Going several days without food does far more than simply force the body to burn fat. A study published in Nature Metabolism has shown that prolonged fasting triggers far-reaching biological changes throughout the body, including changes related to the brain, metabolism, and the immune system. The scientists found that many of the most significant effects did not occur immediately. Instead, after about three days without food, the body appeared to transition into a completely different biological state. The findings provide one of the clearest pictures to date of how prolonged fasting affects the human body at the molecular level. The researchers say this work could ultimately help scientists develop treatments that mimic some of the effects of fasting without requiring people to go without food for days on end.

What Happens During Prolonged Fasting, and What Role Does Chronobiology Play?

Humans have evolved to survive periods of food scarcity. When food is unavailable, the body switches its energy supply from glucose derived from food to the use of fat reserves. In the process, metabolism changes gradually: insulin levels drop, stored energy reserves are mobilized, and the body begins to increasingly use fatty acids and so-called ketone bodies as energy sources. These adaptive mechanisms helped humans survive longer periods without regular food intake throughout evolution. Fasting has been practiced for millennia for religious, cultural, and medical reasons. In many religions, fasting is seen as an expression of discipline, purification, or spiritual reflection. At the same time, it has traditionally been used in various cultures to promote health. In recent years, scientific interest in fasting has increased significantly. Researchers are investigating, among other things, how different forms of fasting affect metabolism, inflammatory processes, weight, cardiovascular health, and aging processes. Intermittent fasting, in particular, is the focus of many studies.

Chronobiology—the science of the body’s internal biological clock—also plays an important role in fasting. The human body follows a circadian rhythm that controls numerous processes such as metabolism, hormone production, sleep, body temperature, and energy expenditure. Researchers believe that it is not only what and how much people eat that matters, but also when they eat. Fasting intervals can influence this internal clock and synchronize certain metabolic processes with the body’s natural day-night rhythm.

Studies suggest that time-restricted eating, in which food intake is limited to specific hours of the day, could positively influence insulin sensitivity, blood sugar metabolism, and possibly also inflammatory processes. It appears particularly beneficial to consume food during the day, when the body is biologically more attuned to energy processing. Eating late at night, on the other hand, is associated with metabolic disorders, sleep problems, and an increased risk of obesity. Scientists also suspect that periods of fasting could support repair and regeneration processes that are closely linked to the biological clock. These include, among other things, cell cleansing processes, hormonal adjustments, and changes in energy metabolism. Nevertheless, researchers emphasize that the connections between fasting, chronobiology, and long-term health are not yet fully understood and continue to be intensively studied.

In recent years, it has also attracted increasing attention as studies establish a link between fasting and intermittent fasting on the one hand, and weight loss, improved metabolic health, and cellular repair processes on the other. Nevertheless, scientists have had only a limited understanding of exactly how the body reacts to prolonged fasting periods. To investigate this, researchers from the Precision Healthcare University Research Institute (PHURI) at Queen Mary University of London and the Norwegian School of Sports Sciences observed 12 healthy volunteers during a seven-day fast in which they drank only water. Blood samples were taken daily before, during, and after the fast. Using state-of-the-art proteomics technology, the team tracked approximately 3,000 proteins circulating in the bloodstream. These proteins can provide clues about what is happening in the organs and tissues throughout the body.

The Biggest Changes Began After the Third Day

As expected, within the first two to three days of fasting, the body quickly switched from burning glucose to burning fat. Participants lost an average of 5.7 kilograms (about 12.5 pounds), including both fat and lean tissue. After the participants had been eating again for three days, most of the lean tissue loss returned, while a large portion of the fat loss remained.

But the researchers discovered something even more surprising: widespread changes in protein activity throughout the body did not occur immediately. Instead, major molecular changes only became clearly noticeable after about three days without calorie intake. More than a third of the proteins studied changed significantly during fasting. Among the most pronounced changes were proteins associated with the extracellular matrix, which provides structural stability to tissues and organs, including nerve cells in the brain. The protein changes were remarkably consistent across the participants, suggesting that the body responds to prolonged fasting with a highly coordinated reaction.

