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*What is intermittent fasting?

 

Intermittent fasting (IF) refers to regular periods with no or very limited caloric intake. Intermittent fasting may also be called alternate-day fasting, reduced meal frequency, and time-restricted feeding. There are variety of protocols including: daily fasting for 16-18 hours; a 24-hour fast on alternate days; a fast 2 days per week on non-consecutive days; or calorie restriction for 5-6 days.

 

Intermittent fasting is one of the latest diet trends in the news; however, fasting is not a new concept. Periods of voluntary abstinence from food have been practiced for centuries by many groups of people around the globe. In ancient Greece, fasting is a part of spirituality practice and has since been adopted as a religious practice by Muslims, Christians, Jews, and Buddhists. One of these fasting ceremonies that continues today is Ramadan. Ramadan is a religious month for Islam, during which Muslims do not eat and drink during the daylight hours. The duration of restricted food and beverage intake is approximately 12 h/day for 1 month. The spiritual and psychological impacts of fasting have been well documented.

 

The health benefits from fasting were not investigated until the early nineteenth century. In 1915, fasting therapy for weight loss was first recognized by Dr. Otto Folin, a professor of biological chemistry at Harvard University. Over the last century we have learned that fasting is not only a strategy for weight loss, but also for longevity. Recent research has found that regular, short periods of fasting have many benefits including weight loss, better insulin sensitivity, lower disease incidence, reduced inflammation, longer lifespan and improved learning and memory functioning. One theory as to why fasting is so beneficial is that during the fasting period the body’s cells are under a mild stress, similar to exercise, and the cells respond to this stress adaptively by enhancing their ability to cope with stress and to resist disease.

 

Interesting fact: Humans can survive without any food for 30–40 days, as long as they are properly hydrated.

 

Arbesmann R. 2017 Fasting and prophecy in pagan and Christian Antiquity. Traditio. 7, 1-71.

 

Folin O, Denis W. 1915 On starvation and obesity, with special reference to acidosis. J. Biol. Chem. 21, 183-192.

 

Kondoh Hiroshi, Teruya Takayuki, Yanagida Mitsuhiro. 2020 Metabolomics of human fasting: new insights about old questions. Open Biol.10200176200176

https://www.cambridge.org/core/journals/traditio/article/abs/fasting-and-prophecy-in-pagan-and-christian-antiquity/C221D5431BFD7B6E25D68D566D6427ED

 

Aksungar, F. B., Topkaya, A. E., & Akyildiz, M. (2007). Interleukin-6, C-Reactive Protein and Biochemical Parameters during Prolonged Intermittent Fasting. Annals of Nutrition and Metabolism, 51(1), 88–95. doi:10.1159/000100954 
sci-hub.se/10.1159/000100954

 

*What is it supposed to do/ not do?

The goal of fasting is to help improve metabolic health, reduce disease incidence, and increase longevity. As mentioned above, recent research has found that regular short periods of fasting have many benefits including weight loss, better insulin sensitivity, lower disease incidence, reduced inflammation, longer lifespan and improved learning and memory functioning. One theory as to why fasting is so beneficial is that during the fasting period the body’s cells are under a mild stress, similar to exercise, and the cells respond to this stress adaptively by enhancing their ability to cope with stress and to resist disease. Another key mechanism is called autophagy.

Autophagy – Pronounced ah-TA-fuh-gee -- Autophagy is a process that maintains cellular homeostasis and provide substrates for energy generation. Autophagy is induced by food shortage (IF) and inhibited under energy-rich conditions. In other words, your body still stays in balance and can operate in a food shortage, but a handy side effect is that it actually makes energy and cellular regeneration – so you get younger! This is the longevity piece!

Fasting is not supposed to make you feel tired, stressed, or hungry. If it does, it is important to correct for the underlying biochemical or hormonal imbalance prior to fasting. Hypoglycemia is one example of what is not supposed to happen. This may need further investigation and medical supervision as well as a slower reduction in calories and feeding window to reduce side effects.

