored and tailored on a case-by-case basis.

Compliance and adherence to IF diets also can vary greatly depending on the individual.

The populations that could benefit from this diet may be those who can tolerate longer periods of little or no caloric intake for specified hours of the day or have trouble with calorie counting or tracking intake. Research also suggests that modified fasting is the preferred regimen when trying IF, as studies on modified IF have the lowest dropout rates and greatest adherence.3

There’s also concern that several days of fasting and caloric restriction may result in unmet nutrient requirements. And long-term intake restrictions may result in nutrient deficiencies. Overall, it’s helpful if interventions are simple to administer and palatable enough to promote long-term adherence.26

Patients who choose to follow any form of IF are encouraged to seek the guidance of an RD to determine whether their intake of essential nutrients is appropriate. Those with a history of nutrient deficiencies should follow up with a physician for proper lab work and other monitoring.

People with type 1 diabetes, those with type 2 diabetes who require insulin, individuals suffering from hypoglycemia, those taking medications that require consumption with food, and pregnant or breast-feeding women typically shouldn’t follow an IF eating pattern. Patients with disordered eating or who have a history of a diagnosed eating disorder also should be cautioned about this restrictive way of eating. If clients have other conditions, RDs should advise them to consult with their physicians before trying IF. Further studies are necessary to determine how IF impacts human health, and more guidance is needed on how IF can be incorporated into a healthful lifestyle and how to manage side effects.

Recommendations for Practice
Since there are only small human studies available, it’s difficult to make determinations about the efficacy of IF. It also should be noted that studies conducted to date are based on short time frames, so it’s unclear whether IF is sustainable long term. Conversely, IF may be advantageous for weight loss or other long-term beneficial health outcomes, including improved glucose control and blood lipid profiles.

IF may be helpful for some clients if they’re meeting their nutrient needs. However, there’s a lack of scientific evidence regarding an ideal regimen, such as the number of weekly fasting days, duration of each fasting period, extent of calorie restriction, and dietary guidelines for nonfasting days. Because there are so many variations of IF regimens, it benefits RDs to be familiar with popular methods such as 5:2 ADF and TRF in 24-hour cycles. Knowledge of these various forms of IF can help RDs safely guide patients who are highly motivated to try them. Based on the data, clients prone to excessive calorie intake from nighttime eating may benefit from some form of TRF but would also benefit from guidance from RDs on how to successfully meet their needs when limiting the timing of their daily intake. RDs also can help educate their clients on the potential dangers of IF if they’re at risk of side effects and contraindications.

— Dana Angelo White, MS, RD, ATC, is president of Dana White Nutrition, Inc, a sports dietitian, and an associate clinical professor of athletic training and sports medicine at Quinnipiac University.

Learning Objectives

After completing this continuing education course, nutrition professionals should be better able to:
1. Counsel clients about the different types of intermittent fasting (IF) methods.
2. Evaluate the current research surrounding IF.
3. Examine the health effects of IF.
4. Provide education on the potential side effects and drawbacks of IF.

CPE Monthly Examination

1. Which type of intermittent fasting (IF) diet has shown the poorest compliance and highest dropout rates?
a. Time-restricted feeding (TRF)
b. Alternate-day fast (ADF)
c. 5:2 method
d. Daily caloric restriction

2. When linked with the circadian clock, which type of IF diet is shown to have the most health benefits?
a. TRF
b. ADF
c. 5:2 method
d. Daily caloric restriction

3. Individuals with what preexisting condition aren’t advised to partake in IF?
a. Hypertension
b. Alzheimer’s disease
c. Type 1 diabetes
d. Obesity

4. Evidence suggests that IF may have an effect on which of the following?
a. Circadian biology
b. Anxiety levels
c. Dementia
d. Inflammation

5. Which religious group has been known to participate in Fast Sundays?
a. Christians
b. Seventh-day Adventists
c. Church of Jesus Christ of Latter-Day Saints
d. Muslims

6. IF protocols include all but which of the following?
a. ADF
b. TRF
c. Eating from 8 AM to 2 PM
d. Daily caloric restriction

7. Which method of dieting often is used as a control in IF research?
a. TRF
b. ADF
c. Caloric restriction
d. Religious fasting

8. According to a review on IF, which hormone is impacted in three out of eight studies?
a. Leptin
b. Ghrelin
c. Testosterone
d. Insulinlike growth factor 1

9. What are common side effects of IF?
a. Headache, fatigue, increased self-confidence
b. Increased energy levels, decreased tension, headache
c. Increased energy levels, decreased tension, gastrointestinal discomfort
d. Increased self-confidence, increased tension, gastrointestinal discomfort

10. Research has suggested that IF is which of the following?
a. A suitable diet for weight loss
b. A suitable diet for cancer prevention
c. A suitable diet for antiaging
d. A subject about which more animal studies should be conducted

1. Patterson RE, Sears DD. Metabolic effects of intermittent fasting. Annu Rev Nutr. 2017;37:371-393.

2. Gabel K, Kroeger CM, Trepanowski JF, et al. Differential effects of alternate-day fasting versus daily calorie restriction on insulin resistance. Obesity (Silver Spring). 2019;27(9):1443-1450.

