FASTING TECHNIQUES – CHANGING THE WAY, YOU LOOK AT THERAPY

At present, various complications such as diabetes, cardiovascular diseases, cancer, and neurological disorders have become treatable, almost completely, but the drugs used for the treatment may cause some severe side effects such as hypoglycemia, kidney complications, diarrhea, anemia, rashes, dyskinesia, insomnia, hypotension, confusion, hallucinations, compulsive behavior, and neurological complications. Some treatments cause defects in whole organ systems including damage to the immune system, lungs, heart, nerve endings, and reproductive organs. Many treatment approaches are using non-pharmacological techniques for treating diseases, without synthetic drugs. One such technique is fasting, a process where starvation conditions are imitated voluntarily. Intermittent fasting is done in ratios of fasting and food intake, where a person deprives himself of food for 16 h and food intake is followed for the rest of 8 h. Alternate day fasting includes alternate days of food intake and fasting. Time-restricted feeding is done by allowing food consumption only during the metabolically active phase of the day. Fasting mimicking diet is done by reducing food intake to very small levels which mimics the conditions of fasting. Reported beneficial effects of fasting have been found in diseases such as cancer, blood pressure disorders, autoimmune diseases, fibrosis, inflammation, insulin sensitivity, and oxidative stress.


INTRODUCTION
In this fast-paced scientific world of today, there has been development and innovation of unimaginable scale. In the field of medical sciences, such developments have found a complete cure for many untreatable diseases; using medicines are researched on with great detail. Today, there is hardly any medical complication that cannot be treated, at least to some extent. However, with great innovations come great risks and the same has been happening all over the world. The techniques, the drugs, the chemicals, etc., even though they are highly effective, come with a lot of side effects, adverse effects, other related complications, and even creating unimaginably painful situations which sometimes even lead to death.
The human body is very complex, and hence there is a whole dimension of problems related to it. However, as a matter of fact, it has defense mechanisms to treat, cure, and prevent itself from almost all such problems. We ignore this fact and force our approach of treatment through the unnatural ways of drugs and other such treatment approaches such as laser therapy, and radiation therapy. We do not allow our bodies to use their defense mechanisms. One such mechanism is "Fasting." It is a process where starvation conditions are imitated voluntarily. Fasting is something that has its roots in every culture, every religion, every country, and almost every human being has practiced fasting in one or the other way, at some point in their life.
In a natural process, all cells are programmed to act in a certain way but under various types of stress conditions they tend to change and defend themselves against that stress, fasting is one such stress (Fig. 1). It has been seen that fasting has beneficial effects on the health of an individual and also during medical complications. This review is all about the beneficial effects of fasting on the health of an individual by acting on various organs, organ systems, tissues, and even at the cellular level. Fasting, when done in a calculated and well-monitored way, has tremendous effects on health. The solutions to the most complex problems are always the simplest ones.
Fasting is classified based on the various parameters such as the period of food deprivation, and the amount of food intake.

IF
IF is the most widely followed type of fasting and it has many subtypes in itself. IF is done in ratios of fasting and food intake like 16:8 where a person deprives himself of food for 16 h and food intake is followed for the rest 8 h of the day. Sometimes the 16 h of fasting are followed overnight or throughout the day [1]. Sometimes the IF can go up to 48 h long fasting time and a smaller period of normal food intake. It was seen that the animals tend to eat more in the food intake hours and hence maintain normal body weight as they are ingesting a similar amount of food as of the ones kept without fasting. IF also has an effect on increasing growth hormone levels if followed compliantly for long periods of time but at the same time it has been seen to have side effects, chronic IF of more than 4-5 months is not suggested [2,3].
In a few studies, done on rats it has been observed that IF results in reduced myocardial damage due to ischemia. A study was done, where myocardial infarction (MI) was induced by coronary artery ligation, there was a significant reduction in the damage due to ischemic injury. A two-fold reduction in MI size and a four-fold reduction in apoptotic myocytes were observed in the intermittent fasted group when compared with the control group. Left ventricular remodeling and MI expansion were seen in the control animal but it was totally absent in the intermittently fasted animals after 10 weeks of induction of MI. They also observed better left ventricular function and no MI expansion in a subgroup at the 1-week period from the induction of MI [1,4].
The mechanism of IF in cardio-protection is largely unknown but few assumptions were made about the mechanism that includeinvolvement of reduced free radical production and improvement in the cellular stress response, focusing on the fact that IF is similar to a mild stress given repeatedly on an everyday basis, hence inducing expression of genes that enhance the ability of the cells to protect themselves in situations with higher stress conditions like that of MI [5]. This assumption was supported with few pieces of evidence like IF initiated induction of the expression of protein chaperones, like glucose-regulated protein-78, and the heat shock protein-70 with few growth factors [6]. Caloric restrictions and various types of fasting techniques help in conditions such as obesity, high blood pressure (BP), and high lipid levels which eventually contribute to complications such as MI and eventually lead to cardiac heart failure [4,7].
IF has beneficial effects in high-fat diet animals such as they increase the metabolic rate and energy intake in such animals, which shows that it also reduces fat due to high energy intake for weight loss programs [8,9]. It reduces body weight and reduces fat pads in the gonadal and inguinal areas of the experimental animals. Furthermore, in a study, it showed to have altered the renin-angiotensin-aldosterone system and hence, exerted beneficial metabolic effects on BP and cardiac structure on high fat-fed or high fructose-fed mice heart [10,11].

