The Physiology of Fasting
Fasting practices vary depending on the purpose of the fast, desired outcomes, and individual goals. Different durations, frequencies, and the amount and type of nutrient restriction involved are all factors that can change per individual. Even though the basis of fasting — overall energy and nutrient restriction — is consistent, the amount of time that one maintains a fast can elicit different responses throughout the body. Depending on the health, genetics, and lifestyle of the individual fasting, responses can vary, but we’re breaking down the general timeline of events for a healthy person embarking on a fasting journey.
Between 0 and 3 hours, the body is still in energy production and storage mode. After the last ingestion of a meal, snack, or beverage, the food item that was consumed is digested and absorbed into the bloodstream as glucose (from carbohydrates), amino acids (from protein), and fatty acids (from fat). Glucose, amino acids, and fatty acids are then either metabolized for energy production or stored for later use.
Hormones play an important role after a meal. After eating something—usually an item high in carbohydrates—the amount of glucose in the bloodstream increases. In order to utilize this source of energy, as well as bring blood glucose levels back to a normal range, insulin is released from the pancreas. Insulin helps shuttle the glucose into cells where it can be used in energy production or stored for later use, either as glycogen (the stored form of glucose), adipose tissue (fat cells), or the synthesis of protein in muscles. Glucose and insulin generally return to pre-meal levels by the 3 hour time mark.
Ghrelin and leptin are two other important hormones to consider when discussing food and nutrient consumption. Ghrelin is the “hunger hormone.” When levels are elevated, it signals to your brain that you are hungry or “turns on” your appetite. Leptin is the opposite of ghrelin. It’s released from fat cells and “turns off” appetite and helps us stop eating. After a meal, within the 0–3 hour mark, leptin will begin to rise and ghrelin fall, increasing the feeling of fullness and decreasing the feeling of hunger.
The 0–3 hour time frame is considered to be an anabolic, or growth period since nutrients are available and are being used as energy or stored for later use. Once digestion, absorption, storage, and energy utilization is complete, nutrient and insulin levels will return to baseline and your body will start to shift toward a catabolic state (i.e. a state of breakdown, usually of stored nutrients).
During the 4–24 hour phase, the body starts switching to the catabolic, or breakdown state, and a shift in the type of fuel used for energy begins. Blood glucose continues to drop, insulin (a growth hormone that helps move glucose into cells) will be low, and glycogen (the stored form of glucose) will begin to be broken down to release glucose for energy. Stored glycogen decreases due to the increase in glucagon (a catabolic hormone that inhibits the synthesis of glycogen and stimulates the breakdown of glycogen into glucose). Glycogen is also broken down in order to help maintain blood glucose levels within a normal range, about 70–120 mg/dL since glucose is still the main fuel source for the body at this time.
As glycogen and glucose continue to be depleted, the body begins to switch from using glucose as its primary energy source to using ketones, fatty acids, and non-hepatic glucose (i.e., glucose not from the liver). Glucose is the preferred fuel source, but once availability is limited, the body must start creating and utilizing fat stores and ketone bodies to provide sufficient energy. Depending on physical activity levels and baseline glycogen stores, at approximately 12 to 24 hours blood glucose levels will be reduced by about 20%.
Once glycogen (the stored form of glucose) is significantly depleted, the body switches primarily to a fat-burning mode, producing and utilizing ketone bodies as energy. Through the process of lipolysis (the breakdown of fat), fat cells in the body release free fatty acids. PPAR-alpha, which is a regulator of lipid (i.e. fat) metabolism in the liver, and which is necessary for the process of ketogenesis, is also activated and promotes the utilization of these fatty acids.
Fatty acids then travel to the liver where they are transformed into ketone bodies through the process of beta-oxidation. Ketone bodies refer to three types of molecules: acetone, acetoacetate, and beta-hydroxybutyrate, or BHB for short. Acetoacetate and BHB can be used for energy production. Blood ketone meters, which many people use while fasting or on a ketogenic diet, measure BHB levels in the blood. BHB levels can vary based on the individual, but within 24–72 hours of fasting, it is likely to see BHB levels between 0.5–2 mM, which is considered nutritional ketosis.
