Intermittent Fasting: History
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Subjects: Nutrition & Dietetics
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Maria Morales-Suarez-Varela

Intermittent fasting (IF) refers to periods of regular times with a very restricted or no caloric intake, that is, periods of voluntary abstinence from food and liquid intake: methods of energy deprivation.

  • intermittent fasting
  • exercise
  • obesity
  • type 2 diabetes
  • multiple sclerosis

1. Introduction

Intermittent fasting (IF) refers to periods of regular times with a very restricted or no caloric intake, that is, periods of voluntary abstinence from food and liquid intake: methods of energy deprivation [1]. Commonly, it consists of a daily fast of 16 h, a 24-h fast on alternate days, or a 2-day-a-week fast on non-consecutive days. During the fasting period, the consumption of calories frequently varies from 0 to 25% in relation to the regular caloric needs. Consumption on non-fasting days can be ad libitum, limited to a certain composition of the diet, or reserved to achieve a specific caloric intake of up to 125% of regular caloric needs. Intermittent fasting can be done with unrestricted consumption when not fasting or in conjunction with other dietary interventions [2]. Fasting, in general, has been rated since the 1960s as a successful strategy to treat obesity and comorbidities, with additional benefits of fasting other than weight loss having been recently uncovered [3]. IF has gained significant public notoriety in recent years thanks to the media; however, it is important to note that it has been performed for several thousand years for health and religious reasons, such as, for example, during the month of Ramadan [4]. Previous studies on fasting have shown generally positive effects on health; however, the benefits and challenges, mainly acceptance and compliance, of a long-term fasting eating behavior still require further research. IF can well fit in everyday life and may be possibly adopted as a lifelong eating behavior [3].
The leading cause of death in developed countries is obesity, and it will soon surpass tobacco-related deaths. As the WHO states, obesity has tripled worldwide since 1975, affecting 13% of the entire adult population in 2016. A new analysis of the body mass index (BMI) of the United States indicated that by 2030, one in two adults will be obese. At the same time that there is an increase in the prevalence of obesity, there is also a prevalence of other chronic diseases, such as cardiovascular diseases and type 2 diabetes [2][4][5]. Currently, more than 90% of people have type 2 diabetes are overweight or obese. It has been proven that a series of modifiable risk factors favor these pathologies, among which are excessive nutrition and sedentary lifestyle. Physiologically, excessive energy intake increases circulating glucose levels and free fatty acids, thus promoting oxidative stress in skeletal muscle, adipocytes, pancreatic β cells, and hepatocytes, modifying the signal transduction of insulin receptors. It decreases the absorption of glucose in the cells by not being able to take advantage of the glucose; there is an increase in liver glycogenolysis and lipolysis of fat tissue, which counteract the effects of insulin. Adipocytes have a restricted capacity to store excess free fatty acids in plasma, which results in the ectopic deposition of fat in the liver, skeletal muscle, or cardiac muscles, contributing to insulin resistance in these tissues. As diabetes progresses, lipotoxicity and oxidative stress limit the secretory function of β cells and promote their apoptosis, leading to insulin deficiency and consequent hyperglycemia [4]. A key component in reversing these metabolic consequences is weight loss. Established dietary interventions to achieve and maintain a 5% weight loss can improve glycemic control and limit the need for glucose-lowering medications in patients with type 2 diabetes who are overweight or obese [6]. Reducing calories is the key to successful weight loss and improved glycemic control [2], raising discrepancies in the scientific literature on what role intermittent fasting has and whether it can be superior to continuous energy restriction in improving lean body mass retention during weight loss. Today, with the prevalence of type 2 diabetes and obesity increasing worldwide, it is essential that physicians and dietitians know whether IF is a feasible dietary therapy for weight loss in patients with these conditions [4][7][8].
Among the diseases studied in relation to intermittent fasting, we find multiple sclerosis (MS), which is defined as an inflammatory demyelinating disease of the central nervous system characterized by different degrees of damage to axons and neurons, supposedly caused by autoimmune mechanisms. MS affects 2.5 million people worldwide, with a significant personal and socio-economic burden. Clinically, MS can be relapsing-remitting or present a progressive course characterized by accumulation of neurological disability with or without superimposed relapsing activity. The development of the disease is not fully explained by genetic risk factors. Environmental factors, such as some infections, low vitamin D levels, smoking, and obesity, have been linked to an increased risk of MS. Experimental autoimmune encephalomyelitis (EAE) is an animal type of MS that has been essential in the development of various treatments for MS [9]. MS is more common in western countries. Eating habits have been considered as a potential factor that helps the epidemiology of MS. There is an added connection between nutrition and immune-inflammatory responses that is the gut microbiome, where diet plays a critical role. Commensal bacteria found in the gut and their metabolites possess the ability to exert both pro-inflammatory and anti-inflammatory responses by controlling T-cell differentiation and immune responses in the gut. After all, this can have systemic effects and lead to or protect against autoimmune diseases even in the EAE type. The intestinal microbiome in patients with relapsing-remitting MS is modified unlike what happens in healthy controls. At the same time, calorie restriction has powerful anti-inflammatory effects. IF is shown to be a protective factor in the animal model of MS through effects on the intestinal microbiota, with similar changes observed in patients with relapsing MS undergoing short-term IF [9].

