Intermittent Fasting and Health – The Scientific Evidence

Intermittent fasting has recently gained popularity as a means of reducing body weight and improving metabolic health. Animal studies also suggest that intermittent fasting may promote healthy aging and increase longevity.

Throughout the ages, humans may have benefitted from limiting food intake for specific time periods, either for religious reasons or when food was scarce.

In fact, the human body has developed many adaptive mechanisms that allow survival during periods of famine. Hence, intermittent fasting is usually well-tolerated and appears to be harmless for healthy, normal weight, and obese adults.

Intermittent Fasting - The Scientific Evidence

However, evidence-based support for intermittent fasting that can be used to generate recommendations for public health practice is still lacking (1).

Intermittent fasting can be performed in many different ways. However, to be safe, it is crucial to eat a balanced diet and conform to the rules of healthy eating.

There are many similarities between the effects of caloric restriction and those of intermittent fasting.

Caloric restriction means reducing the average daily caloric intake below what is habitual. During intermittent fasting, a person does not eat at all or severely limits food intake during certain periods. This often leads to fewer calories consumed. However, intermittent fasting seems to confer health benefits to a greater extent than can be attributed to a reduction in caloric intake  (1).

The objective of this article is to answer several essential questions about how intermittent fasting is practiced, how it affects metabolism and cellular function, and how it may benefit human health and possibly increase longevity.

Intermittent Fasting

Intermittent fasting involves alternating cycles of fasting and eating. This approach encompasses various regimens, including alternate-day fasting, modified alternate-day fasting, the 5:2 diet, and the 16:8 diet.

Alternate-day fasting consists of a day of ad libitum eating, often referred to as the “feed day,” followed by a day with no caloric consumption called the “fast day (2).”

Modified alternate-day fasting allows for some caloric intake on the fast day, though severely restricted (~75% caloric restriction).

The 5:2 diet, or the Fast Diet, prescribes 2 days of severe caloric restriction per week and a regular diet for 5 days (3). The diet allows for a consumption of about 400–600 kcal on the “fasting” days.

Overeating on the “feed day” due to increased hunger following the “fast day” often becomes a concern with intermittent fasting. However, studies have concluded that even after fasting every other day, participants report no compensatory eating and high levels of satiety (2).

The 16:8 method involves fasting every day for 16 hours and restricting the eating window to 8 hours. This is sometimes referred to as time-restricted eating.

All these methods allow drinking unsweetened beverages such as water, coffee, and tea during the fasting period.

Time-Restricted Eating 

Time-restricted eating is a type of diet that focuses on the timing of eating. It implies that eating is restricted to specific hours of the day.

The beneficial biochemical processes associated with fasting are triggered once stored energy is being utilized and, therefore, do not occur during the feeding period (4). Restricting the timing of food intake to a few hours of the day may trigger the fasting physiology after a few hours of feeding cessation daily.

Three variants of time-restricted eating are most common: 16:8, 18:6, and 20:4.The 16:8 method is a typical example. It consists of a 16 hour fast, and then an 8-hour nutritional window. This can, for instance, be achieved by not eating after dinner and skipping breakfast.

Human studies have suggested that time-restricted feeding promotes weight loss (5,6). Some of these studies also showed beneficial effects on fasting glucose as well as LDL and HDL cholesterol.

Some experts have been skeptical about time-restricted eating because it often involves skipping breakfast (7). However, whether skipping breakfast is bad or not is still a matter of debate (8).

The Metabolic Effects of Intermittent Fasting

Many of the beneficial health effects of intermittent fasting are derived from a metabolic switch from the use of glucose as a fuel source to the use of fatty acids and ketone bodies.

The transition is called intermittent metabolic switching (IMS) or glucose-ketone (G-to-K) switchover. Inverse switching, i.e., ketone-glucose (K-to-G), occurs after the interruption of fasting and meal intake (9).

Glucose is the primary fuel for most cells and organs in the body. Once glucose enters our cells, a series of metabolic reactions break it down into carbon dioxide and water, releasing energy in the process.

The body can store excess glucose in the form of glycogen, hence storing energy for later use. Glycogen consists of long chains of glucose molecules and is primarily found in the liver and skeletal muscle. Liver glycogen stores are used to maintain healthy levels of glucose in the blood, while muscle glycogen stores are used primarily to fuel muscle activity (10).