At this point, ketones can now be used as a primary fuel, however some glucose is still needed — therefore a small amount of glycerol from fat, ketones, and amino acids are converted to glucose by the process of gluconeogenesis (the creation of glucose from non-carbohydrate substances). Approximately 80 grams per day of glucose is produced by this process, most of which is used by the brain. The rest of the body can rely almost exclusively on ketone bodies.
Ghrelin, the hunger hormone, also starts to decline. One study showed that even though ghrelin rises and falls in a cyclic pattern related to circadian rhythm, total ghrelin output decreased every 24 hours of fasting. So, by day 3 of a fast, overall ghrelin output was lower than day 2 and day 1. These results may also provide some explanation as to why hunger levels decrease around day 3 and beyond.
The 72–120 hour mark is considered to be in the prolonged fasting category. By this time insulin like growth factor 1 (IGF-1) levels are decreased, glucose and insulin levels remain low, hunger begins to be suppressed, and a steady state of ketogenesis is underway.
Extended, or prolonged fasting, has been shown to suppress growth signaling, as well as activate cellular resistance to toxins and stress in both mice and human studies. IGF-1 is a hormone involved in the growth and development in our bodies. When nutrients are restricted, IGF-1 levels are suppressed due to the decrease in IGF-1 produced by the liver, increases in IGF-1 clearance, and decreased levels of IGF binding proteins (IGFBP). As an adult, short-term decreased IGF-1 activity has been associated with less oxidative stress and may be an important part of anti-cancer and anti-aging dietary interventions.
In some studies, 24 hours of fasting was not enough to see many of these effects — rather, a minimum of 72 hours of fasting was usually required. Prolonged fasting has also shown promising results around immunity, inflammation, neurogenesis, and metabolic health. Benefits can be associated with the lower levels of growth hormones such as IGF-1 and insulin. Fasting for 3 or more days has been shown to have a 30% or more decrease in circulating insulin and glucose, which can contribute to decreased risk of metabolic disease.
Ghrelin, the hunger hormone, has been shown to decrease during prolonged fasts. As mentioned above, this may be one explanation why for many people who embark on a 3 day or more fast usually start feeling less hungry by day 3.
At this point, BHB levels have also continued to rise and likely settle out around 1.5–3 mM. BHB levels above 2.0 mM may correlate with lower hunger levels as well, since the body is now producing sufficient amount of ketones to fuel the body.
By the time you are at 5+ days of fasting, glucose, insulin, and IGF-1 have been significantly reduced and your body is in a steady state of ketosis. Five days of fasting in humans has been shown to cause over a 60% decrease in IGF-1 and a significant increase in IGF-1 inhibiting proteins. This reduction can be attributed to the absence of protein consumption, as well as low levels of insulin from caloric restriction in general. In addition to that, 10 days of fasting has been shown to reduce IGF-1 levels as low as those seen in people with growth hormone deficiency — a population that is associated with reduced risk of cancer, diabetes, and overall mortality.
BHB levels will also continue to rise. One study showed that BHB levels will eventually plateau between 5–6 mM by day 20–25 of fasting. This is an extreme example of a long fast, but these results do provide a nice demonstration of the insulin/BHB feedback loop that a normal human has to prevent dangerously high levels of ketones, also known as ketoacidosis, that is usually only seen in alcoholics, diabetics, and extreme starvation. The presence of insulin in healthy adults tells the body to stop increasing its production of ketones and plateau them at a safe level.
Summary
Overall, there is promising research on the metabolic effects that short-term and prolonged fasts have on the body. Depending on your desired outcomes and ability to fast, anywhere from a multi-hour, time-restricted feeding regimen to a 5+ day fast may provide you the benefits you are looking for. As always, we suggest working with a medical professional to find the plan and approach that’s best for your health and goals.