3. Longo VD, Panda S. Fasting, circadian rhythms, and time-restricted feeding in healthy lifespan. Cell Metab. 2016;23(6):1048-1059.

4. Wilkinson MJ, Manoogian ENC, Zadourian A, et al. Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome. Cell Metab. 2020;31(1):92-104.e5.

5. Special days. Seventh-day Adventist Church General Conference website. https://gc.adventist.org/events/special-days/  

6. Keogh JB, Pedersen E, Petersen KS, Clifton PM. Effects of intermittent compared to continuous energy restriction on short-term weight loss and long-term weight loss maintenance. Clin Obes. 2014;4(3):150-156.

7. Harvie M, Wright C, Pegington M, et al. The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women. Br J Nutr. 2013;110(8):1534-1547.

8. Ravussin E, Redman LM, Rochon J, et al. A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. J Gerontol A: Biol Sci Med Sci. 2015;70(9):1097-1104.

9. Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58.

10. Trepanowski JF, Kroeger CM, Barnosky A, et al. Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults. JAMA Intern Med. 2017;177(7):930-938.

11. Rothschild J, Hoddy KK, Jambazian P, Varady KA. Time-restricted feeding and risk of metabolic disease: a review of human and animal studies. Nutr Rev. 2014;72(5):308-318.

12. Ravussin E, Beyl RA, Poggiogalle E, Hsia DS, Peterson CM. Early time-restricted feeding reduces appetite and increases fat oxidation but does not affect energy expenditure in humans. Obesity (Silver Spring). 2019;27(8):1244-1254.

13. Marinac CR, Sears DD, Natarajan L, Gallo LC, Breen CI, Patterson RE. Frequency and circadian timing of eating may influence biomarkers of inflammation and insulin resistance associated with breast cancer risk. PLoS One. 2015;10(8):e0136240.

14. Heilbronn LK, Smith SR, Martin CK, Anton SD, Ravussin E. Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. Am J Clin Nutr. 2005;81(1):69-73.

15. Bhutani S, Klempel MC, Kroeger CM, Trepanowski JF, Varady KA. Alternate day fasting and endurance exercise combine to reduce body weight and favorably alter plasma lipids in obese humans. Obesity (Silver Spring). 2013;21(7):1370-1379.

16. Moro T, Tinsley G, Bianco A, et al. Effects of eight weeks of time-restricted feeding (16/8) on basal metabolism, maximal strength, body composition, inflammation, and cardiovascular risk factors in resistance-trained males. J Transl Med. 2016;14:290.

17. Castello L, Froio T, Maina M, et al. Alternate-day fasting protects the rat heart against age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-kB activation. Free Radic Biol Med. 2010;48(1):47-54.

18. Shin BK, Kang S, Kim DS, Park S. Intermittent fasting protects against the deterioration of cognitive function, energy metabolism and dyslipidemia in Alzheimer’s disease-induced estrogen deficient rats. Exp Biol Med (Maywood). 2018;243(4):334-343.

19. Zhang J, Zhan Z, Li Z, et al. Intermittent fasting protects against Alzheimer’s disease possible through restoring aquaporin-4 polarity. Front Mol Neurosci. 2017;10:395.

20. Vasconcelos AR, Kinoshita PF, Yshii LM, et al. Effects of intermittent fasting on age-related changes on Na,K-ATPase activity and oxidative status induced by lipopolysaccharide in rat hippocampus. Neurobiol Aging. 2015;36(5):1914-1923.

21. Chung H, Chou W, Sears DD, Patterson RE, Webster NJG, Ellies LG. Time-restricted feeding improves insulin resistance and hepatic steatosis in a mouse model of postmenopausal obesity. Metabolism. 2016;65(12):1743-1754.

22. Carlson O, Martin B, Stote KS, et al. Impact of reduced meal frequency without caloric restriction on glucose regulation in healthy, normal-weight middle-aged men and women. Metabolism. 2007;56(12):1729-1734.

23. Park S, Yoo K, Hyun J, Kang S. Intermittent fasting reduces body fat but exacerbates hepatic insulin resistance in young rats regardless of high protein and fat diets. J Nutr Biochem. 2017;40:14-22.

24. Lv M, Zhu X, Wang H, Wang F, Guan W. Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systemic review and meta-analysis. PLoS One. 2015;9(12):e115147.

25. Di Biase S, Longo VD. Fasting-induced differential stress sensitization in cancer treatment. Mol Cell Oncol. 2015;3(3):e1117701.

26. Johnstone A. Fasting for weight loss: an effective strategy or latest dieting trend? Int J Obes (Lond). 2015;39(5):727-733.