Physiology, Fasting
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Introduction
Fasting is a practice that involves a restriction of food or drink intake for any period. Fasting has been practiced for a variety of reasons that range from dieting to religious beliefs to medical testing. It is commonly used in medical practice for blood glucose and lipid markers laboratory tests to aid in the diagnosis of numerous diseases as well as assessing many risk factors. Variations of fasting have been studied for their ability to improve physiological indicators related to health. Some of these factors include insulin sensitivity, blood pressure, atherogenic lipids, body fat, and inflammation. Many of these studies involve those who participate in the Islamic tradition of Ramadan since participants abstain from food and drink each day from dawn until sunset for an entire month.[1]The compiled results show a variety of metabolic and physiological adaptations that occur from fasting. From a general perspective, this includes the changes in metabolic pathways to create energy for the body.
Issues of Concern
The effects of fasting have been thoroughly studied in populations of healthy adult individuals. However, data concerning underweight, geriatric, and pediatric patients is still lacking. A notable effect at the beginning periods of fasting is a tension-type headache.[2]This type of headache has an etiology that is dependent on multiple factors and the precise cause has not been identified yet. Proposed mechanisms that might lead to a fasting headache include hypoglycemia, dehydration, along with caffeine withdrawal.[2][3]A study has shown that the use of rofecoxib, a COX2 inhibitor, can be effective in reducing and even stopping a fasting headache, suggesting that the etiology may be a product of the pro-inflammatory eicosanoid metabolic pathway.[4]Fasting should always be performed under the supervision of a physician or ideally in a clinical setting.
Cellular
Fasting involves a radical change in cellular physiology and metabolism. Blood glucose normally provides the body with sufficient energy through glycolysis. During a fast, maintenance of blood glucose levels initially relies on glycogen stores in the liver and skeletal muscle. Glycogen is made up of chains of polymerized glucose monosaccharides that are used for energy by the process of glycogenolysis. Most glycogen is stored in the liver, which has the greatest role in the maintenance of blood glucose during the first 24 hours of a fast. After fasting for around 24 hours, glycogen stores are depleted causing the body to utilize energy stores from adipose tissue and protein stores.[5]The drastic change in metabolism that follows glycogen depletion is primarily dependent on the metabolism of triglyceride stores in adipose tissue. Triglycerides are separated into free fatty acids and glycerol that the liver respectively converts into ketone bodies and glucose. Ketone bodies made from free fatty acids through the process of ketogenesis. These ketone bodies travel through the body and are reconverted back into acetyl-CoA at the tissues requiring energy. In addition to adipose catabolism, protein catabolism, through the process of gluconeogenesis, simultaneously takes place in times of fasting.[6][7]Gluconeogenesis produces glucose from amino acids broken down from various tissues including muscle. After glycogen stores become depleted, the dependence of body tissues for glucose gradually declines as ketone bodies become more readily available to metabolize.
Development
One of the most heavily studied fastingregimensis known as intermittent fasting, which involves the restriction of caloric intake during a set period continually. Examples of fasting regimens include restriction of calories for 1 full day out of the week or 2 nonconsecutive days, also known as the "5:2" diet. Animal studies have repeatedly demonstrated a vigorous, positive response of various health indicators to intermittent fasting regimens.[8]These include improved insulin sensitivity and a reduction of body fat, atherogenic lipids, blood pressure, and IGF-1. Animal models have also demonstrated a statistically significant improvement in the ability of intermittent fasting to delay the progression of neurological diseases including Alzheimer’s, Parkinson’s, and Huntington’s disease.[1]Human studies of intermittent fasting also demonstrate promising results in protection against metabolic syndrome and other lifestyle diseases including diabetes and cardiovascular disease.[1][9]A notable cellular process that is upregulated during times of fasting includes the inhibition of the tyrosine kinase enzyme. Inhibition of this enzyme is a backbone for the treatment of many types of cancer, and further research is necessary to evaluate whether fasting regimens can be used concomitantly with chemotherapy to improve patient outcomes.[10]
Organ Systems Involved
The most immediate organ affected by a fast is the pancreas. During times of low plasma glucose, the pancreas will release more glucagon from the alpha cells found in the islets of Langerhans. Glucagon will mainly affect the liver as it stores most of the glycogen in the body. Skeletal muscle is also affected by glucagon, but to a lesser extent since skeletal muscle contains a low glycogen concentration. After hepatic glycogen stores are depleted, the body uses adipose tissue and protein for energy. The liver has an active role in the metabolism of fats as it is the main oxidizer of triglycerides. In more extreme versions of fasting, where fat sources have been expended, the body breaks down skeletal muscle for energy. Catabolism of skeletal muscle provides the body with amino acids that can be metabolized. However, this process also leads to a reduction in muscle mass.