2. Benefits

Both IF and short-term calorie-restricted diets produce similar weight loss in people with obesity and people with type 2 diabetes [10][11][12]. There are few long-term clinical trials, but these have revealed the superiority of IF over caloric restriction in reducing waist circumference and central fat distribution, both of which are beneficial since these parameters are important in reducing cardiovascular risk [13][14][10][15][16][17][18][12]. More long-term studies should be carried out to see how IF affects both obesity and type 2 diabetes [2][13]. Likewise, IF has benefits in slowing the development of atherosclerosis since it inhibits the development of atherosclerotic plaques by reducing the concentrations of inflammatory markers, such as IL-6, homocysteine, and C-reactive protein [19][20]. Some adverse effects of fasting are headaches, which are helped by water intake, bad mood, slight dizziness, and fatigue [16][19].
IF has an important role in the regulation of the levels of different proteins, such as apolipoprotein A4 (APOA4). High levels of APOA4 have been associated with many beneficial phenotypes, such as the promotion of reverse cholesterol transport, increased satiety, and decreased oxidation of LDL-cholesterol particles. IF also has a combined regulatory effect that increases triglyceride lipolysis in chylomicrons and increases the production of mature spherical HDL-cholesterol particles [21][22], thus producing a significant decrease in total triglyceride levels in plasma after a period of IF. However, no significant differences were observed in HDL-cholesterol levels after IF, suggesting more trials with more participants are needed to validate these findings [13][23][24]. In another trial of early time-restricted feeding (eTRF), both LDL-cholesterol and HDL-cholesterol increased in the morning, which can be attributed to the period of prolonged fasting. The metabolism of these people had a greater dependence on fat oxidation [21][25].
Time-restricted feeding (TRF), which is a new form of IF that improves cardiometabolic health, might slow tumor progression, delay ageing, and increase life expectancy in rodents. Pilot studies in humans similarly suggest that TRF improves clinical outcomes, such as body weight, blood pressure, and insulin sensitivity [8][13][14][26][27][10][22][28][19][29], at least when food intake is limited to the beginning or to the middle of the day [21][22]. These effects related to the time of day can be explained by the circadian system, since eating in accordance with the circadian rhythms of our metabolism can have benefits on cardiometabolic health [27][21][29][20]. One clinical trial found that eTRF decreased fasting glucose and insulin levels in the morning, increased fasting insulin at night, and decreased 24-h blood glucose peaks. The decrease in the 24-h glucose peak was unexpected since the maximum level of postprandial glucose was expected to be higher in the eTRF group; the meals had been consumed in a short time. A possible explanation for this decrease was found, especially at lunchtime: it was possible that circulating insulin was still elevated because breakfast had been eaten relatively recently and was still being digested. For this reason, it was not necessary for pancreatic β cells to be activated again to secrete insulin, which resulted in a smaller plasma glucose peak. This relationship of condensing meals to within a shorter stretch of each day is beneficial to the control of 24-h blood glucose levels regardless of the circadian rhythm. This is evidence that should be further investigated in future clinical trials since it could be very effective at controlling 24-h blood glucose levels [27][10][21]. In contrast, IF in this situation would be less effective for the control of 24-h blood glucose since the periods of time between meals are longer. However, IF is not the same as a lower frequency of meals; the relationship between both variables should be studied in greater depth in the future [21].
It has also been observed that eTRF increased β-hydroxybutyrate in the morning in relation to the control diet, which demonstrated that even in short periods of fasting, circulating ketones can be moderately increased [8][14][21]. High levels of ketones reduce oxidative stress [8][26][21], preserve lean mass [28][19], and have other metabolic effects, such as decreased hunger. It has been suggested in previous studies that eTRF may increase amplitude of the cortisol rhythm, providing a mechanism through which meal timing may impact the circadian system [21]. Hormones and genes related to longevity and autophagy, such as brain-derived neurotrophic factor (BDNF), sirtuin 1 (SIRT1), and LC3A, have also been shown to be favorably affected during a period of eTRF [21]. These important findings suggested that eTRF could perhaps positively influence cardiometabolic health, may impact the central circadian rhythms, and may have antiaging effects [21][30].