However, most cells can use fatty acids for energy. When the body’s glycogen stores become depleted, the breakdown of body fat (mainly triglycerides) results in increased availability of fatty acids.

During fasting, triglycerides are broken down into fatty acids and glycerol, which are used for energy. Furthermore, the liver converts fatty acids to ketone bodies that can be used by most cells to provide energy instead of glucose.

When ketone bodies are produced more quickly than the body needs, ketone levels build up in the blood, resulting in a condition known as ketosis. Ketosis is most commonly caused by very low carbohydrate consumption or by fasting.

Because many fatty acids can not pass the blood-brain barrier and reach the brain, the brain becomes dependent on ketone bodies for energy.

Intermittent fasting may improve health span
After nearly a century of research it has been scientifically proven that caloric restriction increases lifespan and healthspan, and promotes healthy aging in animal research models.

The Role of Ketone Bodies?

Ketone bodies produced by the liver during fasting include three compounds: acetone, acetoacetate, and beta-hydroxybutyrate.

Ketone bodies are not only produced when the glycogen stores become depleted. In fact, they are produced by the liver all the time. Research indicates that the heart and kidneys prefer to use ketone bodies rather than glucose as a fuel resource.

To dispose of excess ketone bodies, the body uses the kidneys to excrete them in urine, and they are exhaled from the lungs. During ketosis, ketones can easily be detected in the urine.

The generation of ketone bodies from the liver is the normal physiologic response to fasting. Mild ketosis (ketone body concentration of about 1 mmol/L) develops after a 12- to 14-hour fast. If fasting continues, ketone body concentration continues to rise and peaks at a level of 8 to 10 mmol/L. Beta-hydroxybutyrate is the major ketone body that accumulates.

Ketone bodies are not just fuel used during periods of fasting or during carbohydrate restriction. They are also potent signaling molecules with significant effects on the function of cells and organs (1).

Ketone bodies regulate the activity of many chemical substances that influence health and aging. Researchers have made important strides in understanding the signaling functions of beta-hydroxybutyrate, many of which may have crucial implications for the management of human diseases such as type 2 diabetes and Alzheimer’s disease (11).

Intermittent Fasting, Obesity, and Type 2 Diabetes?

Obesity and being overweight are strong predisposing factors for the development of diabetes, cardiovascular disease, and many types of cancer.

The first clinical study of fasting for the treatment of obesity was performed in 1915 (12). The authors reported that short periods of four to six days of fasting were a safe and effective method for reducing body weight in obese individuals.

Many studies in rodent models of obesity have shown beneficial effects of intermittent fasting.

A study published in 2016 showed that obese mice on a high‐fat alternate‐day fasting regimen lost weight and improved glucose tolerance (13). Another study showed that alternate-day fasting in obese rodents reduced fat accumulation in the liver, inflammatory gene expression, and cancer risk (14).

Studies have found that almost all intermittent fasting regimens can result in some weight loss in humans (15, 16, 17, 1819).

Early in fasting, weight loss is rapid, averaging 0.9 kg per day during the first week and slowing to 0.3 kg per day by the third week (20). This primary weight loss is mostly due to the loss of sodium and water,

A randomized human study showed that the 5:2 diet-induced weight loss and improved several metabolic parameters over a period of 50 weeks (21).

A pilot study published in 2017 showed that short-term daily intermittent fasting may be a safe and tolerable dietary intervention in patients with type 2 diabetes and may improve key outcomes, including body weight and fasting glucose (22).

The longer-term benefits or harms of intermittent fasting amongst people who are overweight or obese is not known and is clearly a priority for further investigation (23).

Intermittent Fasting and Cardiovascular Disease?

Cardiovascular disorders, such as coronary artery disease and stroke, are a common cause of illness and early death worldwide. In theory, measures that improve blood pressure, blood lipids, insulin resistance, and reduce the risk of diabetes and obesity will reduce the risk of cardiovascular disease.

Alternate-day fasting in rodent models of obesity has been shown to reduce blood levels of cholesterol and triglycerides (24).

Human studies have shown that alternate-day fasting lowered total cholesterol, triglycerides, and LDL-cholesterol (25 26). Furthermore, the size of LDL particles was reduced. All these changes may help to decrease the risk of cardiovascular disease. Numerous other human and animal studies have shown similar results.

High blood pressure (hypertension) is a common medical disorder that increases the risk of heart disease, stroke, and kidney disorders. Overall, approximately 20% of the world’s adults are estimated to have hypertension. It is one of the most important causes of premature death worldwide (27).