Mechanism
Fasting is dependent on three types of energy metabolism: glycogen, lipid, and amino acid.
Glycogen
As blood glucose levels fall during fasting, the pancreas secretes increased amounts of glucagon. This action also reduces insulin secretion, which in turn decreases glucose storage in the form of glycogen. Glucagon binds to glucagon receptors at the liver to trigger a cyclic AMP cascade that eventually activates glycogen phosphorylase. Glycogen phosphorylase and debranching enzyme release glucose-1-phosphate (G1P) from glycogen branches at the alpha-1,4 and alpha-1,6 positions, respectively. Then phosphoglucomutase converts G1P to glucose-6-phosphate (G6P). The final step of this process is that G6P is hydrolyzed into glucose and inorganic phosphate by glucose-6-phosphatase.
Lipid
The breakdown of triglycerides begins with the activation of hormone-sensitive lipase (HSL). This enzyme is stimulated by glucagon, epinephrine, cortisol, and growth hormone all of which have increased plasma levels during fasting.[11]Each of these hormones activates HSL through a different pathway. Glucagon and epinephrine bind to adenylyl cyclase (on the cell membrane) creating cyclic AMP. Cyclic AMP activates protein kinase A (PKA), which in turn activates HSL. Cortisol binds to glucocorticoid receptor alpha (GR-alpha) located in the cytosol of the cell. Activation of GR-alpha increases transcription of the protein angiopoietin-like 4 (Angptl4). This protein directly stimulates cyclic AMP-dependent PKA signaling which tells HSL to begin lipolysis.[12]Growth hormone turns on HSL through the phospholipase C (PLC) pathway. PLC activates protein kinase C (PKC) which can either directly or indirectly stimulate HSL. The indirect pathway involves PKC phosphorylating MAPK/ERK kinase (MEK). MEK phosphorylates extracellular signal-related kinase (ERK) which directly phosphorylates HSL.
After HSL is activated, it works with adipose triglyceride lipase to break a fatty acid (FA) from triglyceride reducing it to a diglyceride. HSL and monoacylglycerol lipase break off the other two FA leaving a net total of one glycerol molecule plus three separate FA. Glycerol is converted to glycerol-3-phosphate and then to dihydroxyacetone (DHAP) by glycerol kinase and glycerol-3-phosphate dehydrogenase respectively. DHAP is then metabolized in the glycolysis pathway.
Fatty acids are transformed into fatty acyl CoA through fatty acyl CoA synthetase. Energy from fatty acyl CoA is mainly produced through beta-oxidation and ketogenesis. Omega oxidation is a minor pathway that oxidizes fatty acids into dicarboxylic acids in the smooth endoplasmic reticulum. It remains a minor pathway unless mitochondrial beta-oxidation is defective. The location of beta-oxidation is dependent on the length of the fatty acid chain; short, medium, and long chains are degraded in the mitochondria while very-long and branched chains are degraded in peroxisomes. Every cycle of beta-oxidation produces 1 FADH, 1 NADH, and 1 acetyl CoA molecule. The very last cycle of produces 2 acetyl CoA (from even chained FA) or 1 acetyl CoA and 1 propionyl CoA (from odd chained FA).
The process of ketogenesis first starts with the enzyme thiolase combining two molecules of acetyl-CoA into acetoacetyl-CoA. HMG-CoA synthase then adds another acetyl-CoA to create beta-hydroxy-beta-methylglutaryl-CoA. HMG-CoA lyase removes an acetyl-CoA group from the molecule to form acetoacetate. From this step, acetoacetate is broken down into acetone (by non-enzymatic decarboxylation) and beta-hydroxybutyrate (by D-beta-hydroxybutyrate dehydrogenase).
