writing123edit123Preface:In evolution, the alternation of food availability and food Scarcity is the result of the seasonal cycle of sunshine changes. Before humans were able to effectively preserve food, physiological and behavioral adaptations to survive during periods of limited food have led to the development of metabolic fasting programs

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Preface:

In evolution, the alternation of food availability and food Scarcity is the result of the seasonal cycle of sunshine changes. Before humans were able to effectively preserve food, physiological and behavioral adaptations to survive during periods of limited food have led to the development of metabolic fasting programs.

Humans have also had to adapt to the natural cycle of food shortage for millions of years. Only with the emergence of agriculture in the Neolithic, can we have a more sustainable food supply. This has reached its peak in today's technology, allowing humans from privileged countries to access any type of food at any time of the year.

Extreme situations such as famine, chronic malnutrition, hunger strikes, or chronic anorexia also provide information on human capacity to cope with long-term food shortages.

In medicine, fasting for 2-21 days or longer is known for its numerous therapeutic effects, which has led to multidisciplinary fasting programs that are less well-known among the public and in the scientific community. At the beginning of the 20th century, a total of 31 days of safe fasting was scientifically recorded.

Later, in the 1960s, as obesity began to become a large-scale medical problem, water fasting emerged in the name of a zero calorie diet or complete fasting to treat morbid obesity and complications. The effect of fasting lasting for weeks or months, especially on obesity, has been widely documented.

Nowadays, people's interest in fasting has revived from a different perspective. The new focus is no longer solely on weight loss in morbid obesity, but rather on the effectiveness of the main fasting regimen.

This protocol activates the metabolic transition from glucose derived from the liver to ketones derived from adipocytes (G-to-K) and reverses K-to-G, affecting longevity, extended healthy lifespan, multiple stress resistance and antioxidant defense stimuli, improved performance, and cell regeneration in animal models and humans.

Fasting is defined as voluntary fasting or strict calorie restriction for a limited period of time, triggering significant changes in G-K conversion and signaling pathway activity. When the K-to-G conversion occurs, further effects also occur on the re feed.

When it comes to classifying fasting plans, the biggest challenge is that if we consider animals, such as non obese mice or humans, the duration has very different meanings. A day of fasting leaves mice almost in a state of hunger (reduced ketones and increased protein breakdown metabolism), while a human day is considered an intermittent fasting.

Table 1 summarizes the main forms of fasting and other restricted diets. Calories restriction (China Railway) refers to reducing daily calorie intake by 15-40% without malnutrition. Intermittent fasting (if) refers to a period of fasting between 16 and 48 hours, alternating with normal food intake.

Table 1

The most commonly studied IF program is fasting every other day (automatic direction finder), which means eating normally one day and limiting food the next day. The characteristic of limited time eating/feeding (TRE/TRF) is to consume food within 8-12 hours or less per day.

Periodic fasting describes the cycle of fasting or calorie restricted eating, which is a 5:2 diet (5:2), referring to two consecutive or discontinuous days per week, where food intake sharply decreases to about 600 kcal.

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During this period, provide food that does not contain or contains small amounts of calories within an appropriate schedule, with a maximum of 200 to 250 kcal per day. LF has been well documented in both obese and non obese subjects, as well as in animals.

Other options derived from fasting strategies are the Very Low Calorie Diet (VLCD), a low calorie formula diet that provides 80-100 grams of protein and an average of 1000 kcal/day, aimed at treating obesity and avoiding negative nitrogen balance.

In addition, the diet simulating fasting (family physician) is a low calorie (800-1100 kcal), low protein, Ketogenic diet, which can lead to weight loss and some effects of fasting.

It is worth mentioning that nutrition restricted normal calorie diet, such as Ketogenic diet (carbohydrate restriction) and protein or amino acid (methionine) restricted diet are also being evaluated.

1. Metabolic switch

The beginning of fasting is characterized by metabolic conversion, which defines the fuel conversion that occurs when an organism transitions from a feeding mode (usually including about 50% of carbohydrates) to a fasting mode. After interrupting food absorption for 12-16 hours, glucose levels decrease, followed by a decrease in insulin levels and a decrease in circulating amino acid levels.

Ketones are not only fuels, because they also have signaling effects and regulate the expression and activity of transcription factors. The increase of brain-derived Neurotrophin (BDNF) in the central nervous system (CNS) can enhance brain health.

Ketones are effectively oxidized by the fasted brain and are less willing to give up glucose and metabolize free fatty acids than other tissues. Compared to the eating state, the use of free fatty acids and ketones as energy sources reduces respiratory exchange rate (RER), indicating a higher metabolic efficiency of energy production during weight loss leading to ketosis.

The reduced ATP/AMP ratio will activate AMP activated protein kinase (AMPK) and produce mild oxidative stress leading to antioxidants and cell protective enzymes.

During prolonged fasting periods, ketosis has been shown to reach a plateau after 4 days, with this effect lasting for several hours or days and decreasing when food is reintroduced.

