Recommending Intermittent Fasting

The many mechanisms of action elucidate the variety of health benefits that can be gained with time-restricted feeding

By Ronald Hoffman, MD, and Karolyn A. Gazella

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Abstract

Research regarding the myriad health benefits achieved with fasting has increased significantly over the past 5 years. In addition to expanding the clinical applications beyond weight loss, the scientific literature paints a clear picture as to the many mechanisms of action and pathways positively influenced by this eating style. This review encapsulates the key mechanisms of action, provides an overview of clinical applications, and identifies any contraindications. Based on the research, we can conclude that intermittent fasting, and more specifically time-restricted feeding, is worth discussing with many patients.

Introduction

Intermittent fasting (IF) is a general term that means taking periodic breaks from eating. This is done over various time cycles and may or may not include caloric restriction during times of feeding. Popular types of IF include alternate-day fasting, the 5:2 fast (5 days of normal eating and 2 days of restricted eating per week), and overnight fasting, which is known in medical research as time-restricted feeding (TRF).1 For the purpose of this paper, we will focus on the research regarding TRF.

The overnight fasting period in clinical studies varies and is typically 12 to 16 hours, with many of the studies focusing on a 14-hour overnight fasting window. Some of the research demonstrating efficacy analyzed people participating in Ramadan religious fasting, which can be from 13 hours to 18 hours per day for 30 days.2 Specifically regarding weight-loss applications, animal studies have shown that a fast of less than 12 hours was not effective;4 however, 1 human clinical trial showed that an 11-hour fast resulted in a 1.3% weight loss compared to control.3 It’s important to note that in that study, participants reduced their calorie consumption during their feeding hours. In most of the studies, during the feeding hours, eating is typically ad libitum. Of course, if ad libitum eating focuses on healthier foods, outcomes can be further improved.

In vivo research by Chaix et al demonstrated improved glucose tolerance and reductions in total body fat, insulin resistance, and obesity-related inflammation.4 There has now been a natural progression to human clinical trials to evaluate efficacy of TRF. Much of this research can be divided into 2 types of study designs: those meant to determine mechanisms of action of fasting and those identifying clinical efficacy of fasting for specific conditions.

Mechanisms of Action

Identifying exactly how TRF exerts its positive health effects has been a key research objective. This paper focuses on metabolic influences, genetic interactions, and cellular function. The scientific literature clearly shows that TRF exerts its positive health effects along multiple pathways.

Enhanced Metabolic Efficiency

Energy restriction for 10 to 14 hours or more leads to significant metabolic adaptations including depletion of liver glycogen stores and hydrolysis of triglycerides to free fatty acids (FFAs) in adipocytes. The FFAs are then transported into hepatocytes where they produce ketone bodies and activate transcription factors; these produce and release a protein factor that has widespread effects on cells throughout the body and brain.5

Intermittent fasting in general triggers metabolic adjustments that lead to weight loss and other health benefits. One of the adjustments that comes with TRF is the shift from utilization of glucose as fuel to fatty acid–derived ketones, which represents a transition from fat storage to fat mobilization.6 This explains, in part, TRF’s role in weight loss and related metabolic disorders. Presently, we do not know the exact time it takes to put a body in a state of ketosis, and we expect it will vary by individual.

Flipping the switch from glucose to ketones confers many health benefits because ketone bodies are a far more efficient energy source than glucose, and ketones do not generate as much reactive oxygen species as glucose does.7

According to a 2017 review by Mattson et al, in addition to fasting increasing ketone levels, in vivo research and human clinical trials have demonstrated that fasting works by reducing:8

  • insulin and leptin while increasing insulin and leptin sensitivity,
  • overall body fat,
  • resting heart rate and blood pressure while increasing heart rate variability,
  • chronic inflammation,
  • stress-related damage to the brain and heart, and
  • risk of diabetes.

