What Is Fasting?
Simply put, to fast is to abstain from eating for a given amount of time. Fasting has gained considerable notoriety in the scientific literature due to its health benefits and its impact on anti-aging pathways. In the modern diet, food is constantly within arm’s reach. Our ancestors, although genetically our contemporaries, did not have refrigerators, chemical preservatives, or even predictably available food sources. As a result, our bodies have developed functional adaptations for long periods without eating.
We have dramatically different cellular responses depending on how long it’s been since our last meal, and they tip the scales from tissue growth, cell division, protein production, and energy usage towards survival, efficiency, autophagy, protection, and damage repair.
The metabolic effects of fasting can be seen 3 to 5 hours after eating. An individual is generally considered to be in a “fasting state” after 8 to 12 hours, so many people fast without realizing it. In fact, the first meal of the day is referred to as ‘breakfast’ because it breaks the fast that took place while sleeping.
Fasting is often considered as a type of diet since many people use it for the same health and/or weight-loss benefits as typical diets, but this is technically incorrect. A diet refers to what you eat, while fasting is concerned with when you eat. You could fast very often and for long periods of time and still have a very unhealthy diet, depending on what you eat.
What counts as fasting? What can break a fast?
In the absolute strictest sense of a fast, no food or water is consumed (“nothing by mouth” fasting). However, water fasting is a practice that won’t be covered here, as it has not been linked to longevity. Electrolytes such as sodium, magnesium, and potassium are usually considered acceptable during a fast. In fact, they are essential for multi-day fasts, as they are required for various bodily functions and are lost from the bloodstream relatively quickly. Vitamin and mineral supplements are similarly considered acceptable while fasting in most contexts.
Less strict versions of fasting also include no-calorie drinks, such as black coffee or tea, and caffeine can be a surprisingly effective appetite suppressant. Items with negligible calories, such as gums or mints, may also be acceptable, although these can trigger some reactions from the body in anticipation of food. Similarly, zero-calorie artificial sweeteners can trigger a lot of the same responses as sugar, even though no calories are being consumed.
In the least strict (and less common) sense, exceptions are made for certain food items. In fat fasting, only fats are eaten, usually done to extend the body’s state of ketosis, in which fats are burned for energy. In juice fasting, solid foods are avoided, but calories can be consumed in liquid form.
Minimal calorie consumption may also be considered acceptable to facilitate fasting for lengths of time that would otherwise be impossible. Ultimately, it is important to consider the objective of the fast when determining what constitutes breaking it.
Why do people fast?
Fasting carries with it historical, spiritual, and political significance. Fasting ceremonies are observed in Christianity, Islam, Judaism, Hinduism, Buddhism, and many other religions. Hunger strikes, like those of Gandhi, have been used by a variety of movements.
Fasting is more common for medical reasons. It is needed before surgery to ensure the patient’s stomach contents are empty to prevent aspiration during anesthesia. An even longer fast is required before a colonoscopy to clear further down the GI tract. Some diagnostic tests require fasting beforehand, such as measuring fasting blood glucose. It also can be prescribed to treat health issues such as insulin resistance (diabetes) and high cholesterol. Fasting can also be an excellent weight loss strategy.
However, perhaps the most exciting reason to fast is to trigger some of the body’s natural self-preservation responses, which, in turn, may help extend both healthspan and lifespan.
What are the different types of fasting?
Further complicated by all the different “what counts?” considerations, fasting can also be carried out on many different schedules. Intermittent fasting refers to a regimen that occurs repeatedly to distinguish it from one-off fasts. Intermittent daily fasting or time-restricted eating can be practiced by having the same feeding window every day. The shorter durations are more achievable for most people, and there is some evidence that this strategy works in tandem with the circadian rhythm to provide additional benefits.
Daily fasting regimens have shorthand names designated in hours by the length of fasting and feeding. For example, the most common daily fasting strategy is 16:8, in which an individual fasts for 18 hours and is able to eat for 6 hours. At its most extreme, daily fasting can be practiced as simply one meal a day, or OMAD. Daily fasting regimens may also have “cheat days” built into their schedules for eating regularly.
Other fasters go full days while fasting, such as alternate day fasting, in which each day alternates between fasting and regular eating. In 5:2, the faster goes two days per week without eating but eats normally for the other five. Finally, extended fasting involves single fasts greater than a day. This type of fast should only be done by people who have built up slowly and have close medical supervision and a good understanding of the accompanying physiology.
The fed-fast cycle
The first few hours after eating, your body goes through the process of digesting and absorbing food. Blood sugar increases and insulin spikes in order to transport glucose from the blood into cells. Excess glucose is converted to glycogen and stored in the liver and muscles.
The hormone ghrelin, which helps to signal hunger, also decreases after eating.  Conversely, leptin, which suppresses appetite, is increased. How long this stage lasts depends on the size and composition of the last meal, but it is typically maintained for around 3-4 hours.