ADF
Alternative day fasting technique is alternate days of fasting with alternate days of food intake. i.e., 24 h of fasting and the next 24 h of food availability. Sometimes, this technique is confused with IF, and it actually is a type of IF but due to a 24:24 ratio, it has been named ADF [12,2]. ADF has been seen to have good therapeutic results in cardioprotection, reduced metabolic risk factors, cardiovascular diseases, and mostly age-related complications [13,4].
In 2009, few scientists in Italy studied the effect of ADF on rat heart. The ADF gave significant protection to the heart from age-induced inflammation and fibrosis. The age-related oxidative damage was demonstrated by increased HNE content and protein carbonyl levels, this was accompanied by a decrease in reduced glutathione (GSH), increased oxidized GSH [GSSG], and decreased GSH/GSSG ratio [14]. The above said changes were restored almost entirely by ADF, as the levels were brought to the levels very similar to that of animals as young as 6 months of age [15,16].
There was a significant increase in tumor growth factor-(TGF)-β1 and interstitial collagen deposits at animals aged around 24 months. After the ADF regimen, the animals showed reduced levels of TGF-β1, close to that of 12 months aged animals and the collagen deposit levels were lowered even further to the levels of 6-month animals. Interleukin (IL-6), IL-1β, and tumor necrosis factor (TNF)-α, the pro-inflammatory cytokines were also examined to compare the inflammatory parameters as their levels also change significantly on aging. TNF-α and IL-6 levels were seen at increased levels at 12 months of age, while IL-1β was seen to have increased levels only at 24 months of age. ADF showed protection against this increase, it was seen more effectively for TNF-α and IL-6 as it went down to levels close to 6-month aged animals and IL-1β was reduced close to the young levels too [17,18]. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that has a great role in the transcription of deoxyribonucleic acid (DNA) and cytokine production. This factor is sensitive to stress conditions, cytokines, free radicals, etc., and functions greatly in cell survival. Hence, this factor was also considered for this study and it was found that there was a marked age-related increase in the DNA binding activity of this factor in the heart, starting at age 12 months itself. Although ADF nullified the symptoms of the diseases but also showed synergist action with the therapeutic drugs in the treatment of diseases [16]. Now this, fasting technique can be followed acutely for a short period of time like few days, a week or it can be continued for long periods like months together, then it is called chronic ADF. In a study, they specifically showed that the effect of alternate-day fasting in agerelated complications such as fibrosis and age-induced inflammation and very good results was obtained the fasting almost nullified the harmful effects of age on the heart of rats [19,16].

Time-restricted feeding (TRF)
Time restriction feeding is a form of fasting where food consumption is followed only during the metabolically active phase of the day. This sort of diet leads to better metabolic parameters when a high-fat diet is being followed [20]. This type of fasting helps to reduce maternal

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high fat diet-associated inflammation and hence also in reducing fetal birth defects [21,22].
This type of fasting has a special type of beneficial effect. Time being a factor in this process leads to treating conditions related to biological clock defects [23]. Circadian rhythm impairment can cause serious metabolic complications such as obesity and other metabolic diseases [24]. In such situations, when time-restricted feeding is provided, i.e., food available only during 10 h of the dark phase, then it showed reduction in the complications due to circadian rhythm impairment [25,26]. Even in case of skin complications caused by skin circadian clock defect, it was seen to alter the ultraviolet-B induced DNA damage [23,27,28].
TRF has been observed to have an improved effect on insulin sensitivity, β cell responsiveness, BP, oxidative stress, and appetite when followed during the healthy state [29,20]. TRF even influences the immune response without causing any damage to the muscle performance [30,31].

