Time-Restricted Feeding and Intermittent Fasting as Preventive Therapeutics: A Systematic Review of the Literature

Multiple studies have shown that intermittent fasting (IF) is associated with better health conditions and longer lifespans, as is time-restricted feeding (TRF). One crucial explanation is that IF and TRF permit a set length of time for caloric ingestion, during which our systems activate a variety of mechanisms that lead to the enhancement and renewal of different body systems. Accordingly, the benefits of IF and TRF are a lot greater than those of complete calorie restriction (CR). Accordingly, TRF and IF offered the underpinnings for human studies that revealed that when we eat and when we are fasting, we experience fluctuations in all body systems. For relevant medical literature, we investigated medical databases such as PubMed/Medline, PubMed Central, Cochrane Library, and Google Scholar. The chosen articles were evaluated based on eligibility criteria and vetted by quality evaluation methods; 15 finished research papers were included in the study. Of the 15 recognized studies, four were systematic reviews of literature, and 11 were review articles. The chosen publications all examined the efficacy and comparability with other restrictive diets. The study articles indicated that the advantages of IF and TRF represent complex interplay involving periodic digestion of food, gut flora, and the circadian clock. Accordingly, further research is necessary to get a comprehensive grasp of this very complex molecular blueprint. This could aid in producing an effectively planned food treatment that can regulate numerous chronic health ailments and disorders. Furthermore, it might lead to the development and investigation of new pharmacological medicines that mimic the nutritional and therapeutic benefits of IF for those who are unwilling or unable to follow this kind of feeding regimen.


Introduction And Background
Diverse intermittent fasting (IF) patterns have been studied in human and animal studies. This showed benefits for a variety of conditions, including glucose tolerance, obesity, cardiac conditions, liver alterations, dyslipidemia, and neurologic diseases [1]. All types of IF seem to be potential feeding choices for the treatment of numerous disorders impacting health and well-being. One of the explanations for IF's compatibility with human food patterns may be derived from historical studies of human dietary behaviors. Humans, like other animals, originated in habitats where food was limited, and as a result, they established feeding-fasting cycles dependent on food availability [1]. From a molecular perspective, IF may exert its benefits through a variety of mechanisms, such as reducing oxidative stress, optimizing circadian rhythms, and ketogenesis [2]. Meta-analytic studies may also have positive effects on body mass and adipose mass reduction [3].
In the United States alone, it is anticipated that the medical costs associated with overweight and obesity will exceed $90 billion. Reducing daily caloric consumption is the most frequently recommended method for promoting weight loss; current recommendations prescribe a combination of continuous energy restriction and a comprehensive change in lifestyle as the basis of obesity treatment [4]. Whereas cardiac mortality rates have improved, the drop in deaths has lately ended, and mortality among 35-to 64-year-old men and women in the United States has increased. Obesity and poor nutrition are significant modifiable factors contributing to the increase in cardiovascular disease, with an estimated 13% attributable risk of cardiovascular death [1][2][3]. Intermittent fasting is a dietary strategy that is comparable to calorie restriction (CR) in that it restricts food consumption. Intermittent fasting, on the other hand, focuses on the time when one may take meals within a day or a week. Alternate-day fasting and time-restricted fasting are the two broad categories of intermittent fasting. In alternate-day fasting, a subset may consist of 24-hour fasts followed by a 24-hour eating period that may be repeated multiple times per week, such as a 5:2 approach with two fast days and five nonrestrictive days. Variations for time-limited fast programs include 16-hour fasts with eight-hour meal schedules, 20-hour fasts with four-hour eating times, and other similar forms. While both calorie restriction and intermittent fasting may result in an overall lower caloric intake, intermittent fasting does not need this. In both people and animals, intermittent fasting has been associated with improved glucose management. Long-term adherence to calorie restriction, on the other hand, is poor, although intermittent fasting may be more promising [1,2]. Regardless of diet and macronutrient composition, CR adherence typically declines between one and four months [5].
An increase in the incidence of obesity, type II diabetes mellitus, and metabolic syndrome is linked to the excessive consumption of unhealthy foods such as high-fat, high-carbohydrate foods, and processed foods. IF increases lifespan and reduces the incidence of diseases associated with aging; some examples include overweight people, cardiovascular disease, cancer, renal conditions, and diabetes [1,3,6]. Aerobic exercise in conjunction with IF improved blood pressure lowering in individuals with limited medication response and has the potential to be introduced into regular therapy for these patients [4,6]. A randomized clinical study found that, compared to usual treatment, 12 weeks of moderate-intensity aerobic exercise training plus intermittent fasting (IF) lowered 24-hour systolic blood pressure by 7.1 mm Hg in people with resistant hypertension. Daytime blood pressure (systolic, 8.4 mm Hg; diastolic, 5.7 mm Hg), 24-hour diastolic blood pressure (5.1 mm Hg), and office systolic blood pressure (10.0 mm Hg) were all considerably lower following exercise training compared to standard care [2,3,6]. IF is associated with significant body fat reduction that leads to weight loss over approximately eight to twelve weeks, along with the management of lipid problems, alterations in body composition, and hypertension [6].