The next phase begins with the reverse of the first: blood sugar, insulin, and leptin levels decline, while ghrelin increases and glycogen begins to be converted to glucose for energy. As glycogen stores decrease, the body transitions to breaking down fats and proteins instead.
Once glycogen is completely depleted, the ketosis phase begins, a number of changes occur as the body shifts to utilize fats as its primary source of energy. This state can start as soon as 12 hours, but it really kicks in 18 to 24 hours after the last meal. 
As the fast continues, insulin levels steadily decrease and human growth hormone (HGH) increases. [1, 3-5] BHB, a specific ketone body, steadily rises. The kidneys begin to generate sugar to provide to the brain. The breakdown of BCAAs, a group of three essential amino acids that are consumed for energy early in the fasting state, is reduced as the body adjusts to a state that it can maintain over the long term. Autophagy is highly upregulated by 24 hours. [6-10]
By 72 hours, immune cells are being broken down and replaced. 
Is fasting a good strategy for weight loss?
Weight loss is almost exclusively a matter of calories consumed versus calories burned. It can be accomplished by fasting, although depending on the regimen, it may be easy to overeat during the feeding window and actually consume the same number of calories. As a mechanism for reducing calories, fasting may be particularly beneficial to people who are prone to snacking or late-night pantry raids. Long-term fasting may decrease basal metabolic rate, complicating weight loss, but short-term fasts may actually increase metabolic rate by 3.6-14%. [12, 13]
Psychologically, some people find it easier to restrict when they eat rather than counting calories. It can be mentally taxing to always stay mindful of what and how much you are eating, and fasting can be a simpler alternative. Regular fasting can also change a person’s relationship with food.
Denying food during certain windows can help train the brain that it doesn’t need to eat every time it feels hungry. For most people, feelings of hunger wax and wane. Hunger isn’t actually pervasive for a majority of the time spent fasting.
What are some of the other health benefits of fasting?
Various forms of fasting have been shown to result in a number of health benefits. In mice, fasting has shown profound effects at treating or preventing diabetes, cardiovascular disease, cancer, Alzheimer’s disease, Parkinson’s disease, and stroke while improving overall lifespan.  In humans, it has been shown to improve insulin resistance,  inflammation , and cardiovascular disease risk (cholesterol, blood pressure, etc.) .
Insulin signaling and the mTOR pathways, both of which are active during fed states, activate cell growth, division, and protein synthesis. DNA and other cellular components are highly acetylated during fed states. This acetylation loosens the histone packaging proteins that keep DNA tightly wound. In turn, this reveals more of the DNA to be transcribed for protein synthesis. If the body is constantly in a fed state, these are only turned off during sleep, contributing to insulin sensitivity, cancer, cellular senescence, and proteinopathies. In a fasting state, these growth pathways are downregulated. 
Extended fasting can also reduce insulin-like growth factor 1 (IGF-1) and PKA.  When ketosis is activated, fats are metabolized resulting in ketone bodies, which have a wide range of effects on different anti-aging pathways, including lowering inflammation.
Autophagy is another mechanism by which fasting enacts its benefits. If energy is scarce, cells will look to recycle old and damaged proteins and mitochondria, which contribute to aging when they accumulate in large-enough quantities. AMPK is a major pathway that triggers autophagy and is initiated by fasting. NAD+ levels also rise, activating beneficial sirtuin. SIRT1 and SIRT3, for example, remove the acetyl groups from the histones that package DNA. They also increase promote reactive oxygen species (ROS) scavenging, reducing oxidative stress. 
Does fasting really work?
There are many criticisms, uncertainties, and qualifications regarding the benefits of fasting. One common misconception is that skipping breakfast is unhealthy. However, this is due to the generally unhealthier lifestyles of people who skip breakfast rather than anything inherently unhealthy about skipping breakfast itself.
Still, fasting is not for everyone. There is reason to believe that fasting may do more harm than good for people who have a history of eating disorders, are elderly and frail, or are terminally ill. Women also have additional concerns related to menstruation and pregnancy.
The effectiveness of fasting as a life extension technique is also not beyond question. Multiple published studies have found no difference, especially in non-obese individuals, and negative results often aren’t ever published. Additionally, there are no long-term studies in humans yet.
Further, most studies in humans look at secondary biomarkers rather than disease prevention or reversal. The ideal regimen is also unknown. Finally, dietary studies in humans are notoriously flawed and difficult to interpret. 
Summary and conclusion
Like caloric restriction, fasting has been an early proof-of-concept demonstrating that aging can be modulated. It has served as the basis and inspiration for a broad field of research. Its evidence in the literature is extremely robust, but there are sufficient contradictory studies to be uncertain of its true benefits.
Judging for yourself whether or not fasting is a worthy endeavor to optimize your health, prevent disease, and increase longevity is an extremely personal decision and likely hinges on how difficult you find your regimen to adhere to. However, the only way to find that out is to try fasting for yourself!