Welton S, Minty R, O'Driscoll T, et al. Intermittent fasting and weight loss: Systematic review. Can Fam Physician. 2020;66(2):117-125.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021351/

 

Alirezaei M, Kemball CC, Flynn CT, Wood MR, Whitton JL, Kiosses WB. Short-term fasting induces profound neuronal autophagy. Autophagy. 2010;6(6):702-710. doi:10.4161/auto.6.6.12376

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3106288/

*Is it safe for healthy individuals (and who shouldn’t try this)?

1. Yes, it is safe for most “healthy” individuals. There may be some side effects seen in the first few days such as headaches or lightheadedness, but this typically resolves after 2-3 days. At NGI, we recommend that all menstruating women check their hormones including cortisol levels before any significant fasting cycling.

 

“No serious adverse events were reported in the 27 IF trials. Fasting-related safety concerns include mood-related side effects and binge eating, among other symptoms. Obese participants observing a fast every second day did not develop binge-eating patterns or purgative behavior and reported improved body image and less depression. During the 6-month study by Harvie et al, 32% of participants reported less depression and increased positive mood and self-confidence. Study participants also occasionally reported dizziness, general weakness, bad breath, headache, feeling cold, lack of concentration, sleep disturbance, nausea, and constipation. When compared with baseline, these symptoms were unchanged with fasting.”

 

Welton S, Minty R, O'Driscoll T, et al. Intermittent fasting and weight loss: Systematic review. Can Fam Physician. 2020;66(2):117-125.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021351/

Nakamura Y, Walker BR, Ikuta T. Systematic review and meta-analysis reveals acutely elevated plasma cortisol following fasting but not less severe calorie restriction. Stress. 2016;19(2):151-7. doi: 10.3109/10253890.2015.1121984. Epub 2016 Jan 7. PMID: 26586092.

 

1. Women who are menstruating need to take breaks from fasting regularly to ensure that hormone changes during fasting do not impact normal menstruation. “The clinical observations made in this small sample of lean women showing more profound changes in neuroendocrine function, anovulation, and lengthened follicular phase after fasting suggest that lean women may be more vulnerable to fasting stress than normal weight women.”

 

Ruben Alvero, Lorene Kimzey, Nancy Sebring, James Reynolds, Marion Loughran, Lynnette Nieman, Beatriz R. Olson, Effects of Fasting on Neuroendocrine Function and Follicle Development in Lean Women, The Journal of Clinical Endocrinology & Metabolism, Volume 83, Issue 1, 1 January 1998, Pages 76–80, https://doi.org/10.1210/jcem.83.1.4512

 

 

1. Diabetics may need medical supervision during fasting to prevent hypoglycemia especially if they are taking medications which may need to be adjusted as blood sugar changes. “Use of IF in patients with diabetes poses a risk of hypoglycemia.” 

 

Welton S, Minty R, O'Driscoll T, et al. Intermittent fasting and weight loss: Systematic review. Can Fam Physician. 2020;66(2):117-125.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021351/#b16-0660117

 

1. Those with a history of eating disorders may not be good candidates for fasting. Similarly, fasting is contraindicated for young children and adolescents who have higher caloric needs due to ongoing growth and development.

*How do you do it?

There are several different ways of fasting. Figuring out what works for you may depend on your lifestyle, work schedule and goals. Often fasting or time restricted eating (TR) is easier to maintain than long term calorie restriction (CR). Here are a few of the more popular fasting protocols:

Intermittent Fasting

• During an intermittent fasting program, the individual will fast for an interval of time, usually no more than 48hrs, and then eat normally during the other days of the week. The most common example of this is known as the “5:2” diet, where calories are severely restricted for 2 days (preferably non-consecutive), and then normal eating occurs for the other 5 days in the week.

• Weight loss and fat burning results are seen with this type of intermittent fasting programs.

• Cellular changes such as autophagy requires fasting program for longer than 48 hours.