Amino Acid
During fed and fasting states, amino acids are generally used for the synthesis of physiologically important metabolites. Amino acids are metabolized based on their category and only the liver can degrade all amino acids. Glucogenic amino acids are made into Krebs cycle intermediates or pyruvate. Ketogenic amino acids are processed into acetoacetate or acetyl-CoA. There are amino acids that are categorized as being both glucogenic and ketogenic which means that they can be metabolized by either pathway.
Categorization of Amino Acids
Glucogenic: alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, histidine, methionine, valine
Ketogenic: leucine, lysine
Glucogenic/Ketogenic: isoleucine, phenylalanine, threonine, tryptophan, tyrosine
Related Testing
Fasting is performed clinically when blood tests require minimal caloric intake to aid in the diagnosis of various diseases. Fasting blood glucose is an example of a test that helps to aid in the diagnosis of diabetes mellitus based on a set threshold that determines if a patient’s insulin receptors are functioning properly by their ability to lower blood glucose in response to insulin. In cases of diabetes mellitus type 2, insulin resistance results in high fasting blood glucose. Additionally, high fasting blood glucose has been studied as a risk factor for the development of high blood pressure.[13]
Another test that traditionally requires a patient to be fasting for accuracy includes triglyceride measurement on a lipid panel. Blood triglycerides are present in substantial quantity in the carrier proteins chylomicrons and very-low-density lipoprotein (VLDL). Chylomicrons are responsible for carrying triglycerides from digested food to peripheral tissues while VLDL is made in the liver and represents a baseline blood triglyceride level resilient to food intake. Therefore, an accurate measurement of blood triglycerides in VLDL requires a patient to be fasting to exclude chylomicron triglycerides from the measurement. Recent data suggest that accurate lipid measurement may be possible in the absence of fasting although fasting for lipid panels is still recommended by most national and international guidelines.[14][15]
Pathophysiology
Chronic or excess exposure to glucocorticoids (GCs), such as cortisol, can lead to insulin resistance or even muscle atrophy.[16]This type of exposure can be prevalent in more intense/prolonged versions of fasting. GCs normally relay their signal through the glucocorticoid receptor (GR) found intracellularly in skeletal muscle tissue. One primary action of GR is to regulate transcription of target genes by either directly binding to DNA or tethering itself to other DNA-binding transcription factors. Inappropriate regulation of these target genes leads to the pathophysiological responses of GCs.
Clinical Significance
Fasting is not only important for clinically relevant tests but also has the potential to be used as a treatment for some diseases in humans. One study (sample size of 6) has shown that intermittent fasting, combined with the ketogenic diet, can be successfully implemented in pediatric patients with epilepsy.[17]However, current literature on the subject is still limited and numerous studies still need to be performed to show the actual clinical efficacy of fasting as a treatment for human neurological disorders.[18]Recent data also suggests that larger clinical trials are warranted to further investigate the efficacy of prescribed fasting regimens for the treatment of chronic lifestyle and obesity-related diseases.[19]Most studies related to fasting as a treatment for diseases have been based on animal models.
Article Details
Article Author
Terrence Sanvictores
Article Author
Jarett Casale
Article Editor:
Martin R. Huecker
Updated:
7/25/2022 11:13:30 PM
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References
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Drescher MJ,Elstein Y, Prophylactic COX 2 inhibitor: an end to the Yom Kippur headache. Headache. 2006 Nov-Dec [PubMed PMID: 17115981]
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Browning JD,Baxter J,Satapati S,Burgess SC, The effect of short-term fasting on liver and skeletal muscle lipid, glucose, and energy metabolism in healthy women and men. Journal of lipid research. 2012 Mar [PubMed PMID: 22140269]
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Liang Q,Zhong L,Zhang J,Wang Y,Bornstein SR,Triggle CR,Ding H,Lam KS,Xu A, FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes. 2014 Dec [PubMed PMID: 25024372]
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Secor SM,Carey HV, Integrative Physiology of Fasting. Comprehensive Physiology. 2016 Mar 15 [PubMed PMID: 27065168]
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Caffa I,D'Agostino V,Damonte P,Soncini D,Cea M,Monacelli F,Odetti P,Ballestrero A,Provenzani A,Longo VD,Nencioni A, Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. Oncotarget. 2015 May 20 [PubMed PMID: 25909220]
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FAQs
What are physiological benefits of fasting? ›
Fasting has been associated with several health benefits, including weight loss, improved blood sugar control, decreased inflammation, and enhanced heart health. It might also offer protection against certain conditions like cancer and neurodegenerative disorders.
