A large number of research studies have investigated the impacts of caloric restriction and intermittent fasting in many different species, from fruit flies to mice to monkeys. A quick Google Scholar search yields more than 8,000 results for scholarly articles on “intermittent fasting”.

Relatively few studies have evaluated the impacts of fasting in humans, in comparison to studies of impacts in animal models. These relatively few human studies, however, demonstrate that various intermittent fasting schedules have promising benefits for human health.

Dr. Mark Mattson, a neuroscientist at the National Institute on Aging and a professor of neuroscience at Johns Hopkins University, studies the cellular and molecular mechanisms that underlie these benefits. He likens intermittent fasting to exercise; both are “good” stressors that prompt the body to ramp up stress-busting, self-cleanup and anti-inflammatory processes.

“If you don’t expose yourself to mild bioenergetic stress, whether it’s exercise or fasting intermittently, then it’s not so good for your cells, particularly as you age. You aren’t tapping all of the processes that help cells resist stress, function efficiently and fight disease,” Mattson said.

The analogy between exercise and fasting goes further, especially if you agree with Mattson’s view of fasting and subsequent refeeding as a “metabolic switch” that takes the body through a growth phase, a cleanup phase and back again. In this view of fasting, the refeeding phase is just as important as the fasting phase.

When you exercise, you put stress on your muscles and cardiovascular system in a way that prompts your body to produce more muscle cells and more mitochondria, which are the “power plants” inside of those cells. There are even some studies that suggest that proteins released from muscles during exercise, known as myokines (myo = muscle, kine = signaling), act as signaling molecules in the brain. There they promote new synapse formation between nerve cells, or synaptic plasticity, and the formation of new nerve cells from stem cells in some regions of the brain.

“Synaptic plasticity is the brain’s ability to strengthen or weaken connections between pairs of functionally linked neurons. Neurons form functional circuits through specialized nodes called synapses. The synapse is where one neuron talks to another. Aged neurons in the hippocampus and prefrontal cortex also have fewer synapses…” – Shelly Xuelai Fan, science writer and neuroscientist

But the muscle cell growth and brain health outcomes of exercise don’t happen during your workout – they actually occur when you rest and sleep after a day of physical activity.

“Your muscles aren’t getting bigger when you are lifting weight or exercising,” Mattson laughs. “It’s when you eat and sleep.”

The same appears to be true of intermittent fasting. Fasting puts cells, including muscle cells and likely also nerve cells, into a stress-resistance mode that benefits these cells when nutrients become available again.

“The stress period, whether it’s fasting or exercise, puts the cells in a stress-resistance mode; they don’t grow and they reduce their overall protein synthesis while enhancing their removal of damaged molecules and proteins through autophagy,” Mattson said. “Then during the resting or refeeding period, once the cell has cleared out the garbage, protein synthesis goes up and new, undamaged proteins are created. We have evidence that this doesn’t just benefit muscle cells, but that in the brain, new synapses may be formed between nerve cells, probably during the resting and refeeding period. These wouldn’t have formed if the individual hadn’t been subjected to the stress in the first place, whether through fasting or exercise.”

Of course, most of the studies that have revealed the positive impacts of fasting on autophagy, inflammation (2), synapse formation and other mechanisms underlying chronic disease have been done in animal models, not humans. We certainly need more human studies, particularly investigating the impacts of fasting in specific human populations and for specific disease states, in order for physicians to begin to prescribe fasting interventions with any kind of precision.

But what DO we know today about the impacts of intermittent fasting in humans. What do we know that we can begin to apply?

We recently interviewed Dr. Mark Mattson, a veritable “giant” in the field of intermittent fasting research and its underlying mechanisms, to address this question. He has published a total of four controlled human studies that investigate the impacts of various intermittent fasting interventions. He is also currently conducting a fifth study to look for signs of the cognitive and neurological benefits of fasting. We summarize these five studies in this blog post.

A lot of the initial research on intermittent fasting in humans has been observational, based on results observed in people fasting for Ramadan and in bodybuilders, for example.

“Bodybuilders don’t just want build muscles, but they want them to show. You need two things for that – big muscles and not much fat,” Mattson said. “It turns out that a lot of bodybuilders, perhaps by trial and error, have found that if they don’t eat breakfast, work out midday or around 16 hours fasted, and then eat in the ensuing time, they are able to maintain and build muscle while losing more fat. There have actually been some studies showing this – you can maintain and build muscle while on an intermittent fasting regimen.”

This small scale human study also showed that regular overnight fasting may reduce inflammation and contribute to muscle repair after exercise.

