On 'Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting' by Stephen D. Anton et al.


In “Andreas Michalsen on Fasting” I wrote

I’ll bet that in the environment of evolutionary adaptation our ancestors lived in before the advent of agriculture, involuntary fasting—that is, periods of time with little or no food—were quite common. As a result, many of our bodies’ systems were designed in a way that took as given that there would be frequent periods of little or no food. When people eat all the time, these systems don’t work very well.

In their review article “Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting,” Stephen Anton, Keelin Moehl, William Donahoo, Krisztina Marosi, Stephanie Lee, Arch Mainous, Christiaan Leeuwenburgh and Mark P. Mattson also argue from this perspective. (The remainder of the quotations in this blog post come from their article.)

Many animals in the wild regularly experience extended time-periods with little or no food. For example, packs of wolves living in the Northern Rocky Mountains of the United States typically kill prey, such as deer, elk or bison only once every one or two weeks. Their success depends upon their brains and bodies functioning at a high level so they can work with their pack mates to ‘formulate’ and execute a strategy to capture and kill the prey animal.(28) … Accordingly, those individuals whose brains and bodies performed optimally in a food deprived/fasted state would have a survival advantage.

Knowledge of early human evolution and data from recent studies of hunter-gatherer societies suggest humans evolved in environments where they intermittently experienced extended time-periods with little or no food.(3031

Anton et al. also lay out some of the biological details to back up this idea. In particular, they argue that the body is designed to work well when it will have periods of relying on the burning of body fat for energy. Since the liver’s stores of glycogen have to be run down before body fat is metabolized, making sure there are periods when the body relies on fat-burning requires a minimum number of hours of fasting or something close to fasting. Without those fat-burning periods, many things go wrong. Things go better with periodic fat-burning periods. Here is the explanation given in “Flipping the Metabolic Switch”:

… what is this metabolic switch and how is it flipped? Here, we define the metabolic switch as the body’s preferential shift from utilization of glucose from glycogenolysis to fatty acids and fatty acid-derived ketones. … Of relevance to weight management, this switch represents a shift from lipid synthesis and fat storage to mobilization of fat in the form of free fatty acids (FFAs) and fatty-acid derived ketones. …

The metabolic switch typically occurs in the third phase of fasting when glycogen stores in hepatocytes are depleted and accelerated adipose tissue lipolysis produces increased fatty acids and glycerol.(21) The metabolic switch typically occurs between 12 to 36 hours after cessation of food consumption depending on the liver glycogen content at the beginning of the fast, and on the amount of the individual’s energy expenditure/exercise during the fast. …

There is a lot of evidence that our bodies run better on average when we have substantial periods of fasting. Some of the evidence is on “Time Restricted Feeding” (TRF), which involves an eating window of no more than 12 hours a day and hence daily periods of about 12 hours with no food. Some of the evidence is on alternate-day fasting (ADF), which probably involves fasting periods of 32 hours or more. Other evidence is about modified alternate day fasting (MADF), which restricts calories to something like 500 calories on the “modified fasting” day. Anton et al. argue that the benefits of fasting are greater than the benefits of continuous calorie restriction (CR) which means eating three meals a day on a typical schedule, just less in each meal. Here are some of the benefits as Anton et al. describe them (emphasis added):

Placing time restrictions on feeding has been shown to have broad systemic effects and trigger similar biological pathways as caloric restriction.(5) For example, IF [intermittent fasting] regimens have been shown to improve cardio-metabolic risk factors (such as insulin resistance, dyslipidemia and inflammation cytokines),(13) decrease visceral fat mass,(6) and produce similar levels of weight loss as CR [continuous caloric restriction] regimens.(8) In addition to the weight loss effects and metabolic improvements, several other beneficial effects of therapeutic fasting have been described including improvements in lipid profiles,(14) osteoarthritis,(15) healing of thrombophlebitis,(15) healing of refractory dermal ulcers, (16) and tolerance of elective surgery.(17)

Some people worry that fasting will reduce lean muscle mass. But the evidence suggests that it is continuous caloric restriction that reduces lean muscle mass, not fasting:

… retention of lean mass is increased following IF regimens for weight loss as compared to continuous CR regimens in humans.(8) Additionally, in mice, the decline in muscle mass that occurs during normal aging is prevented by time restricted feeding (TRF) involving 40% caloric restriction.(23)

With caloric restriction, approximately one-fourth to one-third of the weight loss is known to be of lean tissue. In a study of 34 healthy men randomly assigned to either a normal control diet or daily TRF (16 hours of daily fasting) and followed for two months during which they maintained a standard resistance training program, the men in the TRF group showed a reduction in fat mass with retention of lean mass and maximal strength.(125)

Rodent Evidence

References to the emerging human evidence on fasting are sprinkled throughout this post. But some of the important evidence on the benefits of fasting is rodent evidence. In “The Case Against Sugar: Stephan Guyenet vs. Gary Taubes,” I express my doubts about the relevance of rodent evidence when arguing about lowcarb vs. lowfat diets, because rodents are probably much better adapted to a highcarb lowfat diet than humans are. (If nothing else, those rodents than hung around humans had many times as many generations to adapt to the agricultural revolution than humans did because rodent generations are a lot shorter than human generations.) However, when it comes to fasting, it seems more likely that key mechanisms are the same between human beings and rodents. The particular diet rodents are adapted to is different from humans, but the historical need to endure periods of little or no food is similar between humans and rodents. Here is a description of some of the rodent evidence (emphasis added):

Interestingly, the decline in muscle mass that occurs during normal aging in mice is prevented by 40% CR/TRF … (23) …

The decline in cognitive function with age is forestalled in mice maintained on 40% CR/TRF.(97, 98) … (99) … (97)

Recent studies of laboratory animals provide further support that cognitive function and physical performance are enhanced by IF. … (106) … (107) … (108) Thus, findings from pre-clinical trials suggest IF can improve cognitive and locomotor performance even when initiated late in life.

Numerous studies have shown ADF can protect neurons in the brain against dysfunction and degeneration in animal models of a range of different neurological disorders including epilepsy,(109) Alzheimer’s disease,(110) and Parkinson’s disease (111) and stroke (112).

Is Fasting Dangerous?

The simple answer to the question “Is fasting dangerous?” is that complications can arise with fasts of several weeks or more. Anton et al. write “The adverse events described above have only occurred during or following extended fasts of several weeks or more” (emphasis added) about the following list:

… nausea and vomiting,(47) edema,(48) alopecia and motor neuropathy,(14) hyperuricemia and urate nephropathy,(49) irregular menses,(49) abnormal liver function tests and decreased bone density,(17) thiamine deficiency and Wernicke’s encephalopathy,(5051) and mild metabolic acidosis.(52) Additionally, several deaths have been reported during or immediately following therapeutic fasting with the etiologies including lactic acidosis, small bowel obstruction, renal failure, and cardiac arrhythmias.(53)

In human history, there is a lot of experience with fasting. It is not a new idea:

Historically, fasting has been used as both a religious and a medical practice for thousands of years. Fasting for medical purposes has been suggested since the time of ancient Chinese, Greek and Roman physicians.(33) Throughout the millennia, many have recommended fasting for medical reasons. For example, Benjamin Franklin has been quoted as saying “The best of all medicines is resting and fasting.”(34) Similarly, Mark Twain wrote “A little starvation can really do more for the average sick man than can the best medicines and the best doctors. I do not mean a restricted diet; I mean total abstention from food for one or two days.”(35)

Experimental evidence for the benefits of fasting are bolstered by observational evidence of religiously-motivated fasting:

An emerging literature indicates IF can also ameliorate many of the key features of the metabolic syndrome in humans by decreasing fasting glucose, fasting insulin, and insulin resistance.(8, 138) …

… IF regimens ranging in duration from 8 to 24 weeks have consistently been found to decrease insulin resistance.(12, 115, 118, 119, 122, 123, 131, 132, 134, 140) In line with this, many, but not all,(7) large-scale observational studies have also shown a reduced risk of diabetes in participants following an IF eating pattern. For example, in a study conducted by Horne and colleagues,(120) a series of patients in Utah undergoing coronary artery cauterization were surveyed for the practice of periodic fasting (a common religious practice in the Mormon Church) and for the presence of diabetes based on diagnosis and medication use. Participants who reported periodically fasting had a significantly lower odds ratio for having diabetes compared to those who did not report fasting regularly.