 

Prolonged Fasting

 

• The prolonged fasting diet is includes fasting for an extended period. This is usually performed for 4 to 7 consecutive days. The goal is to stress the body over the course of several days to stimulate autophagy. An example of a prolonged fast would be a water fast for 2-5 consecutive days. This is fast is usually done under the supervision of a qualified health professional.

Time Restricted Fasting

• Time restricted fasting is an eating pattern in which all food intake occurs within a restricted amount of time. This realigns eating patterns with natural circadian rhythms that help control metabolism, physiology, and behavior. Choose between a 6- or 8-hour window, such as 12pm to 6pm, in which all calories are consumed. Your unique Basal Metabolic Rate (BMR), activity level, and weight loss goals will determine how many calories you should eat within the time restricted window.

Alternate Day Fasting (adapted from Dr. Krista Varady’s Alternate Day Fasting)

• Picking two to four days per week to limit food and drink consumption to no more than 500 calories. Alternating fasting days with normal days of eating. Daily intake includes:

  • 2-4 cups of fresh non starchy vegetables

  • 3-6 ounces of organic protein such as poultry, fish, seafood, or eggs

  • 1 tbsp or ¼ cup from healthy fats such as unrefined olive or coconut oil or from nuts, seeds, avocado, and olives

  • 1 medium piece of fruit

  • Water, tea, coffee

Periodic Fast Mimicking (adapted from Dr. Valter Longo’s Longevity Diet)

• Choose 5-6 consecutive days to complete the fast. This can be repeated once a month, every 3 months or every 6 months. Frequency will depend on weight loss goals. Food and drink consumption is limited to 800 calories per day. Daily intake includes:

  • 4 cups of fresh non starchy vegetables

  • 3 ounces of organic fish or seafood

  • 1 tbsp ghee or unrefined olive or coconut oil

  • ¼ cup nuts, seeds, avocado or olives

  • Water, tea, coffee

 

ProLon Fasting Program

• Based off Dr. Valter Longo’s work and recent research, ProLon fasting is a 5-day fasting program done once per month for 3 months. During the 25 days that is non-fasting, it is suggested to eat a healthy diet using ProLon’s Fast Bar for snacks.

• ProLon meals come in 5 small boxes (one for each day) that include plant-based energy bars, soups, a variety of snacks, drinks, and supplements. A variety of 5 different soup flavors, sesame kale crackers, chocolate dessert bar, olives, and L-drink for energy.

• “The ProLon Fasting Mimicking Diet is the first and only meal program that has gone through clinical trials at the University of Southern California. Benefits seen in a clinical study of the 5-day ProLon cycle used monthly for three consecutive months”

• https://prolonfmd.com/

 

Min Wei; Sebastian Brandhorst et al.
Fasting‐Mimicking Diet and Risk Factors for Aging, Diabetes, Cancer and Cardiovascular Disease. Science Translational Medicine February 15, 2017 https://www.science.org/doi/10.1126/scitranslmed.aai8700

 

*Will you feel hungry?

Studies on intermittent fasting find that hunger levels either remain the same or decrease. However, there may be some increased hunger during the adjustment period, but this usually resolves and levels off.

 

“Intermittent fasting studies generally find that hunger levels remain stable or decrease during IF. A study of 30 participants over 12 weeks by Varady et al found reports of hunger during IF were no higher than with unrestricted consumption (level I evidence). Kroeger et al found that among those with the highest weight losses over 12 weeks of IF, hunger decreased, and fullness increased. In the study by Harvie et al, 15% of participants reported hunger. Sundfør et al saw higher reported hunger in the IF group compared with those in the calorie restriction group.”

 

Welton S, Minty R, O'Driscoll T, et al. Intermittent fasting and weight loss: Systematic review. Can Fam Physician. 2020;66(2):117-125.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021351/

 

 

*What does the current research say about any potential health benefits— weight loss? reduction of belly fat? anti-inflammatory benefits? boosting the immune system? **

 

 

• Longevity and CLOCK gene expression. The molecular circadian CLOCK gene plays a role in metabolic homeostasis. Recent research has found that physiologically feeding behavior, metabolism and circadian clocks are interlinked. The CLOCK gene plays a central role in the regulation of circadian rhythms that affect physiological functions such as metabolism and sleep. Variations in expression in the CLOCK genes mean you will have a greater risk for obesity, and you will most likely experience greater difficulty in losing weight despite following a low-calorie diet and a healthy lifestyle, especially if you stay up late and do not sleep well. 