Observational studies of Ramadan fasting have also generally shown that fasting may have weight loss and metabolic health benefits. Ramadan fasting typically involves avoiding calories from sunrise to sunset. Studies of Ramadan fasting almost always involve observation rather than controlled experiments, meaning that they can’t tell us if fasting caused the observed health benefits. However, Ramadan fasting has been shown to positively impact body weight and body fat, at least during the month of Ramadan, as well as levels of pro-inflammatory cytokines (IL-6, TNF-α) and blood pressure.

“[Our] results indicate that Ramadan fasting in young healthy individuals has a positive impact on the maintenance of glucose homeostasis. It also shows that adiponectin levels dropped along with significant loss in weight. We feel caloric restriction during the Ramadan fasting is in itself sufficient to improve insulin sensitivity in healthy individuals.” – Gnanou et al. 2015

Observational studies can give us a picture of what impacts fasting has in humans. However, randomized controlled trials are considered to be evidence of a higher standard and necessary to make health recommendations around something like fasting. People participating in a controlled cohort study or controlled trial are given strict guidelines to follow for a health intervention and typically report to a health provider setting in order for their outcomes (weight, blood pressure, blood biomarkers, etc.) to be measured. People participating in a randomized controlled trial are randomly (e.g. by the flip of a coin) assigned to either a group receiving a treatment or intervention of interest, or to a group receiving a placebo or a control treatment. In the best trials of new pharmaceutical drugs, for example, participants are “blinded” to the treatment group they are in – they don’t know if they are receiving the experimental drug or a placebo (e.g. a sugar pill).

For intermittent fasting, it’s difficult to have a “blinded” treatment or a placebo – you know whether you are fasting or not! However, controlled studies of intermittent fasting can compare intermittent fasting to a standard calorie-restricted diet “control”. The control treatment in this case is important in order for researchers to evaluate the benefits of fasting while “controlling” for the benefits that would come from any type of weight loss.

In terms of evidence based on controlled studies of intermittent fasting, we know more about the impacts of fasting in overweight, prediabetic and inflammation-prone individuals, as opposed to healthy individuals. Several controlled studies conducted by Mattson and others reveal that intermittent fasting can promote weight loss (usually to the same extent as standard dieting) and improve biomarkers of metabolic and cardiovascular health for overweight individuals.

“What we can say for sure is that overweight humans who can switch their eating pattern to intermittent fasting and stick with it are going to maintain a lower body weight with lower ‘bad’ fat stores and better glucose regulation,” Mattson said.

Study 1: Intermittent Fasting in Asthma Patients

“Asthma subjects lose weight and exhibit improved mood and peak airflow when maintained on an alternate day calorie restriction diet.” – Johnson et al. 2006

Mattson’s first study of intermittent fasting in humans was a cohort study and investigation into the impacts of fasting in asthma patients. In a study published in 2006, 10 obese individuals (with a BMI over 30) with moderate to severe asthma maintained an alternate day intermittent fasting schedule for 8 weeks. On this dietary regime, they ate what they wanted when they wanted it every other day, while eating less than 20% of their normal calorie intake (partly in the form of a low-carb meal replacement shake) on their fasting days. This was equivalent to less than 500 calories on alternate fasting days.

The researchers measured baseline values on factors including hunger, weight, mood, asthma symptoms, airway resistance and blood markers of inflammation for all of the individuals in the study. The participants then started their alternate day fasting intervention, which lasted two months. The researchers re-evaluated the participants’ hunger, weight, mood, asthma symptoms, airway resistance and various blood markers approximately every two weeks.

The impacts of this study of intermittent fasting were quite significantly positive and have set the stage for many follow-up studies on how fasting can improve markers of inflammation.

The obese asthma patients in this study lost an average of 8% of their body weight during the course of the study. Their ketone levels also increased on fasting days, confirming that they were adhering to their alternate day fasting regimen.

The study participants reported that their mood and energy levels improved throughout the study, with most of these improvements happening over the first three weeks of the regimen and staying elevated thereafter. Their hunger sensation levels on fasting days stayed about the same throughout the study.

The results of the study get exciting when it comes to asthma symptoms and the markers of inflammation and oxidative stress that Mattson’s lab evaluated in the patients’ blood samples.

“Not immediately, but between two and four weeks of having been on the intermittent fasting regimen, the participants’ asthma symptoms and airway resistance improved and their markers of inflammation and oxidative stress went down. This improvement even persisted for up to two months following the intervention,” Mattson said.