How long do you need to fast to deplete glycogen? ›Most glycogen is stored in the liver, which has the greatest role in the maintenance of blood glucose during the first 24 hours of a fast. After fasting for around 24 hours, glycogen stores are depleted causing the body to utilize energy stores from adipose tissue and protein stores.
What are 3 types of fasting? ›There are three main types of fasts: calorie restriction, nutrient restriction, and seasonal eating.
What are the four stages of fasting? ›The four phases include the fed state, early fasting state, fasting state, and long-term fasting state (starvation state). Each phase varies based on the primary source of energy used for the body, as well as how it affects your metabolism and levels of specific hormones.
How long should I fast to cleanse my body? ›Many medical experts agree that a one-day fast can feel great, but extending beyond three days can begin to be harmful, especially if you have other medical conditions, such as diabetes or heart disease. “A fast longer than a day or two can deplete vitamins, minerals and electrolytes,” Dr. Hopkins says.
What are the 5 stages of fasting? ›The 5 Stages of Intermittent Fasting with the LIFE Fasting Tracker app: 1) Ketosis and heavy ketosis, 2) Autophagy, 3) Growth hormone, 4) Insulin reduction, 5) Immune cell rejuvenation!
What happens to liver during fasting? ›The liver takes up glucose and synthesizes glycogen and triglycerides following food intake, releases glucose produced by glycogenolysis or gluconeogenesis and triggers ketogenesis during fasting (23).
What hormone is released when fasting? ›As blood glucose levels fall during fasting, the pancreas secretes increased amounts of glucagon. This action also reduces insulin secretion, which in turn decreases glucose storage in the form of glycogen.
How much walking does it take to deplete glycogen? ›To give you a rule of thumb: after approximately 80 minutes of exercise at a maximum lactate steady state, glycogen stores are depleted.
What is the healthiest fasting method? ›Likely, the best method to fast is a 3-day fast every month or every new season. Be cautious with fasting under certain conditions, including if you are too thin, malnourished, are under 18, have a chronic disease, or are pregnant or breastfeeding.
What is the healthiest fasting? ›
One study reports that alternate day fasting is effective for weight loss and heart health in both healthy and overweight adults. The researchers found that the 32 participants lost an average of 5.2 kilograms (kg), or just over 11 pounds (lb), over a 12-week period.
What is a dirty fast? ›Dirty fasting is a term used to describe consuming some calories during a fasting window. This differs from traditional fasting or “clean” fasting, which restricts all foods and calorie-containing beverages. People who practice dirty fasting will typically consume up to 100 calories during their fasting window.
How do I know I'm in autophagy? ›A key sign of autophagy is reduced appetite. It's likely due to changed levels of hormones like glucagon and insulin. Specifically, levels of glucagon tend to increase during autophagy. Glucagon helps manage your blood sugar levels and has been shown to suppress appetite ( 6 , 10 , 11 ).
What does a 72 hour fast do to your body? ›The 72-h fasting induced significant decreases in glucose level, body weight, and an increase of ketone bodies that confirmed successful fasting of the volunteers. In addition, the median of BDI-2 increased significantly (4 vs. 7, p = 0.006).
Does lemon water break a fast? ›The truth about lemon water and intermittent fasting
Long story short - the answer to the question “Does lemon water break a fast?” is no, lemon water does not break a fast. Lemon water contains almost no calories and zero sugars, it doesn't raise insulin levels, which means it will not break your fast (1).
Larance Lab research
“We know that fasting can be an effective intervention to treat disease and improve liver health.
A new scientific study has backed up some health claims about eating less. The clinical trial reveals that cutting back on food for just 5 days a month could help prevent or treat age-related illnesses like diabetes and cardiovascular disease.
