Intermittent Fasting and Time-Restricted Feeding

Intermittent fasting (IF) is an eating pattern that cycles between periods of fasting and eating. It doesn’t specify which foods to eat but rather when they are eaten. The primary focus is on the timing of meals, with the goal of promoting health benefits, weight loss, or overall well-being [1].

In recent years, fasting has gained popularity as a health and wellness practice due to its potential benefits, such as weight loss [2], improved insulin sensitivity [3], and increased longevity [4]. There are multiple types of fasting, including intermittent fasting, time-restricted feeding, alternate-day fasting, and religious fasting. However, it’s essential to approach fasting responsibly, as it has potential risks and side effects that make it not suitable for everyone.

The role of metabolism during fasting

Fat burning vs. glucose burning

Under normal dietary conditions, the body primarily relies on glucose as its main energy source. However, during fasting, the body undergoes a metabolic shift from burning glucose to burning fat for energy, and this transition is a key part of its downstream effects.

Glucose is obtained from the carbohydrates we consume and is either used immediately or stored as glycogen in the liver and muscles for later use. The process of breaking down glucose for energy is called glycolysis [5]. When we eat regularly, our bodies continue to use glucose as their primary fuel, and there is less need to access stored fat reserves for energy.

When we fast, the body’s glycogen stores become depleted, usually after 12 to 24 hours. In response, the body initiates a process called lipolysis, which breaks down stored fat into free fatty acids and glycerol [6]. The liver converts these free fatty acids into ketone bodies, such as beta-hydroxybutyrate, acetoacetate, and acetone. This metabolic state is known as ketosis [7].

Hormonal changes associated with fasting

Fasting triggers several hormonal changes that help the body adapt to the absence of food and maintain energy balance.

Insulin is a hormone responsible for regulating blood sugar levels by facilitating glucose uptake into cells. During fasting, insulin levels drop, allowing the body to access stored fat for energy. Lower insulin levels also improve insulin sensitivity [3], reducing the risk of type 2 diabetes and other metabolic disorders [8, 9].

Glucagon acts in opposition to insulin, raising blood sugar levels by stimulating the conversion of glycogen to glucose in the liver. Fasting increases glucagon levels, which helps maintain stable blood sugar levels and ensures energy availability for essential bodily functions [10].

HGH plays a crucial role in growth, cell repair, and metabolism. Fasting has been shown to significantly increase HGH, which can promote fat burning, muscle maintenance, and cellular repair processes [11].

Norepinephrine is a stress hormone that increases alertness and the body’s ability to mobilize energy. During IF and TRF, norepinephrine levels rise, stimulating the breakdown of fat cells for energy and enhancing mental focus and concentration.

Cortisol is another stress hormone that regulates various metabolic functions, including glucose production and fat breakdown. Fasting can cause a temporary increase in cortisol levels, which may help maintain energy balance but may also cause stress-related side effects if they remain elevated for extended periods [12].

Leptin and ghrelin are hormones that play crucial roles in regulating appetite, energy balance, and body weight. During fasting, their levels fluctuate, impacting hunger and satiety signals that influence the fasting experience [12, 13].

Leptin, also known as the “satiety hormone,” is produced primarily by fat cells and is responsible for signaling the brain that the body has enough energy stored, reducing appetite and promoting a feeling of fullness [12, 13].

Leptin levels are generally proportional to body fat percentage. During fasting, leptin levels may initially decrease as the body senses a decline in energy intake. This reduction in leptin can increase hunger and appetite, potentially making the initial stages of fasting more challenging [12, 13, 14].

However, over time, the body can adapt to these changes, and people who regularly practice fasting may experience reduced hunger and increased satiety, even with lower leptin levels [12].

Ghrelin, known as the “hunger hormone,” is produced mainly in the stomach and small intestine. It stimulates appetite by signaling the brain that the body needs more energy, promoting hunger and food intake. Ghrelin levels typically rise before meals and fall after eating [12].

Autophagy and cellular repair

Autophagy is a natural cellular process that plays a critical role in maintaining cellular health and function. This term is derived from the Greek words “auto” (self) and “phagein” (to eat), hence its meaning of “self-eating” [15].

During autophagy, cells degrade and recycle their damaged, dysfunctional, or unnecessary components, including proteins, organelles, and other cellular debris. This process helps maintain cellular integrity, prevent the accumulation of harmful waste products, and promote cell survival under stress [15].

Fasting has been shown to stimulate autophagy due to the metabolic and hormonal changes that occur when the body is deprived of nutrients. As food intake ceases, the body undergoes a shift from an anabolic (growth) state to a catabolic (breakdown) state [16, 17].

This transition is marked by reduced insulin levels, increased glucagon levels, and the activation of various signaling pathways, including those involving the proteins AMPK (AMP-activated protein kinase) and mTOR (mammalian target of rapamycin) [13, 18, 19].

The inhibition of mTOR and activation of AMPK during fasting contribute to the initiation of autophagy. By suppressing mTOR, a key regulator of cell growth and protein synthesis, the body conserves energy and resources [20]. Meanwhile, AMPK activation in response to low energy levels serves as a cellular stress sensor, further promoting autophagy [21].