“The improved clinical findings were associated with decreased levels of serum cholesterol and triglycerides, striking reductions in markers of oxidative stress (8-isoprostane, nitrotyrosine, protein carbonyls, and 4-hydroxynonenal adducts) and increased levels of the antioxidant uric acid. Indicators of inflammation, including serum tumor necrosis factor-α and brain-derived neurotrophic factor, were also significantly decreased by [alternate day fasting].” – Johnson et al. 2006

Impressively, the asthma patients who had practiced intermittent fasting for two months showed similar improvements in their asthma symptoms and pulmonary function as patients newly started on controller medications for asthma including a medication called singular (which the author of this blog post personally takes for asthma). Pulmonary function was measured as peak expiratory flow, known commonly as the breathing test measurement if you’ve even been tested for asthma.

“Levels of […] markers of inflammation and oxidative stress were decreased on both ad libitum and CR days, indicating a sustained effect of the [alternate day fasting] diet that did not fluctuate in response to the level of energy intake on the day prior to blood sampling.” – Johnson et al. 2006

Studies 2 and 3: The 5:2 Diet in Obese Individuals

While the study of intermittent fasting impacts on asthma patients described above was promising, it only evaluated impacts in a very small group of patients. Subsequent studies that Mattson worked on tested the impacts of modified fasting for two days every week in larger samples of overweight women.

With first author Michelle Harvie, a research dietitian at the University Hospital South Manchester Trust and a breast cancer researcher associated with the University of Manchester, Mattson published two studies investigating the impacts of fasting in overweight women. These studies, published in 2010 and in 2013, formed the basis of what is today known as the 5:2 diet. This intermittent fasting schedule involves partially fasting two days out of every week by consuming only one moderate-sized meal or under 500 calories on those two days.

The first study was a randomized controlled trial in 107 overweight or obese premenopausal women. These women were randomly assigned to follow either a 5:2 intermittent fasting schedule (75% calorie restriction on fasting days) or a continuous calorie restriction diet (25% calorie restriction every day) for six months. In both groups, the participants could eat foods that included carbohydrates, but were instructed to follow a Mediterranean-type diet. On fasting days in the 5:2 diet group, the women essentially ate around two pints of semi skimmed milk, four servings of vegetables (~80 g/serving), a serving of fruit, a salty low calorie drink and a multivitamin and mineral supplement.

All participants were asked to keep 7-day food diaries so that the researchers could track their adherence to their fasting schedules or diets. They were encouraged to use techniques such as self-monitoring, obtaining peer and family support and avoiding tempting environments in order to maintain their diets. (Our LIFE Fasting Tracker app can help with these techniques!)

About 80% of women who started the study, finished it, with most dropouts occurring in the first three weeks.

“This told us that for people who have always eaten three meals plus snacks, shifting to eating only 500 calories on a fasting day may make them feel very hungry, irritable and unable to concentrate,” Mattson said. “But if they can stick with it for close to a month, those initial side effects often completely disappear as they become adapted.”

The researchers measured the participants’ weight and biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk, at baseline and after one, three and six months on the 5:2 diet. They found that women who practiced the 5:2 diet lost about the same amount of weight as women who counted and restricted their calories on a daily basis.

The intermittent fasters however had slightly greater reductions in insulin levels, while all of the women experienced comparable reductions in leptin (a hormone that regulates appetite and fat storage), free androgen index (a biomarker for breast cancer risk), high sensitivity C-reactive protein (associated with inflammation), total and LDL cholesterol, triglycerides and blood pressure. The menstrual cycle was also longer in women who were practicing a 5:2 diet.

“[T]he greater average cycle length amongst the [intermittent fasting] women may reduce breast cancer risk and reflect increased follicular length.” – Harvie et al. 2010

In a follow-up study and randomized trial with a similar protocol, even greater impacts were observed for women who followed, for four months, a 5:2 diet that restricted not just calories on fasting days, but also carbohydrates. In this case, the participants who fasted consumed less than 40 grams of carbohydrates on fasting days, with relatively higher consumption of protein and fat. On fasting days the women essentially ate 250 grams of protein foods including lean meat, fish, eggs and tofu, along with three servings of low-fat dairy foods, four servings of low-carbohydrate vegetables and one serving of low-carbohydrate fruit. Protein intake, in particular, helped minimize hunger on fasting days.

Participants were women who had a family history of breast cancer. The researchers found that for these women, the 5:2 diet with carbohydrate restriction was superior to a continuous calorie restricted Mediterranean-type diet in terms of promoting greater body fat loss and improved insulin sensitivity.