  • CLOCK genes are components of the circadian clock comparable to the cogwheels of a mechanical watch. They interact with each other in an intricate manner generating oscillations of gene expression. The underlying principle of circadian clocks is successive gene activation in the form of a cycle: the initial activation of a gene is regulated by the last one in the sequence, making up an auto-regulatory feedback loop for which one cycle takes about 24 h.  

  • Fasting helps optimize circadian clock expression by increasing enzymatic activity that impacts cellular maintenance, metabolism, lipid storage and insulin secretion. Said more simply, stress from fasting triggers the body to “increase the fitness of the body.” For those with variations in their CLOCK genes, fasting is indicated for reducing disease risk, maintaining a healthy weight, and increasing longevity.  It is also important to “Go to bed with the sun and rise with the sun” to support optimal circadian rhythm.

 

 

Pan X, Zhang Y, Wang L, Hussain MM. Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP. Cell Metab. 2010;12(2):174-186. doi:10.1016/j.cmet.2010.05.014

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925198/

 

Influence of obesity, weight loss, and free fatty acids on skeletal muscle clock gene expression

Laura Sardon Puig, Nicolas J. Pillon, Erik Näslund, Anna Krook, Juleen R. Zierath

22 DEC 2019https://doi.org/10.1152/ajpendo.00289.2019

https://journals.physiology.org/doi/abs/10.1152/ajpendo.00289.2019?journalCode=ajpendo 

 

Patel, S., Velingkaar, N., Makwana, K. et al. Calorie restriction regulates circadian clock gene expression through BMAL1 dependent and independent mechanisms. Sci Rep 6, 25970 (2016). https://doi.org/10.1038/srep25970

https://www.nature.com/articles/srep25970

 

Pan X, Zhang Y, Wang L, Hussain MM. Diurnal regulation of MTP and plasma triglyceride by CLOCK is mediated by SHP. Cell Metab. 2010;12(2):174-186. doi:10.1016/j.cmet.2010.05.014

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925198/

 

Patel, S. A., Chaudhari, A., Gupta, R., Velingkaar, N. & Kondratov, R. V. Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms. FASEB J. 30(4), 1634–42, doi: 10.1096/fj.15-282475 (2016).

 

Katewa, S. D. et al. Peripheral Circadian Clocks Mediate Dietary Restriction-Dependent Changes in Lifespan and Fat Metabolism in Drosophila. Cell Metab. 23, 143–54 (2016).

 

Froy, O. & Miskin, R. Effect of feeding regimens on circadian rhythms: implications for aging and longevity. Aging (Albany NY) 2, 7–27 (2010).

 

 

 

• Autophagy – Pronounced ah-TA-fuh-gee -- Autophagy is a process that maintains cellular homeostasis and provide substrates for energy generation. Autophagy is induced by food shortage (IF) and inhibited under energy-rich conditions. Recent studies have shown that autophagy is a dynamic process in the biological circadian rhythm, which are controlled by CLOCK genes. Specifically, BMAL1:CLOCK activates the transcription of genes involved in regulating autophagy. Interference with the circadian rhythm of autophagy is associated with many disorders as has been demonstrated in studies of shift work (night work) and its influence on disease rates such as cancer.