DR
This is a type of restriction where the food intake or specific components in food are restricted or reduced for short or long periods [32]. Those components comprise the major dietary constituents such as proteins, lipids, and carbohydrates. This type of restriction is used in experimental animals such as rodents for protection against age-related complications, cancer incidence, and other medical complications such as atherosclerosis, inflammatory conditions, Alzheimer's disease, tumors, and other chronic degenerative diseases. [33,34].
Some studies have even shown attenuation of infection by DR, in the same study they also observed that DR can cause alteration in insulinlike signaling and also help in increasing life span [35].
In a different study done on C57BL/6 mice, where the animals were kept on DR and the results obtained showed that IF caused an increased insulin sensitivity, stress resistance, reduced morbidity, and increased life span. The mechanism for the treatment of various diseases by fasting technique methods are not clearly known, but hypothesis says that long term reduction in food intake/calorie intake is essential for more effective treatment [36,37]. When the mice were kept for IF/ADF their total food intake when compared to the ad libitum (AL) fed animals the same as that of the AL fed mice [38]. This shows that when the DR mice were allowed free access to the food then they ate almost twice the amount of food than the AL fed mice. Hence, the calorie intake was almost the same for both mice groups and hence even their body weight change was not that much. DR fasting though showed more benefits than the caloric restriction group [39,40].
The overall conclusion was that DR fasting has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake [38].

FMD
This type of fasting usually lasts for short periods of time, here instead of actually abstaining from food, the food intake is reduced to very small levels which mimics the conditions of fasting but does not abstain the body completely from the food intake hence prevents some side effects which can be caused due to prolonged effects of strict fasting [8,41]. This type of mimicking diet has shown the effects of enhancing the microbiota growth in the intestine, which reduces the pathology of irritable bowel disease greatly [42].
FMD and a special type of nutrition could be used for treating autoimmune diseases and immunosenescence, i.e., natural deterioration of the immune system brought on by normal aging process [43]. FMD in mice during an experiment showed induction of stepwise expression of Sox17 and Pdx-1, followed by the Ngn3-driven generation of insulinproducing β cells which reversed the diabetic effects. Hence, we can conclude that the FMD is not only beneficial for inflammatory bowel disease but also diabetes [44,45].

CR
This is a type of fasting where the total number of calorie intake is reduced significantly to a specific calculated level [46]. This type of fasting is followed widely for weight loss and other physical fitness applications. Here, the food is taken time but the quantity of food is restricted to a calculated level and that level is not exceeded in a day, more than its limit [47,48]. CR on experimental animals was shown to increase the life span of the animals and also showed increased insulinlike growth factor (IGF)-1 levels [19,49].
Oxidative stress in any organism leads to hypertrophy of the heart and hence leading to heart failure [50]. Cardiac tissues respond to different types of stresses and hence get hypertrophied in the presence of oxidative stress [51]. However, when caloric restriction is followed it prevents the production of the reactive oxygen species and maintains enzymatic antioxidant activity [52]. Hypertrophy was seen to get reduced significantly after caloric restriction. In the process of reducing hypertrophy, a mechanism involving the activation of mitochondrial adenosine tri phosphate sensitive K + channel was involved [53,54]. Caloric restriction not only has its effects on cardioprotection and IGF-1 levels but also on psychological complications. In a study caloric restriction was seen to prevents stress-related anxiety and despair [55].
Fasting causes changes in the fundamental processes and hence has an effect on almost all body organ systems. Glucose metabolism and glucose homeostasis are also affected by various types of fasting. In a study, fasting was carried out in streptozotocin (STZ)-induced diabetic rats, the effect of the fasting was measured by the individual β-cell area and individual islet areas. Parameters such as pancreas weight, β-cell mass, apoptotic β-cells, plasma D-glucose, plasma insulin, and other tests including the intra-peritoneal glucose tolerance test (IPGTT) were considered to analyze the effects of fasting [56]. Many methods were totally followed in the study including STZ-Induced diabetes, starvation, and restricted food supply, body weight and food intake, IPGTT, insulin secretion (in-vitro), immunohistochemical study, β-cell mass assessment, glucagon immunodetection, and apoptosis detection. It was observed that IF showed significant improvement in glucose tolerance, increased plasma insulin, and lowered the homeostasis model assessment index [57].
In this same study, the data were compared between intermittently fasted animals (IF), caloric restriction (CR), and non-fasted animals (NF) without any fasting. Two major groups were made, one being the control group the other being the STZ group. The subgroups were NF, IF, and CR sub-groups. It was seen that the improvement and changes that IF showed were not observed in the case of caloric restriction [57]. An assumption can be made from this observation, that fasting does more to an organism than just starvation. Fasting needs prolonged and strict food restriction during fasting hours. Moreover, if not completely, IF can still cause significantly large prevention to the glucose homeostasis disturbances.