Figure 1: Induction of metabolic transition from carbohydrates to fatty acids and ketones through 10 days of fasting (consuming approximately 250 kcal of energy per day and multidisciplinary planning)

The conversion from G to K is a key mechanism for saving protein by reducing protein utilization, as reflected by changes in nitrogen balance [citation 41]. It is regulated by inhibiting the mTOR (mechanical/mammalian target of Sirolimus) signaling pathway, thereby reducing protein synthesis and enhancing autophagy, leading to the recycling of endogenous proteins.

Relying on ketones to provide energy during weight loss has the advantage of promoting lean weight maintenance; The same situation may not occur after regular CR. This conclusion has not been supported in the most extensive ADF research to date.

At present, the substantial benefits of fasting therapy for maintaining lean weight need to be reconsidered. Although adaptation to long-term fasting can promote the maintenance of lean weight, there is no clear evidence to suggest that this situation occurs first after IF rather than after CR.

It should be noted that low energy and/or high fat diets can also lead to ketosis. The strict high fat Ketogenic diet with normal calories was successfully used in epileptic children who did not respond to drug treatment.

The transition from a carbohydrate diet to a lipid rich diet has been successfully used for weight loss, although based on current evidence, low CHO and extremely low CHO diets do not seem to be significantly superior to other dietary methods. As an energy source, ketone is metabolized into Acetyl-CoA (AcCoA), enters the Citric acid cycle, and produces Adenosine triphosphate (ATP).

They maintain muscle and brain cell function during fasting and prolonged physical activity. In addition, ketosis leads to complete compensatory Acidosis, which is considered to be the reason why there is no sense of hunger during fasting.

Lack of hunger can improve compliance. Blood sugar stabilizes at a lower normal level and remains stable throughout the entire fasting period, as long as fat reserves can provide fuel for metabolism and protein stores remain at physiological limits.

At the same time, the hormone secretion of Glucagon increases (stimulating Glycogenolysis and Gluconeogenesis), growth hormone (involving lipolysis), cortisol and adrenaline regulate the fasting process. In addition, with the decrease of adipose factor leptin and the increase of Adiponectin, fasting significantly reduced Insulin-like growth factor (IGF) -1.

Only by limiting the normal daily energy demand to 50% or more can IGF-1 levels be reduced. Low levels of IGF-1 reduce intracellular Mitosis promoting signaling pathways, and lead mammalian cells to enter a non mitotic or hypomitotic state, and put energy resources into cell protection to resist various injuries (multiple stress resistance).

Because there is little or no foreign protein or sugar entering the system during fasting, nutrition dependent signal transduction pathways are closed [mTOR and Ras Adenylyl cyclase (AC) - protein kinase A (PKA)], and transcription factors such as SIRT and forkhead box O1 (FOXO1) are de inhibited, leading to many special features of the fasting mode.

The promotion of multiple stress resistance is characterized by increased antioxidant defense, increased DNA repair and reduced inflammation. In addition, most cardiovascular risk factors (waist circumference, blood lipids, blood pressure, and insulin resistance) are improved through CR, IF, or LF.

Once a mixed diet is reintroduced, the fasting pattern will be reversed, triggering the K-G transition: increased glucose and insulin levels, decreased ketones, reactivation of mTOR, resulting in increased protein synthesis and mitochondrial biosynthesis, as well as reduced autophagy. With the increase of mesenchymal cells and progenitor cells, cell regeneration occurs in multiple systems.

During this stage of re feeding, specific effects occur along with cell growth and plasticity, leading to functional tissue remodeling [citation 25] and providing a unique opportunity to promote cell and tissue regeneration in adult life.

In some cases, the Species reintroduction of inappropriate food can lead to recurrence of symptoms, as seen in the LF prescription for multiple arthritis.

2. The signaling pathway of fasting regulation

BDNF regulates hippocampal Neurogenesis, dendritic morphology and Synaptic plasticity, and increases the ability of neural stem cells to generate new neurons. The decrease in blood glucose levels during fasting is parallel to the increase in ketone levels, which is related to the reduction of glucose responsive Ras-AC-PKA pathway and the prolongation of lifespan.

The other important consequence of fasting is a decrease in insulin/IGF-1 signaling, leading to a decrease in synthetic metabolic processes and a decrease in ATP/AMP ratio, thereby activating AMPK. This final step triggers the repair and inhibition of the synthetic metabolic process (Figure 2).

Another mechanism related to fasting induced AMPK activation is autophagy in muscle cells, which is a process of maintaining blood sugar levels during fasting.

As a proof of concept, the selective skeletal muscle consumption of AMPK leads to hypoglycemia and hyperketosis. This effect is not due to the oxidative damage of fatty acids, but due to the reduction of autophagy of muscle cells, resulting in the reduction of the circulating level of Essential amino acid alanine required for Gluconeogenesis.

Figure 2: Signal Pathway Regulation of Fasting Performance

The specific liver knockdown of SIRT1 leads to a decrease in fasting dependent downregulation of adipose gene expression (SREBP-1c), indicating the mechanism by which SIRT1 regulates multiple SREBP-1 target genes. SIRT1 inhibits glucose production by inhibiting CREB regulated transcriptional coactivator 2 (CRTC2) mediated Gluconeogenesis, which is activated during the G-to-K transition.