(I used to be a Mormon, so this is relevant to my personal experience. See “"A Barycentric Autobiography.”)

What Does This Mean for You?

First, you should think of fasting as being in the same angelic category as exercise. Anton et al. write:

Accumulating evidence suggests some organ systems exhibit similar cellular and molecular responses to aerobic exercise and IF (e.g., suppression of mTOR, stimulation of autophagy, and mitochondrial biogenesis).(83, 84)

The effects of ADF on heart rate, blood pressure and heart rate variability are very similar to the effects of endurance training, suggesting similar underlying mechanisms.(94)

Second, don’t fall into the pattern customary for our culture of three meals a day, every day:

Individuals with a typical Western eating pattern of three or more meals per day never flip the metabolic switch and thus their ketone levels remain continuously low. Additionally, as their insulin resistance increases with excess weight and diabetes, the time it takes to flip the switch is prolonged (Figure 2). … IF [intermitten fasting] eating patterns may result in a wide range of beneficial effects on health including improved glucose metabolism,(7, 10, 114116) reduced inflammation,(117, 118) reduced blood pressure,(12, 75, 115, 119) improved cardiovascular health,(120123) and increased resistance of cells to stress and disease in humans (Figure 3).(118, 124)

I have a lot of posts about fasting listed in my bibliographic post “Miles Kimball on Diet and Health: A Reader's Guide.”

What Further Research is Needed?

Anton et al. call for the following additional research:

Human trials of IF that include cognitive and physical performance outcomes are unfortunately limited. Studies of cognition and mood during extended fasts, however, suggest few or no adverse effects, and improvements in performance in some cognitive domains including executive function have been reported.(142144) In regards to physical performance, a recent randomized controlled trial of IF (20 hours of fasting 4 days/week) during one month of resistance training in men demonstrated superior improvements in upper and lower body endurance in the IF group compared to the control group.(130)

While our review suggests IF results in both weight and fat loss (even when caloric intake is not limited), as well as increased insulin sensitivity in overweight subjects, there remains an important need for randomized controlled trials (RCTs) of IF in normal weight subjects. Emerging findings indicate that IF when combined with resistance training can produce beneficial changes in body composition and strength in young, healthy males. Additional studies are needed to better understand the effects of combining IF with resistance training on body composition and strength outcomes in other populations.

There remains an important need for interventions that can improve unhealthy changes in body composition that occur during aging. Given the known loss of lean mass that occurs during both aging and continuous CR, IF regimens may be an effective approach to help older adults lose unhealthy weight while retaining larger amounts of lean mass.

I notice one other huge hole in the research that has been done so far. I am gradually learning more about research on diet and health. So far, it is my sense that research on what to eat (especially the lowcarb vs. lowfat debate) and research on when to eat have proceeded mostly in isolation from one another. This is too bad. If I have had one big them on this blog is that lowcarb (or really, low-insulin-index) eating (see “Forget Calorie Counting; It's the Insulin Index, Stupid”) is the key to making fasting easier.

I read the evidence so far as indicating that both lowcarb eating and frequent fasting are separately beneficial. But I’ll bet that together they are even better. We need evidence to test this idea. The concept of a metabolic switch helps explain why lowcarb eating and fasting might go together well. If you are eating highfat lowcarb, it is more similar metabolically to the body metabolizing its own fat, so there is less of a wrenching changeover during fasting. (I hasten to add that when I say highfat, lowcarb, that carbs like nonstarchy vegetables are totally exempted. By lowcarb, I only mean low in easily digestible carbs like processed food, starchy vegetables and excessive fruit.)


There are many areas where the lack of research angers me. Fortunately, research on fasting is coming thick and fast. The evidence is coming in so strongly, that pro-fasting attitudes are likely to begin to appear more and more in popular culture. But everyone who wants to try fasting should also try combining it with a low-insulin-index diet to see if my prediction that fasting will then be easier is borne out for them.

For annotated links to other posts on diet and health, see “Miles Kimball on Diet and Health: A Reader's Guide.”