Mattson’s 2019 review with de Cabo published in the New England Journal of Medicine states that the many health benefits of intermittent fasting do not come solely from weight loss and reduced free-radical production. They write, “Instead, intermittent fasting elicits evolutionary conserved, adaptive cellular responses that are integrated between and within organs in a manner that improves glucose regulation, increases stress resistance, and suppresses inflammation.”5

Improved Cellular Function and Regeneration

In addition to the metabolic switching that takes place with TRF, this form of eating also leads to systemic cellular responses that carry over into the feeding hours. During fasting, cells activate the autophagy defense pathways that remove and repair damaged molecules, and during the feeding hours, these responses continue to activate cell growth, plasticity, and regeneration.8

On an intracellular level, TRF enhances mitochondrial health, DNA repair, and autophagy.7,9 In addition, TRF has been shown to positively influence key cellular pathways in the liver, as well as skeletal muscle. As levels of amino acids and glucose are reduced, there is a corresponding reduction in mTOR (mammalian target of rapamycin) pathway activity and an up-regulation of autophagy.5

In vivo research shows that TRF normalizes genes expressed in the liver that are involved in fatty acid metabolism, β-oxidation, and antioxidant defenses and can prevent accumulation of lipids in the liver caused by a high-fat diet.10

Regarding skeletal muscle, it is widely understood that muscle mass can decline with age. In vivo research shows that TRF can prevent muscle mass decline while concurrently improving agility performance.11

Interestingly, for both men and women, clinical trials demonstrate that when a 16-hour fast was combined with exercise, the benefits of both the TRF and the exercise were enhanced.12,13 The combination of TRF and exercise increases the adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio and stimulates mitochondrial biogenesis and mitochondrial stress resistance, resulting in improved exercise performance.5

In the brain, in vivo research shows that TRF, via the metabolic switching pathway, enhances synaptic plasticity and neurogenesis.14

Influencing Key Genes

Fasting and calorie restriction have long been associated with increased longevity and healthy aging. TRF exerts its antiaging effects by influencing the entire family of clock genes and sirtuins, which are modulators of aging, age-related diseases, and the circadian system.

We often think of the physiology of the human circadian rhythm as it relates to the cycling of light and dark. However, the timing of feeding and fasting over a given 24-hour period also profoundly influences the physiology of our circadian rhythm through interactions with nutrient-sensing pathways in the body.15 Circadian rhythms feature an oscillating genetic network that operates on a roughly 24-hour cycle. Dysfunctional genetic expression in the circadian system can negatively impact metabolic function and increase the risk of obesity, heart disease, diabetes, cancer, and accelerated aging.16 Gene-expression studies demonstrate that TRF supports circadian rhythm and metabolic homeostasis.17

Interestingly, for both men and women, clinical trials demonstrate that when a 16-hour fast was combined with exercise, the benefits of both the TRF and the exercise were enhanced.

All cells in the body have a clock that influences biological rhythms and homeostasis. Specifically, the BMAL1 gene and CLOCK gene create a feedback loop that regulates the transcription of hundreds of other genes that influence metabolism, inflammation, endocrine function, and the microbiome. Preliminary research indicates that TRF can positively and selectively modulate the BMAL1 gene and CLOCK gene involved with circadian rhythm.18,19

Research shows that polymorphisms in the CLOCK gene are linked, at least in part, to obesity, type 2 diabetes, cardiovascular disease, and various cancers.20,21 A study by Pagliai et al involving older adults found an association between CLOCK gene polymorphisms and cardiovascular risk factors such as elevated low-density lipoprotein (LDL) cholesterol and triglycerides, as well as quality-of-life issues such as depression and cognitive decline.22 TRF’s influence on the family of clock genes could explain, in part, why TRF has such diverse health benefits.

Sirtuin genes play a key role in oxidative and genotoxic stress, as well as enhanced health and longevity.23 In addition, SIRT1 in particular regulates the circadian clock genes BMAL1 and CLOCK.24 Research demonstrates that the sirtuins, specifically SIRT1 and SIRT3, are activated by fasting.25 A small double-crossover, double-blinded, randomized clinical trial showed an increase in SIRT3 in participants who were taking part in an alternate-day fast.26 More research is needed to confirm the connection between TRF specifically and the sirtuins.

