In Healthy Eating Less is More: The Science Behind Intermittent Fasting

Mix a love of eating with a desire to live a long, healthy life what do you get? Probably the average 21st-century person looking for a way to continue enjoying food despite insufficient exercise and/or an age-related decline in caloric needs.

Enter intermittent fasting, a topic that has found its way into most news sources, from National Institutes of Health (NIH) and Proceedings of the National Academy of Sciences publications to WebMD and even the popular press. For instance, National Public Radio’s “The Salt” writers have tried and written about their experiences with dietary restriction.

While fasting has enjoyed fad-like popularity over the past several years, it is not new. Fasting, whether purposely not eating or eating a restricted diet, has been practiced for 1,000s of years. What is new is research studies from which we are learning the physiologic effects of fasting and other forms of decreased nutrient intake.

You may have heard the claims that fasting makes people smarter, more focused, and thinner. Researchers today are using cell and animal models, and even human subjects, to measure biochemical responses at the cellular level to restricted nutrient intake and meal timing, in part to prove/disprove such claims (1,2).

I confess to coveting those benefits, but fasting is no piece of cake. I’d like to understand how intermittent eating affects cellular processing and physiology.  To that end, here are two recent reports:

Plant-based foods. Original image by Keith Weller, USDA ARS – This image was released by the Agricultural Research Service, the research agency of the United States Department of Agriculture, with the ID K3839-3 (n
Licensed under Wikimedia Commons. See:

In a 2017 report in Science Translational Medicine, “Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer and cardiovascular disease”, Wei et al. studied the results of caloric restriction on human volunteers. Their study involved 100 volunteers divided into two groups; One group followed an unrestricted diet for 3 months. The other group followed an FMD (fasting-mimicking diet), which was low in calories, sugars, and protein but high in unsaturated fats. The FMD subjects consumed the special diet for 5 consecutive days per month, and ate an unrestricted diet the other 25 days of each month, for 3 months. The study participants ranged in age from 20 to 70 years of age.

Briefly, here are some of the FMD study results.

Waist circumference of the FMD group was reduced by 4.1 +/- 5.2cm (P = 0.0035 between groups).
Insulin-like growth factor-1 (IGF-1) of FMD group decreased by 21.7 +/- 46.2 ng/ml (P = 0.0017 between groups). IGF-1 is widely recognized as a cellular protection mechanism in cases of fasting. IGF-1 is well-studied in metabolism and growth as well as for its association with aging and cancer.
Systolic blood pressure decreased by 4.5 +/- 6.0 mm Hg
Diastolic blood pressure decreased by 3.1 +/- 4.7mm Hg (P = 0.053 between groups).

Safety Considerations and Details about the FMD
The FMD authors note that a restrictive diet such as FMD for 5 days, should only be undertaken with medical supervision, as this is considered a prolonged period of fasting. The FMD is a plant-based diet designed to attain fasting-like effects on serum levels of IGF-1, IGFBP-1, glucose, and ketone bodies while providing macro and micronutrients to maintain health. The FMD comprises proprietary formulations of vegetable-based soups, energy bars and drinks, snacks, and tea plus a supplement of minerals vitamins, and essential fatty acids. The items were prepackaged into daily allotments, to assure subjects ate only their daily amount.

Wei et al. concluded that three cycles of FMD reduced body weight, trunk and total body fat, blood pressure, and IGF-1 in comparison to a normal diet. In this publication, Wei et al. also note the need for additional studies. The paper also has a link to a website where you can learn more about the foods used in the FMD.

Also very interesting is a 2014 PNAS perspectives article, “Meal frequency and timing in health and disease” that included author, British physician, and television broadcaster Michael Mosley. The paper’s lead author Mark Mattson works at the Laboratory of Neurosciences, National Institutes on Aging in Baltimore, MD.

These authors noted that

“Emerging findings from studies of animal models and human subjects suggest that intermittent energy restriction periods of a little as 16 hours can improve health indicators and counteract disease processes.”

The mechanisms involved are a shift to fat metabolism and ketone production, plus stimulation of adaptive cellular stress responses that prevent or repair molecular damage. The goal of this work was to examine the physiological response of both lab animals and human subjects to variations in meal size, frequency and timing.