The stimulation of autophagy leads to cell repair through multiple mechanisms. Autophagy is a cellular process that involves the degradation and recycling of damaged or unnecessary cellular components, such as proteins and organelles, to maintain cellular homeostasis and promote cell repair [22].

Autophagy helps to clear damaged organelles, such as mitochondria and the endoplasmic reticulum, as well as misfolded or aggregated proteins. By removing these damaged components, autophagy prevents the accumulation of toxic byproducts and promotes overall cellular health [22].

The process of autophagy allows for the breakdown of cellular components into their basic building blocks, such as amino acids, lipids, and nucleotides. These building blocks can then be reused for the synthesis of new proteins and organelles, facilitating cell repair and regeneration [22].

Autophagy plays a crucial role in maintaining mitochondrial quality by selectively targeting damaged or dysfunctional mitochondria for degradation, a process known as mitophagy. This helps maintain a healthy pool of functional mitochondria, which are essential for energy production and various cellular processes [23].

By eliminating damaged cellular components and maintaining mitochondrial quality, autophagy can reduce oxidative stress within the cell. Oxidative stress can cause damage to cellular structures, including DNA, proteins, and lipids, ultimately impairing cellular function and repair [24].

Autophagy can help to eliminate intracellular pathogens, such as bacteria and viruses, by targeting them for degradation. This not only protects the cell from damage but also aids in the overall immune response of the organism [25, 26].

Autophagy plays a dual role in promoting cell survival and initiating cell death, depending on the context. By maintaining cellular homeostasis and removing damaged components, autophagy can promote cellular survival under stress conditions [27].

However, if cellular damage is too extensive, autophagy may trigger programmed cell death (apoptosis) to eliminate damaged cells and prevent further harm to the organism [27].

Types of fasting 

Intermittent fasting

Intermittent fasting (IF) is an eating pattern that involves cycling between periods of fasting and eating. It is not about specific foods to eat or avoid; instead, it focuses on when you eat in order to activate the fasting state [17]. There are several popular methods of intermittent fasting.

The 16/8 method involves fasting for 16 hours and restricting the eating window to 8 hours per day. For example, you might eat between 12 PM and 8 PM and fast from 8 PM until 12 PM the next day [28].

The 5:2 diet involves eating normally for five days of the week and drastically reducing calorie intake to about 500-600 calories per day for the remaining two non-consecutive days [29].

The Eat-Stop-Eat method entails a 24-hour complete fast once or twice a week. During the fasting period, no food is consumed, but water, coffee, and other non-caloric beverages are allowed [30].

Alternate-day fasting is a type of fasting that involves alternating between days of regular eating and days of fasting or very low-calorie intake (about 500 calories) [31].

The Warrior Diet involves eating small amounts of raw fruits and vegetables during the day and consuming one large meal in the evening, typically within a 4-hour eating window [29].

Time-restricted feeding

Time-restricted feeding (TRF) is a form of intermittent fasting that emphasizes limiting the window of time during which you eat each day. The main goal is to align your eating patterns with your body’s natural circadian rhythm, allowing for longer fasting periods that can potentially improve metabolic health, support weight loss, and offer other health benefits [2, 32, 33].

Benefits of fasting 

Weight loss and improved body composition

The weight loss benefits from fasting can be pronounced, but they vary depending on the individual, the fasting method, and other factors such as diet quality, physical activity, and adherence to the fasting protocol. Fasting can help create a calorie deficit, which is essential for weight loss, by reducing the overall calorie intake and promoting fat burning [2, 34].

Intermittent fasting (IF) and time-restricted feeding (TRF) have been shown to be effective for weight loss in several studies. Fasting can contribute to weight loss in multiple ways:

Reduced calorie intake: By limiting the eating window or restricting calorie intake on specific days, fasting can help reduce overall calorie consumption, leading to weight loss [34].

Increased fat oxidation: Fasting can promote a metabolic shift from using glucose to utilizing stored fat as a primary energy source, which can result in fat loss [34].

Hormonal changes: Fasting can affect hormones like ghrelin (hunger hormone) and leptin (satiety hormone), as well as increase the release of human growth hormone (HGH), which can contribute to fat burning and muscle preservation [12].

However, the weight loss benefits from fasting may not be solely attributed to the fasting itself. Other factors, such as the quality and composition of the diet during the eating periods, play a crucial role in determining the overall effectiveness of fasting for weight loss [12]. Eating a balanced diet rich in whole foods, lean proteins, healthy fats, and complex carbohydrates, as well as maintaining a regular exercise routine, can enhance the weight loss benefits of fasting [35]. However, individual results can vary, and not everyone will experience the same level of weight loss from fasting.

Improved cardiovascular health

Fasting can improve cardiovascular health through several mechanisms, including improved lipid profiles. Fasting can reduce total cholesterol, LDL, and triglycerides. Fasting may also increase HDL, the “good” cholesterol that helps protect against heart disease [36].