LDF
This type of CR technique focuses on the feeding time; hence, the feeding time or food availability hours are taken into consideration for the fasting. Hence, the food is made available for a few hours or for some times when the animals are allowed to ingest food [36]. The rest of the hours they will be left for fasting, here no specific ratio is followed. Limited daily feeding usually has significant effects on physiological parameters such as body temperature, heart rate, BP, and decreased glucose and insulin levels [58].
Limited daily feeding was seen to have a significant effect on the brain and its activity. The effect is different in different parts of the brain it was shown to reduce the glucose transporter type 3 (GLUT 3) levels in the cortex region while no effect on the hippocampus region [59]. LDF

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in young rats showed decreasing levels of GLUT 3 but increasing levels of GLUT 3 in the aged animal. It was also seen to reduce lathosterol levels on the hippocampus and in the cortex, but only in the young animals [60,61]. This study suggested that age is a major factor when taking fasting into consideration. Fasting has different effects on different body parts comprising of similar cells, at different ages [62,63].

Effects of fasting on cancer
One of the major effects of fasting was seen against cancer. Few studies point toward the effect of CR type of fasting in having multiple significant effects in cancer-induced animals and tumor cell lines of various types [64,65]. It was seen that animals kept under restricted calorie intake, were more protected differentially against tumor growth [66,67]. It was also seen to have increased chemotherapeutic index for the anticancer drugs hence a huge possibility of increased potency and hence reduced dose was observed [68,69].
The growth hormone and the IGF-1 axis undergo significant changes when an organism stays in starvation conditions [70]. Growth hormones directly regulate IGF-1 production. Animals deficient in IGF-1 signaling have been seen to have much longer lives [68,71].
Under normal circumstances, the organism tends to utilize the gained energy for the growth of the organism. However, under stress conditions like fasting they shift the energy utilization from growth to maintenance and hence on the cost of growing the protection of the animals is achieved [72]. Normal cells hence tend to seize their growth under starvation conditions. On the contrary, the cancer cells which are self-sufficient in growth signals, do not get affected much on starvation, as they lack growth-inhibitory signals [73,74]. This type of environment change leads to better protection and increased permeability of healthy cells to chemo toxic agents. Cancer cells undergo no such phenomena and hence are more prone to chemotoxicity and hence partial or differential protection and resistance to chemo toxic agents is achieved leading to protection of healthy cells and hence more toxicity on the tumor cells thereby causing death to them [75,76]. This type of protection toward chemotoxicity is achieved by a phenomenon called differential stress resistance achieved by healthy cells and differential stress sensitization of cancer cells. One of the mechanisms for this differential chemotherapy protection is due to the reduction in the production of IFG-1 caused by starvation [77,78].
In a study, ADF was seen to increase the life span of rats inoculated with ascitic tumor cells, there was a 45% increase in survival after the animals were kept on fasting on alternate days than the animals who had food ad libitum.
Another study conducted on colon cancer showed that fasting leads to the induction of autophagy in colon cancer cells and also downregulates the adenosine levels which in return increases the M2 polarization of the tumor associated macrophages through the pathway involving JAK/STAT3. All of this leads to tumor growth suppression while stimulating antitumor immunity.
Side effects due to chemotherapy drugs are a major issue in the case of cancer treatment. Nausea and vomiting are a few of the most uncomfortable side effects caused by many anti-cancer drugs. In a study, doxorubicin related nausea and vomiting were used as a parameter to check for efficacy of fasting in controlling side effects from chemotherapeutic toxicity. Dogs were given doxorubicin treatment and were kept under fasting conditions. There was a reduction from 67% to 10% in the incidence of vomiting when the animals were kept under fasting conditions. Such significant data show that fasting not only increases the chemotherapeutic efficacy of the chemotherapeutic agent but also reduces the side effects caused by the drugs itself [79][80][81].

CONCLUSIONS AND SCOPE
Scientific development does not always have to be for increased use of technology but it could also be used for the reduction of its usage. Various types of fasting techniques with their duration of fasting and feeding in some of the diseases are shown in Table 1. Natural ways of treatment and prevention should be the first choice of treatment as they include no side effects, least cost, and possibly a complete cure. Technology and nature could be used in such a synchrony that the synergism of both of them gives us a side effects free, highly efficacious, Fasting is one such method that is easy and effective. Every household already follows this technique once in a while for various reasons. Now it is time to use it clinically for treatment, prevention, and management of highly dangerous diseases. When even a disease like cancer could be prevented and managed with such easy techniques then there leaves no room for the use of highly toxic and costly chemotherapy which is almost not affordable by many people. There is still a lot of space to do research in this field. Fasting techniques could also be used in various patterns to influence medical complications and hence there is still a lot of scopes left for further research in this field.

AUTHOR'S CONTRIBUTION
Collection of articles, studying the materials and preparation of this review was done by the first author. The second author reviewed the draft copy and made appropriate changes as required to form the final review paper.

CONFLICTS OF INTEREST
There were no conflicts of interest for this review paper.

AUTHOR'S FUNDING
There was no funding for this study. Minor expenses were done by the author themselves.