In this work, Mattson et al. studied three dietary regimens: 1) Caloric restriction in which daily calorie intake is reduced by 20–40% but meal frequency is unchanged; 2) Intermittent energy restriction (IER) involving fasting or greatly reducing daily calorie intake (e.g., 500 calories per day) intermittently, such as for 2 days/week; 3) time-restricted feeding (TRF), which involved limiting daily food and beverage intake to a 4- to 6-hour time window.

We Didn’t Always Eat This Way
The authors note that consumption in modern human societies generally follows a daily schedule of three meals plus snacks, and that this habit is abnormal from an evolutionary standpoint. They point to historical and modern animal habits of intermittent eating, such as carnivores that kill and eat prey only a few times per week, sometimes even less frequently.

Mammals have adaptations for intermittent food supply, including organs for uptake and storage of readily available glucose (stored as glycogen in the liver) and longer-lasting energy substrates like fatty acids stored in adipose tissue. Furthermore, wild animals and modern hunter-gatherer societies (like the Kalahari Bushmen of Africa and Spinifex in Australia), intermittent eaters all, are rarely if ever obese. On the other hand, those of us consuming 2-3 daily regularly scheduled meals, as well as our ad libitum-fed dogs and cats are frequently on the high side of what is considered a normal healthy weight.

Circadian Rhythms and Meal Timing
Circadian rhythms are approximately 24-hour oscillations in physiology, behavior and metabolism that probably evolved to enable a response to daily changes in light and dark connected to changes in food availability. Studies have shown that more than 10% of expressed genes in a given organ show circadian oscillation (2).

While light is the primary timing cue for the main circadian clock organ, the hypothalamic suprachiasmatic nucleus (SCN), timing of food intake affects the phase of peripheral tissue clocks including those of liver, muscle and adipose tissue (2). Studies in flies and humans have shown that modern exposure to prolonged artificial light and erratic eating behavior interrupt the circadian system. In rodent models, extended illumination has increased disposition to metabolic disease. Flies that were shifted to a nighttime feeding schedule showed interrupted fat metabolism and reproduction. Human subjects exposed to a 12-hour change of sleep/wake and fasting/feeding, while maintaining their usual caloric intake, showed reduced glucose tolerance, elevated blood pressure and a decrease in the satiety hormone leptin (2).

Furthermore, Mattson et al. mention several studies tying circadian clock components to particular nutrient metabolism. For instance, the nuclear hormone receptors REV-ERBs are integral to circadian clock activity and directly regulate transcription of several rate-determining enzymes for fatty acid and cholesterol metabolism.

Results of Intermittent Energy Restriction (IER)
In a variety of creatures (yeast, worms, mice and monkeys) dietary energy restriction has been shown to extend lifespan compared to ad libitum-fed controls. IER/fasting has been shown to stall and even reverse disease progression in animal models of certain cancers, cardiovascular disease, diabetes and neurodegenerative disorders. The authors briefly highlighted four general mechanisms by which IER protects at the cellular level.

Stress Response: Laboratory animals exposed to alternate day fasting showed a reduction in antioxidant enzymes superoxide dismutase 1 and catalase in liver cells, while IER increased levels of antioxidant enzymes NADH-cytochrome b reductase and NAD(P)H-quinone oxidoreductase 1 in muscle. These effects were extended by exercise.

IER has been shown to protect neurons against oxidative, metabolic and proteotoxic stress in models of neurodegenerative disorders such as Alzheimers and Parkinson’s diseases. IER has been shown to protect heart muscle against ischemic damage in an animal model of myocardial infarction.

Mattson et al. summarize a number of IER and alternate day fasting studies, stating that IER has a beneficial effect that they call “hormesis” or “preconditioning”, where exposing cells to a mild stress (such as caloric restriction due to intermittent feeding) results in adaptive responses that protect against more severe stressors.