In rodents, IF has a positive impact on adult hippocampal neurogenesis (AHN). IF cannot only improve AHN in healthy mice but also protect against neuronal loss caused by excitotoxic damage in the hippocampus, with a greater survival of neurons than observed in mice fed ad libitum. IF attenuates the decrease in locomotion related to age and disease and the decrease in exploratory behavior and memory retention in mouse models of Alzheimer’s disease, which also demonstrates neuroprotective benefits [22]. Energy restriction can affect the expression of genes involved in neurogenesis and increase the proliferation of neural cells. Low-energy diets during adolescence increase cell proliferation and the number of neurons in the hippocampus and can result in better cognition in adulthood. The restriction of energy intake and not the composition of the diet is important for preventing learning and memory deficits. More human trials should be performed to clarify these results.
IF has neuroprotective and anti-inflammatory effects, which were demonstrated in animal models of stroke and systemic infection as well as in humans with systemic inflammatory conditions. However, few trials have confirmed the effects of IF on immune function or autoimmune diseases such as multiple sclerosis. In mice, IF reduces inflammation, demyelination, and axonal damage in EAE. The immune cells of the peripheral lymph nodes reduce the antigen-specific immune responses and the production of proinflammatory cytokines [9]. Microbiota transplantation from mice that underwent IF to immunized recipient mice produced a reduction in the proliferation of myelin antigen-specific lymphocytes and in the severity of EAE in recipient mice fed a standard diet. These findings lead us to believe that the modifications produced by IF have a beneficial effect on the intestinal microbiome of mice, since they can intercede in the systemic immunomodulatory response to myelin antigens in vivo [9]. In another study on mice, IF delayed the onset of disease, led to a lower severity of the disease, and promoted a decrease in the important markers of inflammation and metabolic hormones, such as leptin [17].
Given this, it could be speculated that since IF may produce an increase in bacterial richness and is also associated with a decrease leptin, bacterial richness and circulating levels of leptin could be negatively correlated. These data confirm what has already been observed in other studies: lower richness of the intestinal microbiota is associated with higher serum levels of leptin and lower levels of adiponectin, in accordance with a systemic proinflammatory phenotype. IF has a surprising effect on the composition of the intestinal microbiota, with the enrichment of the Bacteroidaceae, Lactobacillaceae, and Prevotellaceae families. In EAE, changes in the intestinal microbiota or its metabolites can modulate inflammation and demyelination. Of special importance was the abundance of lactobacilli caused by intermittent fasting, which are commonly used as probiotics given their positive effects, including a decrease in inflammatory immune responses [9]. Together, the above findings demonstrate beneficial changes in the metabolism and in the intestinal microbiome of mice and humans with multiple sclerosis who intermittently fast [9]. The human studies have had limitations, such as the sample size or the short experimental period. For this reason, IF should continue to be studied in more patients over longer periods to corroborate what has been observed thus far [9].
Trials in healthy men and patients with multiple sclerosis have shown that IF can significantly improve depression scores, suggesting an “antidepressant-like” effect, potentially through upregulation of AHN, which has an important role in mood modulation [22][17].

3. Conclusions

IF shows a superior effect to diets with caloric restriction with respect to waist circumference and central fat distribution, and appears beneficial in reducing cardiovascular risk in people with obesity or diabetes mellitus. IF is identified as having an important role in regulating the levels of different proteins of lipid metabolism. Likewise, it increases triglyceride lipolysis in chylomicrons and increases the production of HDL-cholesterol particles, and this causes the levels of total triglycerides in plasma to decrease significantly. eTRF is beneficial for the 24-h control of glycemic levels of people with diabetes. It also increases β-hydroxybutyrate, which causes ketone levels to rise, and oxidative stress is reduced, lean mass is preserved, and the feeling of hunger decreases. Additionally, IF modifies the composition of the intestinal microbiota, enriching the Bacteroidaceae, Lactobacillaceae, and Prevotellaceae families. The abundance of lactobacilli brought about by IF has positive effects, such as lowering inflammatory immune responses, helping to treat people with MS.

This entry is adapted from the peer-reviewed paper 10.3390/nu13093179

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