Intermittent fasting or time restricted eating has become increasingly trendy, but do you know what it means, and if there is supporting evidence?
A diet of 3 meals and snacks every day is so ingrained in our culture, that changing this pattern is rarely contemplated. However, there have been many studies now providing a large body of evidence about what happens when we intermittently fast. Some of this research has been performed in animals and then replicated in clinical trials on humans. While intermittent fasting has been associated with weight loss, many of the metabolic benefits do not seem to be simply the result of this. To understand the efficacy, mechanism and safety profiles of interventions in humans, research using animal models is almost always carried out first. Animal studies are important to enable scientists to understand more about the mechanisms of an intervention, such as a drug or fasting and to check the basic safety profile. However, animals do not precisely mimic humans so research is still needed in the context of clinical trials to ensure that the same effects are seen, and ensure safety. In human studies the most widely studied regimens are firstly alternate day fasting, secondly the 5:2 diet with fasting on 2 days each week, and thirdly daily time-restricted eating.
Intermittent fasting elicits evolutionarily conserved, adaptive cellular responses that are integrated across the body (de Cabo & Mattson, 2019). This fasting induces cells to switch on a coordinated response to stress, with resultant increased expression of antioxidant defences, repair of DNA, higher standards of protein quality control, and reduced levels of inflammation.
A number of studies have now compared body composition and weight in mice on either non-time restricted diets or time restricted ones (de Cabo & Mattson, 2019; Hatori et al., 2012; Mattison et al., 2017). Below is an example of one such study, that compared a high fat diet and normal chow diet in mice (Hatori et al., 2012). The mice were randomised to receive either diet, and then further randomised to eat either whenever they fancied, or only within an 8 hour window each day (Hatori et al., 2012). Regardless of the time the mice were allowed to eat, the total calorific intake was the same depending on which diet they were on (Hatori et al., 2012). The image below shows two example mice, both who were on the high fat diet, one could eat whenever they fancied (FA), while the other was restricted to the same diet, just ate it all within 8 hours per day (FT). This study demonstrated that time restricted eating (intermittent fasting) can protect against the weight gain usually seen with eating a high fat diet in mice (Hatori et al., 2012). These protective effects were also seen at a metabolic level as well.
A number of preclinical studies in animals have shown that intermittent fasting has robust disease modifying effects on a range of chronic disorders, including obesity, diabetes, cardiovascular disease, cancers, and neurodegenerative brain diseases (de Cabo & Mattson, 2019). Making this metabolic switch during intermittent fasting, results in the formation of ketone bodies or ketones, which not only provide fuel but also are used to communicate changes at both a cellular and global (systemic) level. Ketone bodies influence health and aging, by regulating the expression and activity of many proteins and molecules (de Cabo & Mattson, 2019). These changes carry over into the fed state, with positive effects on mental and physical performance, and resistance to disease (de Cabo & Mattson, 2019). Ketone bodies have also been shown to stimulate the expression of the gene for brain-derived neurotrophic factor, which have implications for brain health, and both psychiatric and neurodegenerative disorders (de Cabo & Mattson, 2019).
Intermittent fasting also inhibits a key metabolic pathway, called the mTOR (mammalian target of rapamycin) protein-synthesis pathway. This pathway is frequently activated in cancers, with some chemotherapy agents designed to target and inhibit this pathway. These responses to the intermittent fasting state, enable cells to remove damaged proteins, and recycle undamaged molecules, thereby temporarily reducing protein synthesis to conserve molecular resources and energy.
Studies have looked at the life span of mice and rats on intermittent fasting. One found that the average life span of rats was increased by 80% when they were started on alternate day fasting as young adults (Mattison et al., 2017). However, the degree of these effects varied, and were influenced by sex, diet, age, and genetic factors (Mattison et al., 2017). One study combined multiple trials and analysed the combined data (meta-analysis), finding that caloric restriction increased the median life span by 14 to 45% in rats, but only 4 to 27% in mice. While these studies highlight the positive effect of intermittent fasting on mice and rats, evidence in monkeys is mixed, and as yet no clinical trial on humans has been of sufficient duration and follow up to determine if the same association is seen.
While weight loss is associated with intermittent fasting, many studies have found that several of the benefits of intermittent fasting are not due to weight loss. These benefits include improvements in blood pressure, heart rate, glucose regulation, abdominal fat loss, and the efficacy of endurance training (de Cabo & Mattson, 2019).
Studies in both mice and humans have found that physical function is improved (de Cabo & Mattson, 2019). In mice of similar body weight, those maintained on alternate-day fasting have been found to have a better endurance running ability compared to those with unlimited access to food (de Cabo & Mattson, 2019). A study in young men, found that those who use time restricted eating (16 hour fast per day), lose fat, while maintaining muscle mass during 2 months of resistance training (de Cabo & Mattson, 2019).
Animal studies have shown that spatial memory, associative memory and working memory are all improved with intermittent fasting. In one clinical trial of older adults, intermittent fasting was associated with improved verbal memory(de Cabo & Mattson, 2019). A large, multicentre, randomised clinical trial showed over a longer period (2 years) that a significant improvement in working memory was seen with daily caloric restriction (de Cabo & Mattson, 2019).