Bioenergetics: You have perhaps heard the claims that fasted persons have more energy. Here is how it works. Humans that switch from three meals a day to an IER diet of one moderate meal every other day or 500-600 calories for 2 days/week exhibit marked energy metabolism changes including increased insulin sensitivity, reduced levels of insulin and leptin, fatty acid mobilization and elevation of ketone levels. Ketones are known to have beneficial effects on energy-requiring cells such as neurons. Dietary energy restriction can prevent age-related decline in mitochondrial oxidative capacity in skeletal muscle and can even induce mitochondrial biogenesis.

Where IER/fasting is beneficial and overeating detrimental to many normal cells, IER has been shown to be detrimental to tumor cells. In numerous animal studies, IER inhibits and even reverses tumor growth for tumors including neuroblastoma, breast and ovarian cancers. Ketogenesis due to IER may be at play here, since tumor cells are reliant on glucose/glycolysis and can’t use ketones as an energy source.

Inflammation: We know that all major diseases, cardiovascular, cancer, arthritis, neurodegenerative and diabetes, involve chronic inflammation locally, and in many cases, systemically. We also know that the incidence of many of these diseases is on the rise. Local tissue inflammation involves hyperactivation of macrophages and microglia in the brain and production of proinflammatory cytokines like Il-1, TNF and IL-6, plus reactive oxygen species. In animal and human subjects, IER has been shown to suppress inflammation.

Obese women who changed from multiple daily meals to alternate-day energy restriction exhibited significant reduction in circulating IL-6 and TNF. Multiple studies have shown that fasting lessens symptoms in patients with rheumatoid arthritis and data show that IER may lessen pathogenesis of autoimmune disorders including MS, lupus and type I diabetes (2).

Improved Cellular Repair/Removal: Two dedicated mechanisms for removal of damage cellular components are tagging with ubiquitin, which targets damaged proteins for degradation via the proteasome, and autophagy, where damaged or dysfunctional cell components are directed to lysosomes for removal. Studies have shown that when organisms receive a steady supply of nutrients cells remain in growth mode with protein synthesis and suppressed autophagy. The mTOR pathway is nutrient-driven and blocks autophagy, while fasting inhibits mTOR, upregulating autophagy in many cell types. Thus fasting provides a cellular cleanse, removing damaged molecules and organelles.

The authors emphasize that much more work needs to be done to tease out the effects of fasting or energy restriction on cells and on people.

These articles do not intend to provide guidance on fasting or an intermittent energy diet, and the authors of these papers note that no strict dietary changes should be made without the supervision of your personal physician.

This is really interesting preliminary information on how we may be able to improve health by limiting consumption. It makes sense from an evolutionary standpoint—our long distant relatives not only survived without indoor plumbing and heat but also with sometimes severely limited access to food.

For me, one big question is if I stop eating as frequently, what to do with the time that was previously spent in consumption? More exercise? Reading? Implementing an energy-restricted diet will definitely require planning.

Have you tried IER or fasting? How did it work for you and have you kept at it? We’d love to hear your story.


  1. Wei, M. et al. (2017) Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer and cardiovascular disease. Sci. Transl. Med. 9, 377.
  2. Mattson, M. et al. (2014) Meal frequency and timing in health and disease. PNAS 111 (47) 16647.
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Kari Kenefick

Kari Kenefick

Kari has been a science writer/editor for Promega since 1996. Prior to that she enjoyed working in veterinary microbiology/immunology, and has an M.S. in Bacteriology, U of WI-Madison. Favorite topics include infectious disease, inflammation, aging, exercise, nutrition and personality traits. When not writing, she enjoys training her dogs in agility and obedience. About the practice of writing, as we say for cell-based assays, "add-mix-measure".


  1. I haven’t tried a fasting diet myself but a couple people I work with have tried ‘The Fast Diet’, which is very much like the IER (2 days a week are 500-calorie days), and were happy with it for a while. It’s a difficult one to maintain in a society where most social interactions revolve around food or alcohol consumption… It probably helps if your friends or colleagues are like-minded to keep the temptations to a minimum!

    1. I agree, Teresa! Eating is very social–super tough to spend a night out and eat only 500 calories! Alcohol is very calorie-intense too!
      Thanks for ‘weighing in’ ]; > -Kari

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