Animal and human studies suggest that intermittent fasting lowers blood pressure (28, 29).

Animal studies suggest that intermittent fasting may help to reduce the risk of stroke (30).

Intermittent Fasting and Cancer?

Almost 90 years ago, German physician Otto Warburg first posed the question of why cells consume nutrients differently. He knew that normal cells use oxygen to turn food into energy through a process called oxidative phosphorylation. But when he observed cancer cells, he found that they preferred to fuel their growth by consuming and breaking down glucose for energy. The phenomenon was coined “the Warburg effect.” Its discovery laid the foundation for the field of cancer metabolism and earned Warburg the Nobel Prize in 1931 (31).

The Warburg effect implies that whereas cancer cells depend on glucose to maintain their high rate of cellular proliferation, healthy cells can cope with glucose deprivation since glucose can be replaced by ketone bodies and fatty acids as a primary energy source.

Intermittent fasting reinforces the stress resistance of healthy cells, while cancer cells appear to become more sensitive to toxins. In humans, intermittent fasting may be a feasible approach to enhance the efficacy and tolerability of chemotherapy.

Numerous animal studies have shown that caloric restriction and intermittent fasting reduce the occurrence of spontaneous tumors in rodents (1). Furthermore, intermittent fasting may increase the sensitivity of some cancers to chemotherapy and reduce the side effects of cytotoxic treatments (32).

Animal studies suggest that multiple cycles of fasting could potentially replace or augment the efficacy of certain chemotherapy drugs in the treatment of various cancers, such as breast cancer, melanoma, neuroblastoma, pancreatic cancer, and colorectal cancer (33).

In contrast to most cancer therapies, intermittent fasting only has mild side effects, such as headaches, dizziness, nausea, weakness, and short-term weight loss in humans (34).

It is crucial to underscore that clinical research in this area till in its infancy. Ongoing and future clinical studies will hopefully tell which cancers, and at which stage of the cancer process, intermittent fasting regimens will prove most useful.

Intermittent Fasting and Neurodegenerative Diseases?

Neurodegenerative disorders such as Alzheimer’s and Parkinson’s all too often reflect the vulnerability of the nervous system to aging.

Excessive accumulation of amyloid-β (Aβ) in the brain is found in patients with Alzheimer’s disease (34). Aβ clearance has been considered to be crucial in the development of the disease, and enhancing Aβ clearance may be a target for treatment.

Research has shown that chronic intermittent fasting improves cognitive functions and brain structures in mice (35).

Another animal study study showed that intermittent fasting seems to protect against Alzheimer Disease in mice, most likely through protection against Aβ deposition in the brain (36).

Neurons in the hippocampus play an essential role in cognitive processes such as learning and memory, and they are susceptible to dysfunction and deterioration with advancing age

Intermittent fasting induces a mild stress response in brain cells, increasing activity in hippocampal neurons and producing brain-derived neurotrophic factor (BDNF). BDNF stimulates the growth and upkeep of synapses and dendrites and increases the renewal of neuronal cells. These findings imply that intermittent fasting can be a viable tool to help replace diseased hippocampal neurons, aiding in the deceleration of some neurodegenerative disorders (37)

Research has shown that chronic intermittent fasting improves cognitive functions and brain structures in mice (38).

Intermittent fasting may improve muscle mass and exercise performance
It has been proposed that intermittent fasting may help maintain muscle mass and promote fat loss in healthy individuals.

Intermittent Fasting, Muscle Mass and Exercise Performance

It has been proposed that intermittent fasting may help maintain muscle mass and promote fat loss in healthy individuals. Hence, time-restricted feeding has become very popular among fitness practitioners.

One study showed that in conjunction with resistance training, an 8-hour time-restricted eating window in healthy males resulted in a decrease in blood glucose, blood insulin, and fat mass while maintaining muscle mass (39).

Another study found that resistance-trained females who followed the same time-restricted feeding protocol experienced an increase in muscle mass and performance similar to women in a control diet group who ate all their food within a 13-hour per day period (40).

Time-restricted feeding also appears to enhance the aerobic capacity of mice. Mice that ate during a 9-hour time-restricted feeding window ran approximately one hour longer than mice of similar weight that had unrestricted access to food (41).

Additional studies are needed to investigate the long-term effects of intermittent fasting on muscle mass and exercise performance.

Intermittent Fasting and Inflammation?