Similar to SIRT1, mitochondrial deacetylase SIRT3 regulates metabolic homeostasis during fasting and CR. SIRT3 is crucial for fatty acid oxidation and ketone production during fasting by regulating the deacetylation state and the activity of mitochondrial enzymes involved in metabolic transitions.

Adjusting diet and eating frequency, as well as several fasting patterns, can represent a new paradigm in today's medical methods. As recently emphasized by Cabo and Mattson, Homo sapiens has adapted to fasting, enabling the body to endure or overcome challenges, and then restore internal balance.

An increasing number of physiological effects related to IF can also be applied to LF, at least in the initial stage, leading to (I) weight loss and metabolic reset, (ii) increased insulin sensitivity, (iii) reduced inflammation and oxidative damage to proteins, lipids, and DNA, and (iv) enhanced immune system function. All of these mechanisms are definitely valuable in the treatment of obese and non obese subjects.

Although the changes in metabolic conversion and signaling pathways mentioned above also apply to the onset of LF, the question is whether these effects persist, decrease, or increase during the LF process. Obviously, this will depend on the duration of fasting, individual circumstances, including age, nutrition, and health status, as well as individual preferences for the program.

In Europe, especially in Germany, the practice of medically supervised LF has a long tradition. Recently, the security of this scheme has been proved in a large Cohort study.

This type of LF usually lasts for 4 to 21 days and has been studied in various clinical conditions: chronic inflammatory diseases and Rheumatoid arthritis, hypertension, irritable bowel syndrome, insulin resistance, type 2 diabetes and metabolic syndrome, Fibromyalgia, breast cancer and ovarian cancer, Osteoarthritis, obesity, and fatty liver.

Since 1959, LF has been recorded for the first time in many publications among subjects with morbid obesity. By 1975, the reported fasting period ranged from a few days to 249 days, or in extreme cases, to 382 days, known as a "zero calorie diet" or "complete fasting," sometimes taking multiple vitamins and potassium supplements.

At that time, the main focus was on elucidating how humans could fast for such a long time, with limited possibilities for breaking down their protein pool, and the need to provide energy to the central nervous system: the brain needs 400 to 570 kcal of calories per day during the feeding phase, which is provided by 100 to 145 grams of glucose.

If these needs must be met through gluconeogenesis, because fatty acids cannot be converted into glucose, this will mean that 200 grams of protein will be catabolized every day. Because the total amount of protein in the human body is approximately 6000 to 8000 grams and the decrease cannot exceed 1/3, this will reduce the ability to fast for a long time.

In fasting subjects, after the depletion of glycogen reserves, carbohydrate oxidation and protein breakdown metabolism rapidly decrease. Measurement of urinary nitrogen excretion can determine protein utilization.

A zero calorie diet, which only allows calorie free beverages, is relatively well tolerated within weeks or even months, even if obese individuals often do not have exercise, psychological support, or nutritional education to prevent recurrence.

The pioneers of this fasting method for treating obesity even suggested that obese subjects should not fast for more than 100 days without nitrogen balance monitoring. A death case caused by acute refractory cardiac arrest was reported, which occurred on the seventh day of re feeding in a 20 year old woman.

She went on a zero calorie diet for 30 weeks and lost weight from 118 kilograms to 60 kilograms. By simple calculation, this will mean a protein utilization rate of 4000g, which exceeds 50% of her protein library, which is the most reasonable cause of death.

At the autopsy, it was diagnosed that the diameter of myofibrils in the heart decreased with significant fragmentation. Individual deaths caused by a zero calorie diet for weeks or months of morbid obesity may not always have such a clear cause; Other possible causes of death include potassium or vitamin deficiency, incomplete patient selection or compliance, related drugs or preexisting diseases, and other factors.

epilogue

Although clinical studies on fasting have generally shown positive effects on health and lifespan, further research is needed to document the benefits and challenges of long-term fasting. Whether Spontaneous generation repeated fasting cycles in animals can increase benefits is still waiting for a clear answer.

After being evaluated as a successful strategy for treating obesity and comorbidities in the 1960s, it was discovered that fasting had other benefits besides weight loss. This includes improvements in glucose regulation, blood pressure and heart rate, as well as a reduction in abdominal fat. The key points of clinical fasting methods will depend on acceptance and compliance, as well as safety.

These issues are related to emotional and physical health, lack of hunger, and professional guidance. TRE and IF can adapt well to daily life and may serve as a lifelong dietary behavior. In fact, long-term fasting requires a special environment and may be far from the usual environment.

A new aspect of the fasting strategy plan is the post fasting period, when food is reintroduced. When the fasting process is reversed, symptoms may recur in the absence of specific nutritional guidelines.

This may partially reduce the many health benefits of fasting. The individual restrictions of this operation need to be carefully analyzed, and similar to any operation to control food intake, care must be taken, especially in the case of elderly subjects and low Body mass index, oligomyosis or Eating disorder.

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