Does fasting make you poop more? ›Usually, fasting doesn't cause diarrhea on its own. In fact, you're more likely to get diarrhea from breaking your fast than you are while performing the fast. That's because your bowel's ability to function properly decreases when it's not used.
At what point is fasting unhealthy? ›Longer periods without food, such as 24, 36, 48 and 72-hour fasting periods, are not necessarily better for you and may be dangerous. Going too long without eating might actually encourage your body to start storing more fat in response to starvation.
Does coffee break a fast? ›The short answer is yes, you can drink coffee while intermittent fasting. But, this answer comes with a big caveat: You can drink black coffee while intermittent fasting, but coffee drinks with cream, sugar, or other forms of calories technically break your fast.
Does fasting burn belly fat? ›
Intermittent fasting is a convenient way to lose weight without counting calories. Many studies show that it can help you lose weight and belly fat.
Can fasting damage your organs? ›Yes, it is possible to lose calories, fat and weight from this popular diet. However, it is also possible to quickly gain the weight back, develop low energy stores which can result in a depressed mood, have problems sleeping and even develop organ damage if the fasting is extreme.
Can intermittent fasting reverse fatty liver? ›None of the six included studies were confounded by exercise or other interventions. Therefore, intermittent fasting has an independent and significant benefit on weight loss and improvement of liver function in patients with NAFLD.
Why does fasting reduce inflammation? ›A 2013 study concluded that fasting for more than 24 hours may lower inflammation by reducing oxidative stress in cells. A 2014 study found that both intermittent fasting and alternate-day fasting were as effective as limiting calorie intake at reducing insulin resistance.
Can fasting reset your metabolism? ›To accomplish the 24-hour fast, you would continue fasting until dinner the following day. This resets the metabolism every time. It works because of the effect it has on two hormones, insulin and growth hormone. When in the non-fed state, insulin goes down which allows the body to access and utilize fat as fuel.
Will fasting reset my hormones? ›Intermittent Fasting can also help balance hormones, confirms James Roche, “There is substantial research that suggests that intermittent fasting may help to improve hormonal balance. This can enhance metabolism and sleep, leave us feeling more energized and also help us to more effectively burn more calories.”
What happens in the brain during fasting? ›Animal studies suggest that fasting protects brain cells by providing ketones for fuel instead of glucose. Ketones appear to help the brain produce brain-derived neurotrophic factor (BDNF), a compound that promotes the growth of new brain cells and new connections between them.
What exercise depletes glycogen most quickly? ›If you are going to try glycogen depletion workouts, the best time to do them is during long runs because your body will naturally run out of glycogen after 90 minutes or so.
How do I know if my glycogen stores are depleted? ›Once all the stored glycogen is depleted, you will feel tired, fatigued, and your exercise performance will suffer. The glycogen that is stored in our muscles is for “locals only.” In other words, once it's stored in muscle, it's not capable of being transported to other areas of the body to provide fuel.
What burns glycogen faster? ›In a high-intensity workout, although your body uses your glycogen stores first for 'fast energy', it depletes the glycogen stores rapidly enough to force your body to tap on the fat storage. This means that high-intensity workouts are more efficient in burning way more total calories – both glycogen and fat calories.
What fat burns first when fasting? ›
You will first lose hard fat that surrounds your organs like liver, kidneys and then you will start to lose soft fat like waistline and thigh fat. The fat loss from around the organs makes you leaner and stronger.
Which fasting method burns the most fat? ›Occasional fasting combined with regular weight training is best for fat loss, Pilon says. By going on one or two 24-hour fasts during the week, you allow yourself to eat a slightly higher number of calories on the other five or six nonfasting days.
Can fasting reverse aging? ›The fountain of youth may be a myth, but you can turn to the next best option: the anti-aging impact of intermittent fasting. Intermittent fasting triggers multiple changes in your body that slow down aging by keeping cells and DNA healthy.
Does sleeping count as fasting? ›Does sleeping count as fasting? A. Yes, while following intermittent fasting, sleeping is considered a fasting period. Therefore, one does not consume food or drinks during this state.