“For the first time, we can see what happens at the molecular level throughout the body when we fast,” said Claudia Langenberg, director of the Precision Health University Research Institute (PHURI) at Queen Mary University. “Fasting, when done safely, is an effective measure for weight loss. Popular diets that involve fasting, such as intermittent fasting, promise health benefits that go beyond weight loss. Our findings provide evidence for the health benefits of fasting beyond weight loss, but these only became apparent after three days of complete calorie restriction—later than we had previously assumed.”

Potential Benefits Beyond Weight Loss

The researchers used genetic data from large-scale human studies to investigate how the protein changes observed during fasting might influence long-term health. The results suggested potential links to improvements in several biological signaling pathways associated with disease risk, inflammation, and cellular metabolism. The scientists also identified changes in proteins involved in the brain’s supportive structures, immune responses, and cellular repair and stress processes. Some of these changes were linked to signaling pathways that also play a role in aging processes, neurodegenerative diseases, and metabolic disorders. The findings have therefore sparked interest in whether fasting might one day help researchers develop therapies that mimic certain biological effects of fasting without requiring people to completely abstain from food for extended periods.

Interest in fasting research has continued to grow since the publication of the 2024 study. More recent reviews link intermittent fasting to improved insulin sensitivity, healthier blood lipid levels, and potential benefits for brain and cardiovascular function. Other recent studies on long-term fasting also show that during fasting periods lasting several days, the body enters a deep ketogenic state, fundamentally altering the way it produces energy. Researchers are also investigating whether fasting could activate processes such as autophagy—a kind of cellular “recycling program” in which damaged cell components are broken down. These mechanisms are considered a possible explanation for why fasting is associated with effects on cellular health, inflammation regulation, and aging processes.

The Potential Risks

Although fasting is associated with positive biological effects such as improved metabolic markers or changes in certain inflammatory markers, scientists caution against viewing prolonged or extreme fasting as fundamentally risk-free. In particular, fasting for several days while consuming only water places a significant strain on the body and can trigger various physiological stress responses.

In a proteomics study on prolonged water fasting, researchers observed, among other things, evidence of heightened inflammatory responses, increased platelet activation, and changes in signaling pathways involved in blood clotting. The authors speculate that these may partly be short-term adaptive responses by the body. At the same time, however, they emphasized that it remains unclear what long-term effects repeated or very prolonged fasting might have on the cardiovascular system, immune function, and metabolism.

Furthermore, prolonged fasting can lead to an insufficient supply of energy, fluids, and essential minerals. Potential electrolyte imbalances—such as changes in sodium, potassium, or magnesium levels—are particularly critical, as these can cause cardiac arrhythmias, muscle weakness, or neurological symptoms, among other issues. Dizziness, headaches, difficulty concentrating, low blood pressure, fatigue, and circulatory problems are also common. If the body receives too little protein over an extended period, muscle mass may also be lost. Special caution is advised for people with pre-existing conditions. In diabetes, fasting can increase the risk of hypoglycemia or severe blood sugar fluctuations. People with eating disorders may reinforce problematic behavioral patterns through restrictive forms of fasting. Prolonged fasting can also pose health risks for those with cardiovascular diseases, chronic kidney diseases, liver problems, or during pregnancy and breastfeeding. Experts therefore recommend not undertaking prolonged fasting regimens without medical supervision. In particular, extreme fasting over several days or weeks should be individually assessed by a doctor to identify potential risks early and avoid health complications.

Why Scientists Are Excited About the Results

Researchers say one of the most important findings was the timing of the body’s response. Many common fasting approaches focus on shorter fasting periods, but this study suggests that some of the more dramatic molecular changes in the body may require several days of complete calorie restriction. “Our findings provide a basis for long-standing knowledge about why fasting is used for certain conditions,” said Maik Pietzner, head of the Health Data division at PHURI and co-leader of the Computational Medicine group at the Berlin Institute of Health at Charité. “While fasting can be beneficial in treating some conditions, it is often not an option for patients with health issues. We hope that these findings will shed light on why fasting is beneficial in certain cases and that these insights can then be used to develop treatment methods that are feasible for patients.”