Fasting also tends to lower blood pressure. High blood pressure is a major risk factor for heart disease and stroke. The reduction in blood pressure may be attributed to weight loss, improved insulin sensitivity, hormonal changes resulting from fasting, and reduced inflammation [36].

Improved cognition

Studies on the cognitive benefits of fasting have shown mixed results, and research is ongoing. However, several potential cognitive benefits have been reported in both animal and human studies, although the exact mechanisms and extent of these benefits are not yet fully understood. Some potential cognitive benefits associated with fasting include:

Enhanced neuroplasticity: Fasting may improve the brain’s ability to adapt and reorganize itself by promoting the growth of new neurons and the formation of new synapses [37].

Improved learning and memory: Some studies have suggested that fasting can enhance cognitive function, including learning and memory, by increasing the production of brain-derived neurotrophic factor (BDNF), a protein that supports the growth, survival, and differentiation of neurons [38, 39].

Fasting might help the brain to better cope with stress, as it has been shown to increase the production of stress-response proteins, which may improve the brain’s resilience to stress-related damage [37].

Fasting may reduce inflammation in the brain, which has been linked to a variety of cognitive disorders, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis [40].

Promotion of autophagy: As a result of its cellular effects, this process is thought to be important for maintaining the health and function of brain cells [41].

Possible prevention or delay of neurodegenerative diseases: Some studies have suggested that fasting might help to prevent or delay the onset of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, although more research is needed to confirm these findings [34].

Most of the research on fasting and cognitive benefits has been conducted in animals, and human studies are limited.

Cancer prevention

Fasting has been proposed as a potential strategy to reduce the risk of cancer and improve the outcomes of cancer treatment. However, like with cognition, information on the relationship between fasting and cancer prevention is still limited and largely based on animal studies or preliminary human trials. More extensive research is needed to establish a clear connection.

There are several mechanisms through which fasting might help prevent cancer or improve cancer treatment outcomes. These mechanisms include cellular autophagy [42], reduced inflammation [43], and reduced growth factors [44, 45].

Fasting has been shown to reduce levels of growth factors, such as insulin-like growth factor-1 (IGF-1). Elevated IGF-1 has been associated with an increased risk of certain types of cancer [45, 46].

Fasting can lead to a more efficient metabolism, which could help the body better manage oxidative stress and the production of reactive oxygen species (ROS). Excessive ROS can cause cellular damage and contribute to the development of cancer [47].

Increased longevity

Fasting has been studied as a potential intervention to promote healthy aging and extend lifespan. Much of the evidence supporting this idea comes from animal studies, and some preliminary human trials have also been conducted. Here are some key findings from the research:

Caloric restriction: Caloric restriction (CR) is a well-studied intervention in which animals are fed a reduced calorie diet, typically 20-40% fewer calories than normal, while still receiving adequate nutrients. Many studies have shown that CR can extend lifespan and promote healthy aging in various species, including yeast, worms, flies, and rodents [48]. Fasting and intermittent fasting regimens can mimic some of the beneficial effects of CR, suggesting that they might also have longevity benefits [48].

Intermittent fasting: Intermittent fasting (IF) involves periods of fasting followed by periods of eating. Studies in rodents have shown that IF can extend lifespan and improve health outcomes, even when the animals consume the same number of total calories as ad libitum fed controls [34].

Precautions and potential risks of IF and TRF

Fasting, when done correctly and under appropriate supervision, can be a safe and beneficial practic. However, there are potential risks and safety precautions to consider before starting a fasting regimen:

Before starting any fasting regimen, it is essential to consult with a healthcare professional, especially if you have any pre-existing medical conditions, are taking medications, or have a history of disordered eating.

If you are new to fasting, it is recommended to start with shorter fasting periods and gradually increase the duration as your body adapts. This can help minimize potential side effects and make the transition easier [28].

Hydration can be a problem when fasting. In some cases, you may need to consume electrolytes to replace those lost through sweat and urine. Water loss during fasting comes from reduced food intake: 20-30% of daily water intake comes from food, breakdown of muscle glycogen, and loss of electrolytes that hold water in the body [49].

When breaking your fast, start with small, easily digestible meals and gradually increase the size and complexity of your meals. This can help prevent gastrointestinal discomfort and ensure proper nutrient absorption [50].

Pay attention to how your body responds to fasting. If you experience severe dizziness, extreme fatigue, or other unusual symptoms, stop fasting and consult a healthcare professional.

Nutrient deficiencies and hypoglycemia can also occur, especially in people with diabetes or who take medications that affect blood sugar [51-53].

Dehydration and electrolyte imbalances can lead to dizziness, weakness, and in severe cases, dangerous heart rhythm abnormalities [49, 51]. Prolonged fasting can lead to muscle loss, especially if not accompanied by proper nutrition and resistance training [54, 55].

Fasting can trigger disordered eating patterns or exacerbate existing eating disorders in some individuals. Prolonged fasting might weaken the immune system, making some people more susceptible to infections [51].

Fasting is not suitable for everyone, including pregnant or breastfeeding women, children, elderly individuals, and people who have certain medical conditions [51, 56, 57].

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