“The take-home of these two studies is that women on the 5:2 diet had improved glucose regulation and lost more abdominal fat than women who counted calories for every meal of every day,” Mattson said. “This is because on the days they were eating only 500 calories, they depleted all of the energy in their liver and started using fats. By comparison, with a continuous calorie restriction diet, even if you have a reduced calorie intake at every meal, you are still replenishing your liver energy stores every time you eat.”

It’s intriguing to look at adherence to the 5:2 diet versus the continuous calorie restriction diet in these studies. By three months into their diets, the intermittent fasters in the second study were still adhering to their calorie and low carbohydrate goals on 70% of their designated fasting days. On the other hand, people following the continuous calorie restriction diet were only hitting their calorie goals approximately every one out of three days (39% of days).

“Although weight control is beneficial, the problem of poor compliance in weight loss programmes is well known (9). Even where reduced weights are maintained, many of the benefits achieved during weight loss, including improvements in insulin sensitivity, may be attenuated due to non-compliance or adaptation (10). Sustainable and effective energy restriction strategies are thus required. One possible approach may be intermittent energy restriction (IER), with short spells of severe restriction between longer periods of habitual energy intake. For some subjects such an approach may be easier to follow than a daily or continuous energy restriction (CER) and may overcome adaption to the weight reduced state by repeated rapid improvements in metabolic control with each spell of energy restriction (11).” – Harvie et al. 2010

What do you find easier? Restrictive diets or intermittent fasting?

Study 4: Intermittent Fasting for Multiple Sclerosis

More recently, Mattson helped to conduct a study in collaboration with Drs. Kate Fitzgerals and Ellen Mowry, neurologists at Johns Hopkins, to evaluate the safety and feasibility of intermittent fasting interventions in 36 patients with multiple sclerosis. Mattson helped design the study.

The researchers again used a 5:2 diet protocol, with 75% calorie restriction or energy need reduction on two fasting days per week. They compared this to a continuous calorie restriction diet and a stable diet. The researchers did not observe any adverse events for the patients during the study.

All of the patients on either the 5:2 diet or the continuous calorie restriction diet lost weight, but the weight loss wasn’t significantly different between these groups. These patients did however, over the course of 8 weeks, report significant improvements in emotional well-being and depression when compared to patients on a stable diet (the control group).

Based on this study, Mattson and colleagues are seeking funding to conduct a larger and longer term study of intermittent fasting on symptoms and health in patients with multiple sclerosis.

Drs. Mowry and Fitzgerald are also currently performing a trial of daily time-restricted feeding in multiple sclerosis patients.

Study 5: Moving Forward with Brain Health

We need more studies of intermittent fasting in humans, particularly to demonstrate the touted cognitive function and brain health benefits of fasting. Mattson is working as we speak to address this gap, in collaboration with Dr. Dimitrios Kapogiannis, a neurologist in Mattson’s group at the National Institute on Aging.

“There’s quite a bit of evidence that, as with your other organ systems, long-term chronic obesity bodes poorly for your brain health as you age,” Mattson said. The idea is that intermittent fasting could help people achieve weight loss as well as reduce inflammation levels in their brains in a way that would help delay and even prevent neurodegenerative disease.

“A major ecological factor that drove the evolution of cognition, namely food scarcity, has been largely eliminated from the day-to-day experiences of modern-day humans and domesticated animals. Continuous availability and consumption of energy-rich food in relatively sedentary modern-day humans negatively impacts the lifetime cognitive trajectories of parents and their children.” – Mattson, 2019

Mattson and Kapogiannis have recruited 40 individuals who are at risk of cognitive impairment and Alzheimer’s disease because of their age (they range from 55 to 70 years old) and their metabolic status (they are obese and insulin resistant) to participate in this new study. These individuals will be randomly assigned to either a 5:2 diet or a health intervention that involves simply advice for healthy eating and lifestyle.

At baseline and at two months into the fasting intervention, the researchers will collect brain health data via a battery of psychological tests of cognition as well as via functional MRI (magnetic resonance imaging). Functional MRI can create a map of brain activity by measuring changes associated with blood flow. This imaging and other data the researchers will collect will reveal whether intermittent fasting can impact nerve cell network activity and improve learning and memory in the aging brain!

Mattson will also help analyze cerebral spinal fluid from the intermittent fasting individuals, obtained via spinal taps, to look for changes in the levels of a brain cell growth regulator called BDNF. Mattson has shown in his research that the neurochemical BDNF, brain-derived neurotrophic factor, increases in the brains of mice and rats when they are put on intermittent fasting regimens. Increased BDNF is thought to be responsible for some of the mental clarity and improved cognitive function associated with intermittent fasting in humans.

“From the cognitive health standpoint, our data is looking really good so far,” Mattson said.

We will be excited to hear about the results!