 Amole, N. and Unniappan, S. Fasting induces preproghrelin mRNA expression in the brain and gut of zebrafish, Danio rerio. General and Comparative Endocrinology (2009), https://doi.org/10.1016/j.ygcen.2008.11.002
 Anton, S.D., et al., Flipping the metabolic switch: understanding and applying health benefits of fasting. Obesity (2018), https://dx.doi.org/10.1002%2Foby.22065
 Rudman, D., et al., Effects of human growth hormone in men over 60 years old. The New England Journal of Medicine (1990), https://doi.org/10.1056/NEJM199007053230101
 Aguiar-Oliveira, M.H. and Bartke, A. Growth hormone deficiency: health and longevity. Endocrine Reviews (2019), https://doi.org/10.1210/er.2018-00216
 Caicedo, D., et al. Growth hormone (GH) and cardiovascular system. International Journal of Molecular Sciences (2018), https://doi.org/10.3390/ijms19010290
 Alirezaei, M., et al. Short-term fasting induces profound neuronal autophagy. Autophagy (2010), https://doi.org/10.4161/auto.6.6.12376
 Jamshed, H., et al. Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans. Nutrients (2019), https://doi.org/10.3390/nu11061234
 Petrocola, F., et al. Metabolic effects of fasting on human and mouse blood in vivo. Autophagy (2017), https://doi.org/10.1080/15548627.2016.1271513
 Vendelbo, M.H., et al. Fasting Increases Human Skeletal Muscle Net Phenylalanine Release and This Is Associated with Decreased mTOR Signaling. PLOS ONE (2014), https://doi.org/10.1371/journal.pone.0102031
 Bagherniya, M., et al. The effect of fasting or calorie restriction on autophagy induction: A review of the literature. Ageing Research Reviews (2018), https://doi.org/10.1016/j.arr.2018.08.004
 Cheng, C-W., et al. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell (2014), https://doi.org/10.1016/j.stem.2014.04.014
 Mansell, P.I., et al. Enhanced thermogenic response to epinephrine after 48-h starvation in humans. American Journal of Physiology (1990), https://doi.org/10.1152/ajpregu.1990.258.1.R87
 Zauner, C., et al. Resting energy expenditure in short-term starvation is increased as a result of an increase in serum norepinephrine. American Journal of Clinical Nutrition (2000), https://doi.org/10.1093/ajcn/71.6.1511
 Mattson, M.P., et al., Impact of intermittent fasting on health and disease processes, Ageing Research Reviews (2017), https://doi.org/10.1016/j.arr.2016.10.005
 Barnosky, A.R., et al. Intermittent fasting vs daily calorie restriction for type 2 diabetes prevention: a review of human findings. Translational Research (2014), https://doi.org/10.1016/j.trsl.2014.05.013
 Johnson, J.B., et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radical Biology and Medicine (2007), https://doi.org/10.1016/j.freeradbiomed.2006.12.005
 Aksungar, F.B., et al. Interleukin-6, C-reactive protein and biochemical parameters during prolonged intermittent fasting. Annals of Nutrition and Metabolism (2007), https://doi.org/10.1159/000100954
 Faris, M.A-I.E., et al. Intermittent fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects. Nutrition Research (2012), https://doi.org/10.1016/j.nutres.2012.06.021
 Varady, K.A., et al. Short-term modified alternate-day fasting: a novel dietary strategy for weight loss and cardioprotection in obese adults. American Journal of Clinical Nutrition (2009), https://doi.org/10.3945/ajcn.2009.28380
 de Avedo, F.R., et al. Effects of intermittent fasting on metabolism in men. Revista da Associação Médica Brasileira (2013), https://doi.org/10.1016/j.ramb.2012.09.003
 Goodrick, C.L., et al. Effects of intermittent feeding upon growth and life span in rats. Gerontology (1982), https://doi.org/10.1016/j.ramb.2012.09.003
 Sogawa, H. and Kubo, C., Influence of short-term repeated fasting on the longevity of female (NZBxNZW)F1 mice. Mechanisms of Ageing and Development (2000), https://doi.org/10.1016/S0047-6374(00)00109-3
 Javaid, N. and Choi, S. Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets. Genes (Basel) (2017), https://doi.org/10.3390/genes8080196
 Longo, V.D. and Mattson, M.P. Fasting: molecular mechanisms and clinical applications. Cell Metabolism (2015), https://doi.org/10.1016/j.cmet.2013.12.008
 Hwangbo, D-S., et al. Mechanisms of Lifespan Regulation by Calorie Restriction and Intermittent Fasting in Model Organisms. Nutrients (2020), https://doi.org/10.3390/nu12041194
 Harvie, M. and Howell, A. Potential Benefits and Harms of Intermittent Energy Restriction and Intermittent Fasting Amongst Obese, Overweight and Normal Weight Subjects—A Narrative Review of Human and Animal Evidence. Behavioral Sciences (2017), https://doi.org/10.3390/bs7010004