Clinical Applications

From a clinical perspective, the key appeals of TRF are high compliance and easy sustainability. Some patients find TRF easier to follow than daily calorie restriction or specialized diets such as the ketogenic diet. In addition, a 2014 in vivo study found that animals that did an overnight fast during the week and ate ad libitum on the weekend still experienced the protective health benefits, which provides encouraging preliminary potential regarding human feasibility.27 For patients to get the long-term health benefits of TRF, this eating style should become more of a way of life versus a quick-fix, short-term diet strategy.

Based on preclinical studies and clinical trials, the following are some of the conditions that may benefit from TRF.

Obesity

Most of the studies involving TRF have been designed to evaluate efficacy regarding weight loss. The research consistently demonstrates that TRF can help with weight loss. This makes sense as individuals who fast overnight are typically taking in fewer calories; however, given the mechanisms of action regarding fasting, the timing of eating (versus lower caloric intake) likely contributes to the weight loss. A 2019 pilot study showed that a 15- to 16-hour fast resulted in a significant 2-inch reduction in waist circumference.28 Another 2019 pilot study observed overweight older adults who fasted for 16 hours overnight for a month and experienced an average weight loss of nearly 6 pounds.29 In that study, other quality-of-life parameters, including walking speed and mental function, also improved. In a 2020 pilot study, patients diagnosed with metabolic syndrome who fasted for 14 hours not only experienced abdominal and total weight loss, they also had improvements in blood pressure, cholesterol, and blood sugar control.30 In addition, a 2019 review of randomized trials found that TRF was just as effective at weight loss as calorie restriction.31

Cardiovascular Disease

Research demonstrates that TRF positively influences LDL cholesterol, triglycerides, and total cholesterol, and this eating pattern has also been shown to inhibit the formation of atherosclerotic plaque.32 A 2019 clinical trial showed that patients with metabolic syndrome who fasted overnight for 14 hours experienced a significant reduction in blood pressure, total body fat, and waist circumference.33

Cancer

Cancer is known to have many metabolic aberrations including increased rate of glucose uptake (through heightened sensitivity to insulin and insulin-like growth factor 1 [IGF-1]), dysfunctional autophagy, abnormal mitochondrial function, and many proliferative signaling pathway activations (eg, mTOR), all of which can be positively influenced by TRF.34 In their 2016 review, Longo and Panda described preclinical research showing that TRF along with chemotherapy not only enhanced the drugs’ toxicity to cancer cells but also protected healthy cells.15 A 2019 review of preclinical studies by de Groot et al further confirmed that TRF can simultaneously increase the efficacy of many chemotherapy drugs while reducing side effects and protecting healthy cells from DNA damage.35 TRF is also associated with improved biomarkers of breast cancer risk, including hemoglobin A1c concentrations and glycemic regulation.36

Diabetes

Given TRF’s metabolic mechanisms of action, it makes sense that this eating pattern may confer benefits for patients with type 2 diabetes. A 2017 two-week pilot study showed that an overnight fast of about 17 hours significantly decreased fasting blood glucose and favorably decreased postprandial hyperglycemia.37 The authors also noted that the diet was well tolerated and safe, with no instances of hypoglycemia.

Cognitive

Regarding improved cognition, the human clinical trials have focused on calorie restriction versus TRF. For example, in 2016 Horie et al evaluated a group of elderly adults with mild cognitive impairment and showed that a calorie-restricted diet (reduction of 500 calories per day for a minimum of 1,200 calories total per day) for 12 months resulted in improved verbal memory, verbal fluency, executive function, and global cognition.38 Results from an in vivo study from 2013 demonstrated that TRF specifically improved memory and learning.39