 

Wang Xiang, Xu Zhijie, Cai Yuan, Zeng Shuangshuang, Peng Bi, Ren Xinxin, Yan Yuanliang, Gong Zhicheng. Rheostatic Balance of Circadian Rhythm and Autophagy in Metabolism and Disease. Frontiers in Cell and Developmental Biology. 8: 2020     

https://www.frontiersin.org/article/10.3389/fcell.2020.616434

 

Alirezaei M, Kemball CC, Flynn CT, Wood MR, Whitton JL, Kiosses WB. Short-term fasting induces profound neuronal autophagy. Autophagy. 2010;6(6):702-710. doi:10.4161/auto.6.6.12376

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3106288/

 

Keller, C. W., Munz, C., and Lunemann, J. D. (2020). Autophagy pathways in CNS myeloid cell immune functions. Trends Neurosci. 43, 1–10. doi: 10.1016/j.tins.2020.09.003

 

Potter Gregory D. M., Wood Thomas R. The Future of Shift Work: Circadian Biology Meets Personalised Medicine and Behavioural Science. Frontiers in Nutrition. 7: 2020

https://www.frontiersin.org/article/10.3389/fnut.2020.00116

 

 

• Immune function: Autophagy plays an important role in the development, organization, and functions of the immune system, including cell survival, cell defense and regulation of complex immune responses. As an example, autophagy is necessary for keeping T cell production and survival. T cells are essential for fighting off viral and bacterial infections.

  • Long COVID – Autophagy initiates antiviral activity by directly degrading viral particles (xenophagy) and destroying viral components (virophagy). Secondly, it induces the innate and adaptive immune systems to produce antiviral humoral and/or cell mediators.

 

Taming the Autophagy as a Strategy for Treating COVID-19. Blanca Estela García-Pérez, Juan Antonio González-Rojas, Ma Isabel Salazar, Carlos Torres-Torres and Nayeli Shantal Castrejón-Jiménez. Cells. 2020

https://www.mdpi.com/2073-4409/9/12/2679/pdf

 

Maity Subhajit, Saha Abhik. Therapeutic Potential of Exploiting Autophagy Cascade Against Coronavirus Infection. Frontiers in Microbiology. 12: 2021

https://www.frontiersin.org/article/10.3389/fmicb.2021.675419

    

 

• Weight Loss - Intermittent fasting (IF) refers to regular periods with no or very limited caloric intake. It commonly consists of a daily fast for 16 hours, a 24-hour fast on alternate days, or a fast 2 days per week on non-consecutive days.

  • In all 27 trials, IF resulted in weight loss, ranging from 0.8% to 13.0% of baseline body weight. Weight loss occurred regardless of changes in overall caloric intake. In the 16 studies of 2 to 12 weeks’ duration that measured BMI, BMI decreased, on average, by 4.3% to a median of 33.2 kg/m2. Waist circumference decreased by 3 cm to 8 cm in studies longer than 4 weeks that recorded it.

  • The largest study comparing IF with calorie restriction was by Headland et al in 2019 of 244 obese adults who achieved a mean 4.97-kg weight loss over 52 weeks versus a mean weight loss of 6.65 kg with calorie-restricted diets

  • Twelve studies used calorie-restricted diets as a comparator to IF and found equivalent weight loss in both groups.

  • Most of the weight loss with IF is fat loss. A 2011 study by Harvie et al calculated that 79% of weight loss was owing to loss of fat specifically (level I evidence).27 Participants regained some weight during follow-up after intervention, although average body weight remained statistically significantly lower than baseline levels. Weight regain did occur after 6 months.

  • They found weight loss doubled (6 kg) when exercise was added to IF

  • The practical length of a fast to effect changes in weight appears to be 16 hours

 

 

Welton S, Minty R, O'Driscoll T, et al. Intermittent fasting and weight loss: Systematic review. Can Fam Physician. 2020;66(2):117-125.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021351/

 

 

• Diabetes – Fasting improves insulin sensitivity, reduces C-peptide and insulin levels, and decreases hemoglobin A1C level. It is important to note that the use of IF in patients with diabetes poses a risk of hypoglycemia. Diabetics may need medical supervision during fasting to prevent hypoglycemia especially if they are taking medications which may need to be adjusted as blood sugar changes.