Obesity and Diabetes
Intermittent fasting has been shown to improve insulin sensitivity, and prevent the obesity caused by a high-fat diet in animals (de Cabo & Mattson, 2019). In human studies, daily caloric restriction improved cardiometabolic risk factors in people of healthy body weight. More interestingly, insulin resistance in patients with prediabetes or type 2 diabetes, was reversed with 4:3 intermittent fasting (24-hour fasting 3 times a week) (de Cabo & Mattson, 2019). However, these effects have yet to be replicated longer term.
In both animals and humans, intermittent fasting is associated with improved blood pressure, cholesterol profile, lower resting heart rate, and decreased insulin, glucose, and insulin resistance. Markers of inflammation and oxidative stress that are associated with the formation of atherosclerosis (cholesterol plaques in blood vessels) are also seen (de Cabo & Mattson, 2019). Approximately 2-4 weeks after starting intermittent fasting, improvements in cardiovascular health is seen, and then dissipates over a period of a few weeks, once a normal diet is resumed.
Studies in animals have found a decreased number of spontaneous tumours during normal aging in mice and rats are seen with intermittent fasting. There is some evidence that activation of specific metabolic pathways by intermittent fasting may provide protection against cancer, while improving the stress resistance of normal cells (de Cabo & Mattson, 2019). In humans, clinical trials are in their infancy, establishing that intermittent fasting is safe during chemotherapy, and looking at biomarkers (markers to identify which metabolic processes are being turned on and off) (de Cabo & Mattson, 2019).
Excessive energy intake, particularly in middle age, has been associated with an increased risk of strokes, Parkinson’s disease and Alzheimer’s disease. Alternate day fasting has been robustly shown in animal models to delay the onset and progression of animal models of both Alzheimer’s and Parkinson’s disease.
Multiple animal studies have found that traumatic injury, and inflammation are reduced in animal models of surgical procedures when preoperative intermittent fasting is performed.
To summarise, during fasting there is good quality evidence that the following things happen:
- cells activate pathways that enhance defence against stress (metabolic and oxidative) including increased antioxidant defences, DNA repair, and protein quality control
- damaged molecules are preferentially removed or repaired
- cellular responses lead to improved glucose regulation, increased stress resistance, and suppression of inflammation
- formation of chemicals called ketone bodies, (or ketones), which may have positive effects on brain health, and in particular working memory
- While some of the health benefits are due to metabolic changes, some are because of the associated weight loss.
- but even in non-obese people enrolled in a multi-centre trial, daily caloric restriction still improved cardiometabolic risk
- These pathways are only activated by fasting, and area suppressed or unused in people who are sedentary and overeat.
- 2 studies showed that 24 hour fasting 3 times a week reversed insulin resistance in patients with pre-diabetes or type 2 diabetes
- intermittent fasting in humans and animal studies improves blood pressure, resting heart rate, cholesterol profile, glucose and insulin levels.
- Many animal studies have shown daily or alternate day caloric restriction reduces the occurrence of spontaneous tumours in rodents, while increasing sensitivity to chemotherapy and irradiation.
- Preoperative fasting reduces tissue damage and inflammation and improves the outcome of surgical procedures.
Starting an intermittent fasting program should be done in the setting of a registered nutritionist or dietician, to ensure all nutritional needs are met. Many people will find that they experience hunger, irritability, and a reduced ability to concentrate during periods of food restriction, when they start intermittent fasting (de Cabo & Mattson, 2019). These initial side effects should resolve within a month.
The goal of intermittent fasting is to fast for 16 to 18 hours a day. It can be easier to start gradually, and increase the number of hours per day by half an hour a day until the target is reached. Another option is to follow the 5:2 pattern, where you gradually decrease the number of calories consumed on the 2 fasting days from 900-1000 for one month, then dropping to 750 calories for the following month, until down to 500 calories.
While there is lots of strong evidence in both animal and human studies to support intermittent fasting, there are still limitations. Most of the studies to date have been performed on overweight young and middle-aged adults, and so it is not possible to generalise to other age groups in terms of both benefit and safety (de Cabo & Mattson, 2019). The specific mechanisms switched on by intermittent fasting are not fully understood yet. More research needs to be performed, but certainly in the right setting there is strong evidence to support the use of intermittent fasting.
Even if you do not need to lose weight, intermittent fasting has the potential to have wide ranging positive effects on your health.
Many people say the major hurdle to changing the timing of eating, is going out to work. So while most of us are working from home during the SARS-CoV2 pandemic, have you thought about starting time restricted eating?
de Cabo, R., & Mattson, M. P. (2019). Effects of Intermittent Fasting on Health, Aging, and Disease. New England Journal of Medicine, 381(26), 2541–2551.
Hatori, M., Vollmers, C., Zarrinpar, A., DiTacchio, L., Bushong, E. A., Gill, S., et al. (2012). Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metabolism, 15(6), 848–860.
Mattison, J. A., Colman, R. J., Beasley, T. M., Allison, D. B., Kemnitz, J. W., Roth, G. S., et al. (2017). Caloric restriction improves health and survival of rhesus monkeys. Nature Communications, 8(1), 1–12.
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