Review Methodology
We did a systematic evaluation using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines to describe our approach and results.

Study Duration
This review started on June 10th, 2023.

Eligibility Criteria and Study Selection
To assess eligibility, two investigators carefully read the full title and content of each paper. We selected the latest literature and articles published in the past five years, including papers written in the English language or if a full free-text English-language translation is available. Articles were excluded if the full free text of the papers could not be retrieved. Articles focusing on the different diets used as optional therapeutics for inflammatory bowel disease (IBD) gray literature and proposal papers were also not included.

Data Management
Two independent writers evaluated papers based on titles and abstracts. Following that, significant abstracts were examined for a complete, free full-text examination. The selected studies were evaluated, and if there was any dispute, the research was evaluated by a third author. Information from the relevant publications was then collected. The first author's name, type, year of publication, study design, and results were taken as priorities. Finally, duplicates were deleted.

Quality Assessment
We used the assessment of multiple systematic reviews (AMSTAR) quality tool for systematic review literature and the scale for the assessment of narrative review articles (SANRA) quality tool for literature review (LR).

Search Results
A total of 21,708 studies were found after searching the aforementioned databases; 20,152 were marked as ineligible by an automation tool. There were a total of 1,556 studies that underwent a selection by title and abstract screening, with 1,387 papers being discarded. The remaining 169 papers were chosen by full-free text evaluation in the previous two years, and after discarding duplicates, resulting in the elimination of 154 studies, only 15 studies were enlisted for the final collection of data ( Figure 1).  lipoprotein; SANRA: scale for the assessment of narrative review articles; AMSTAR: assessment of multiple systematic reviews.

Discussion
According to Jebeile et al.'s LR, numerous studies have shown that IF is a beneficial and manageable strategy for obese individuals, particularly obese adolescents [16]. CR has been a key treatment modality for obesity for a long time; recently, IF has been considered an alternative dietary approach to CR; people who practice IF say that doing this is easier than CR [7].
Santos et al.'s thorough review and meta-analysis indicated that IF is a helpful lifestyle change because it enhances the lipid profile and reduces body weight [17]. According to research, eight consecutive weeks of ADF led to a 6.8% decrease in blood glucose levels after fasting and a 22% decrease in insulin concentrations in obese individuals [11]. Due to the depletion of liver glycogen stores during fasting, ADF increases blood lipid levels while decreasing body mass and body weight; triglyceride levels suggest that free fatty acids circulate into liver cells to produce ketone energy [18]. Additionally, a significant reduction in insulin levels was noticed in both groups [21].
Harvie et al.'s LR revealed that both diastolic and systolic blood pressure decreased after twenty-four to forty weeks of intervention with a 5:2 IF, and the reductions were comparable to those of CR [22]. In two studies, LDL cholesterol and triglyceride rates improved over time [21]. According to a meta-analysis conducted by Morales-Suarez-Varela et al., IF and short-term CR diets had almost the same outcome in weight loss in adults with obesity and individuals with type 2 diabetes [12]. There are few long-term clinical studies, but these have demonstrated that IF is preferable to CR in reducing waist measures and central fat distribution, but both are still important for reducing cardiovascular risk [21]. An LR conducted by de Cabo et al. demonstrated that prolonging the time expended in the fasting state enhances metabolic homeostasis and protects against cardiovascular, neoplastic, and neurodegenerative conditions in humans [23]. A threemonth study comparing daily CR versus IF (5:2 dietary regimen) in obese women aged 20 to 69 revealed that while both resulted in a significant reduction in body weight, the 5:2 diet resulted in a greater reduction in body fat percentages and a boost in insulin sensitivity [24].
In a randomized controlled trial, Welton et al. found that IF is a moderately effective method for weight loss and has the potential to improve glycemic control. The majority of participants in these studies had type 2 diabetes [20,25]. In initial research conducted in 2016, Carter et al. compared two fasting days a week with an otherwise normal diet to daily calorie restriction, showing a reduction in body weight and body fat percentage in the two fasting day groups in comparison with the control group [25]. A 2013 review of the literature by Gasmi et al. found that fasting may be an option for reducing systemic low-grade inflammation and age-related degenerative diseases associated with immune senescence without impairing physical performance [26].

Conclusions
We may infer that IF and TRF can be utilized therapeutically and preventively after examining and choosing the most relevant information. However, because of the limited amount of research, it has been overestimated. IF and TRF may be utilized specifically in patients with T2DM and obesity; however, it is believed because of the idiosyncrasy of the mind when the phrase "do not eat for a certain time" is used, leading to the belief that it means "not having good health". Several of the investigated studies provide us with alternative viewpoints on how to target IF and TRF not only to reduce weight but also for a variety of other ailments such as cancer, immunological and gastroenterological diseases, and aging, among others. Even reading an article on the renowned Ramadan diet led to the conclusion that a short period of IF resulted in a change in the quality of life. However, IF and TRF have not been extensively researched in long-term trials to provide additional evidence for their dubious advantages. It highlights the need for further long-term research to establish the specificities of IF and TRF that may be used as preventative therapy regimens for a variety of illnesses in the future.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.