How many hours is a healthy fast? ›Most of these regimens advise short fast periods of 8–24 hours. However, some people choose to undertake much longer fasts of 48 and even up to 72 hours. Longer fast periods increase your risk of problems associated with fasting.
Which intermittent fasting is best for belly fat? ›As part of a 2019 study, researchers followed 19 adults with metabolic syndrome whose meals were spread over a 14-hour window and found limiting meals to a 10-hour window (followed by 14 hours of fasting) was associated with weight loss, smaller waist circumference, lower blood pressure and LDL “bad” cholesterol.
What foods won't break a fast? ›- Water. Plain or carbonated water contains no calories and will keep you hydrated during a fast.
- Coffee and tea. These should mostly be consumed without added sugar, milk, or cream. ...
- Diluted apple cider vinegar. ...
- Healthy fats. ...
- Bone broth.
Other foods allowed during fasting are vegetables, whether fermented or unfermented, sauerkraut, tempeh, lettuce, celery, tomatoes, strawberries, cucumber, skimmed milk, and plain yoghurts. You should also make sure to drink lots of water during this period.
Will gum break my fast? ›Gum contains calories
For stricter forms of fasting like water fasts, consuming any calories technically breaks your fast. This is especially true if you're chewing multiple sticks of gum per day or choosing a type of gum that's high in sugar.
The Effect of Short-Term Fasting on Human Psychological Health. Some studies reported that short-term fasting can increase negative emotions (depression, anxiety, anger, irritability, fatigue, and tension) and decrease positive emotions and vitality [25–29].
Does fasting have scientific benefits? ›
Fasting has been shown to improve biomarkers of disease, reduce oxidative stress and preserve learning and memory functioning, according to Mark Mattson, senior investigator for the National Institute on Aging, part of the US National Institutes of Health.
How long can a person fast safely? ›There is no set time that water fasting should last for, but medical advice generally suggests anywhere from 24 hours to 3 days as the maximum time to go without food.
Is fasting good for the liver? ›A 2021 systematic review and meta-analysis out of Frontiers In Nutrition found that intermittent fasting could reduce liver enzyme levels (ALT,AST) in people living with fatty liver disease.
What does 7 days of fasting do? ›Studies have shown that extended fasting, such as water fasting for a week or more, can result in positive effects like weight loss, body fat loss, reduced levels of perceived stress, increased ketogenesis, and decreased blood sugar levels.
What is the most effective fasting? ›Likely, the best method to fast is a 3-day fast every month or every new season. Be cautious with fasting under certain conditions, including if you are too thin, malnourished, are under 18, have a chronic disease, or are pregnant or breastfeeding.
What happens to your body when you fast everyday? ›After eight hours without eating, your body will begin to use stored fats for energy. Your body will continue to use stored fat to create energy throughout the remainder of your 24-hour fast. Fasts that last longer than 24 hours may lead to your body to start converting stored proteins into energy.
What happens to your brain when you fast? ›Animal studies suggest that fasting protects brain cells by providing ketones for fuel instead of glucose. Ketones appear to help the brain produce brain-derived neurotrophic factor (BDNF), a compound that promotes the growth of new brain cells and new connections between them.
Can fasting heal depression? ›Can fasting help with depression? Some researchers believe that fasting can help reduce certain mental health issues, including depression. For example, a 2021 review reported that people who fasted had lower anxiety and depression scores than control groups who did not fast.
What organs benefit from fasting? ›The liver helps by converting non-carbohydrate materials like lactate, amino acids, and fats into glucose energy. Because our bodies conserve energy during fasting, our basal metabolic rate (the amount of energy our bodies burn while resting) becomes more efficient, thereby lowering our heart rate and blood pressure.
What are the benefits of a 48 hour fast once a week? ›Fasting for 48 hours may boost your health by promoting weight loss, improving insulin sensitivity, and reducing inflammation. It may also help you live longer by delaying cell aging.
What happens after 24 hours of fasting? ›
Once you pass 24 hours of fasting, your body will enter into a state called ketosis, where you're reliant on burning your fat stores for energy. As fat cells are broken down for energy, ketone bodies are created and released into the bloodstream. Ketone bodies act as fuel for the brain when glucose is scarce.