 

“They found improved glycemic control with lower morning, postprandial, and average mean daily glucose levels (level II evidence). These improvements regressed once participants returned to their usual diets. Corley et al enrolled 41 individuals with diabetes in a 2018 study of twice-weekly 1-day fasts for 12 weeks; fasting glucose levels decreased by 1.1 mmol/L and hemoglobin A1c levels by 0.7% (level II evidence), a decline similar to that in the earlier study by Carter et al.  Kahleova et al found a more modest decrease in blood glucose levels (−0.78 mmol/L) with a daily 16-hour fast; no adverse events were reported.”

Welton S, Minty R, O'Driscoll T, et al. Intermittent fasting and weight loss: Systematic review. Can Fam Physician. 2020;66(2):117-125.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021351/#b16-0660117

 

• Fat Loss and Heart Disease – During intermittent fasting when glucose reserves are exhausted, fatty acids are released from fat cells in the process of lipolysis. This process is called ketosis. Ketosis increases fat availability in the form of ketones that can be used for energy in the absence of glucose. Fasting also reduces total cholesterol, triglycerides, and low-density cholesterol (LDL) as well as the size of these molecules, lowering the risk of developing heart disease.

 

Malinowski B, Zalewska K, Węsierska A, et al. Intermittent Fasting in Cardiovascular Disorders-An Overview. Nutrients. 2019;11(3):673. Published 2019 Mar 20. doi:10.3390/nu11030673

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471315/

 

 

• Inflammation – Inflammation is an important contributor of cardiovascular disease. Pro-inflammatory factors, such as homocysteine, interleukin 6 (IL6), and C reactive protein (CRP), contribute to the development of atherosclerotic plaque. Intermittent fasting reduces the levels of these pro-inflammatory markers.

Aksungar F, B, Topkaya A, E, Akyildiz M: Interleukin-6, C-Reactive Protein and Biochemical Parameters during Prolonged Intermittent Fasting. Ann Nutr Metab 2007;51:88-95. doi: 10.1159/000100954

https://sci-hub.se/10.1159/000100954

 

 

• Antioxidant Activity - Oxidative stress has an adverse effect on cells and tissues while ANTI-oxidation protects and preserves cellular function. Research has found that antioxidative metabolites are increased during fasting, reducing oxidative stress and modulating lifespan.

 

Kondoh Hiroshi, Teruya Takayuki, Yanagida Mitsuhiro. 2020 Metabolomics of human fasting: new insights about old questions. Open Biol.10200176200176

https://royalsocietypublishing.org/doi/10.1098/rsob.200176

 

 

• Improved Energy and Mitochondrial Function – Mitochondria are your cell’s powerhouses. They create the energy that your body needs to function properly. Fasting has been found to enhance mitochondrial function and increase energy output.

“In addition to established fasting markers, several TCA cycle-related compounds (cis-aconitate, malate, 2-oxoglutarate and succinate) and coenzymes (nicotinamide and pantothenate, a precursor for acetyl-CoA) were also increased, reflecting enhanced mitochondrial activity in tissues during fasting. Notably, 44 of 120 metabolites increased 1.5- to 60-fold during this period. Thus, our whole blood metabolomics revealed unexpected dynamics of diverse metabolite increases resulting from greatly activated catabolism and anabolism, stimulated by fasting.”

 

These metabolomics are measured specifically by tests at NGI and can be measured before and after to determine if the fasting is in fact effective in increasing mitochondrial and energy output.

 

“Time-controlled fasting (>24h) boosts mitochondrial oxidative metabolism in skeletal muscle that confers an adaptive stress resistance to nutrient fat overload.”

 

Kondoh Hiroshi, Teruya Takayuki, Yanagida Mitsuhiro. 2020 Metabolomics of human fasting: new insights about old questions. Open Biol.10200176200176

https://royalsocietypublishing.org/doi/10.1098/rsob.200176

 

Lettieri-Barbato D, Cannata SM, Casagrande V, Ciriolo MR, Aquilano K. Time-controlled fasting prevents aging-like mitochondrial changes induced by persistent dietary fat overload in skeletal muscle. PLoS One. 2018;13(5):e0195912. Published 2018 May 9. doi:10.1371/journal.pone.0195912

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942780/