Inflammation can be both acute and chronic. Acute inflammation is the initial response of the body to harmful stimuli.  Prolonged or chronic inflammation is characterized by simultaneous destruction and repair of the tissue from the inflammatory process.

When inflammation is appropriate, it protects  from disease. When inflammation is inappropriate or gets out of hand, it can cause disease (42).

Today it is believed that inflammation plays a causative role in many chronic diseases such as cardiovascular disease, type 2 diabetes, and many cancers (43).

It is well known that our dietary choices may affect inflammatory responses in our body (44).

In a study published recently, Mount Sinai researchers found that fasting reduces inflammation and improves chronic inflammatory diseases (45). The study showed that intermittent fasting reduced the release of pro-inflammatory cells called “monocytes.” During periods of fasting, these cells go into “sleep mode” and are less inflammatory than monocytes found in those who were fed.

Adiponectin is a protein secreted by fat tissue. Adiponectin levels are lower among obese people than those who are normal-weight. Low levels of adiponectin are associated with inflammation, lipid abnormalities, insulin resistance, and increased risk of diabetes, coronary heart disease, and cancer (46).

One study reported that Ramadan fasting resulted in increased levels of plasma adiponectin and decreased levels of TNF-α (a protein that promotes inflammation) (47).

Intermittent Fasting, Life Expectancy, and Aging?

To understand the effects of caloric restriction on longevity, it is essential to differentiate between average lifespan and maximal lifespan. Average life span is the mean age of death in a population, whereas the maximal lifespan is a measure of the highest age at death of one or more members of the society.

In 1919, the average lifespan for people born in the U.S. was about 56 years. Today, it has risen to almost 79 years (48). However, the maximal lifespan has remained mostly unchanged.

Average lifespan has increased mainly because of improvements in public health and health care. In contrast, maximal life span can only be increased by actually decreasing the rate of aging.

After nearly a century of animal research, it has been scientifically proven that caloric restriction increases lifespan as well as healthspan and promotes healthy aging. Healthspan is the number of years in which an individual remains in good health.

Interestingly, caloric restriction has been shown to increase both the average lifespan and the maximal lifespan of laboratory animals (49).

In one of the earliest studies on intermittent fasting, published 1982, it was shown that the average lifespan of rats increased by 80 percent when they were maintained on a regimen of alternate-day feeding  (50).

In another study, mice that were fed one meal per day lived approximately 11 to 14 percent longer when fed the same caloric content as mice that ate freely, This suggests that time-restricted feeding not only improves metabolic health but may be a contributor to longevity even in the absence of caloric restriction (51).

There is evidence that cumulative oxidative damage to macromolecules, such as protein, lipids, and DNA, plays a significant role in aging. Interestingly, caloric restriction appears to attenuate both the degree of oxidative damage and the associated decline in function (52).

Evidence suggests that intermittent fasting evokes adaptive cellular responses that improve glucose regulation and stress resistance and suppress inflammation (1). During fasting, cells seem to become more resistant to oxidative and metabolic stress and become more able to remove and repair damaged molecules (53).

In humans, intermittent fasting helps to ameliorate obesity, improves insulin resistance and lipid abnormalities, and positively affects hypertension and inflammation. However, it has not been scientifically proven that intermittent fasting increases life expectancy in humans.

The Bottom Line

Animal studies suggest that intermittent fasting may have several health benefits. Some of these benefits, in particular, the effects on obesity, type 2 diabetes, and cardiovascular risk factors, have been confirmed in studies on humans.

However, the popularity of intermittent fasting within the general public is in stark contrast with the gaps in evidence on the clinical benefits of this approach.

For example, although short term studies are promising, we do not know conclusively whether long term intermittent fasting is safe or effective for subjects who are overweight or obese. Furthermore, it is unknown to what extent intermittent fasting provides benefits for normal-weight individuals.

To date, there have been no well-controlled scientific studies to determine the effects of long-term intermittent fasting on humans.

Although intermittent fasting appears to improve several risk factors for cardiovascular disease, such as high cholesterol and hypertension, it is yet unknown whether this translates into a lower risk of cardiovascular disease and improved survival.

Intermittent fasting may be a feasible approach to enhance the efficacy and tolerability of chemotherapy. However, clinical research evaluating the potential of intermittent fasting in cancer treatment is still in its infancy.

Randomized studies are desperately needed to assess the possible benefits of intermittent fasting further.

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