Arthritis

As described, TRF has anti-inflammatory effects, so it may be beneficial for patients with inflammatory conditions such as arthritis. According to a 2019 multicenter study involving patients with psoriatic arthritis, patients who fasted for 17 hours overnight experienced significant improvements in tender and swollen joints, pain, discomfort, fatigue, and C-reactive protein (CRP) levels.40 Presently there is a trial underway at Germany’s largest university hospital, Charité in Berlin, to evaluate the effects of fasting on rheumatoid arthritis.41

Contraindications

While there is a paucity of research thoroughly exploring TRF contraindications, this eating pattern may not be appropriate for children, women who are pregnant or lactating, or other populations that have higher nutrient needs.42

As mentioned, the preliminary research shows that TRF may benefit individuals who have type 2 diabetes. However, caution should be used with patients who have insulin-dependent diabetes (type 1), since they are at increased risk of ketoacidosis, or with anyone whose blood sugar issues include hypoglycemic episodes.

With cancer, caution should be exercised with patients who have cachexia or are at risk of malnutrition.

Patients who are nutritionally compromised due to conditions associated with malabsorption or limited caloric intake (eg, inflammatory bowel disease) must be carefully vetted for suitability.

TRF is not recommended for patients with an existing eating disorder or those with a history of an eating disorder such as anorexia or bulimia. Stice et al published data from their 5-year prospective study showing that fasting was more predictive of future recurrent bulimia than the widely used Dutch Restrained Eating scale.43 While that study featured a periodic 24-hour fast and did not specifically focus on overnight TRF, any type of consistent fast could theoretically increase risk of eating disorder relapse.

Conclusion

While the research regarding TRF is gaining momentum, the completion of additional longer-term, larger trials would help bolster confidence in recommending this eating style.

Most patients should start off gradually with an overnight fast of 10 to 12 hours, working up to a goal of 14 to 16 hours. Mattson and de Cabo recommend that the transition period take 4 months with the physician and clinic closely monitoring body weight, blood glucose, and ketone levels throughout this period.8 Fasting duration can be adjusted according to the patient’s tolerance and compliance, as well as to address either concomitant comorbidities, such as hyperglycemia and hypertension, or pain amelioration and improved mobility if the target is rheumatological conditions. Such rigorous clinical oversight may not be necessary if there are no comorbidities and the patient is in fairly good health.

Physicians can also explain to patients that feeling hungry is actually a good sign because that’s when the body is actively working to restore and maintain optimal health. Getting patients comfortable with a few hunger pangs can lead to successful long-term fasting. In addition, patients should be counseled about making healthy food choices when they are not fasting.

Given TRF’s various mechanisms of action, if the goal is sustained healthy longevity, TRF introduces structure and rigor into what for some Americans are chaotic and unrestrained eating patterns that tend to span all waking hours. As we grapple with the existing obesity epidemic, we should focus at least some of our attention on the timing of food consumption. TRF is a dietary lifestyle that can be sustained and confers many health benefits. It’s worth exploring with patients who are overweight or obese, as well as those who have or are at increased risk of developing metabolic and/or inflammatory health conditions. TRF can act both as a therapeutic and preventive tool to enhance health in certain patient populations.

About the Authors

Ronald Hoffman, MD, is a physician in private practice of integrative medicine in New York City. He is a graduate of Columbia College and Albert Einstein College of Medicine. Since 1984, he has served as Medical Director of the Hoffman Center in Manhattan. Hoffman is past president of the American College for the Advancement of Medicine.

Hoffman is the host of Intelligent Medicine, a nationally syndicated radio program, and he produces the daily Intelligent Medicine podcast. He is a Certified Nutrition Specialist, and the author of several books, including How to Talk with Your Doctor (About Complementary and Alternative Medicine)

For more information, visit drhoffman.com.

Karolyn A. Gazella has been writing and publishing integrative health information since 1992. She is the publisher of the Natural Medicine Journal and the author or coauthor of hundreds of articles and several booklets and books including her latest book The Definitive Guide to Thriving After Cancer that she wrote with Lise Alschuler, ND, FABNO. Gazella is the co-creator and Chief Executive Officer of the iTHRIVE Plan, an innovative online wellness program specifically for cancer survivors.

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