Intermittent fasting isn’t just a weight loss strategy or a hack that bodybuilders use to lose fat quickly while maintaining lean muscle mass. It is at its best a healthy lifestyle informed by human evolution and the study of metabolism. It asks the human body to be much more efficient and self-protective than it is accustomed to being in modern times.

There are many things that happen during intermittent fasting that either don’t happen when we are always in a fed state, or that happen very slowly in the background of glucose metabolism. Scroll down to learn more about the five stages of intermittent 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!
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!

In a well-fed state, the individual cell in your body is in “growth” mode. Its insulin signaling and mTOR pathways that tell the cell to grow, divide and synthesize proteins are active. By the way, these pathways, when overactive, have implications in cancer growth.

The “mammalian target of rapamycin” or mTOR loves having plentiful nutrients around, especially carbohydrates and proteins. When active, mTOR tells the cell not to bother with autophagy (literally cellular “self-eating”), a recycling and cleanup process that rids your body of damaged and misfolded proteins, for example. The well-fed cell isn’t worried about being efficient and recycling its components – it’s too busy growing and dividing.

In a well-fed state, your cells and their components are also highly acetylated. This means that various molecules in your cells, including the “packaging” proteins called histones that wrap your DNA up nicely within the core of your cells, are “decorated” with acetyl groups on their lysine (amino acid) residues. Don’t worry if you don’t understand the jargon in that last sentence. What you really need to know is that the well-fed cell has many genes, including those associated with cellular survival and proliferation, turned on. This is because acetylation tends to loosen the packaging proteins that normally keep your DNA wrapped up, and lets your DNA be read for protein production.

While your cells turn on cellular growth and proliferation genes when you aren’t fasting, they also turn other genes off. These include genes related to fat metabolism, stress resistance and damage repair. Actually, with intermittent fasting some of your fat gets turned into ketone bodies that appear to reactivate these genes, leading to lowered inflammation and stress resistance in the brain, for example.

But during starvation, things are very different. When you practice intermittent fasting, your body reacts to what it sees as an environmental stress (low food availability) by changing the expression of genes that are important in protecting you from, well, stress.

We have a well-preserved starvation “program” that kicks our cell into a completely different state when food, particularly glucose or sugar, isn’t around. With intermittent fasting and exercise, you activate the AMPK signaling pathway. AMPK or 5′ AMP-activated protein kinase is the brake to mTOR’s gas pedal. AMPK signals the cell to go into self-protective mode, activating autophagy and fat breakdown. It inhibits mTOR. At the same time, while you are fasting the levels of a molecule called NAD+ begin to rise because you don’t have the dietary proteins and sugars around that normally convert NAD+ to NADH through the Krebs cycle. NAD+, a molecule whose precursor is Vitamin B3, activates the sirtuins, SIRT1 and SIRT3. (Have you heard of the “longevity” molecule in wine called resveratrol? Yep, it became famous as being a potential activator of the sirtuins). These sirtuins are proteins that remove the acetyl groups we talked about above from histones and other proteins. In this process, the sirtuins silence genes related to cell proliferation and activate proteins involved in creating new mitochondria (the power-generating factories of your cells) and cleaning up reactive oxygen species.

Ketones, also produced during fasting, work as deacetylase inhibitors (in other words, keeping acetyl groups in place). This turns on genes related to antioxidant processes and damage repair.

Whew, that’s a lot happening while your body isn’t taking in any calories. But when exactly do these things happen? We’ve helped you visualize the timeline below and in the LIFE Fasting Tracker app, with a series of icons on the LIFE Fasting arc that represent the five stages of  intermittent fasting!

The Five Stages of Intermittent (and Prolonged) Fasting

KetosisBy 12 hours, you’ve entered the metabolic state called ketosis (Anton et al., Obesity 2018). In this state, your body starts to break down and burn fat.

Some of this fat is used by the liver to produce ketone bodies (ketones). The two main ketones, acetoacetate and β-hydroxybutyrate (BHB), serve as an alternative energy source for the cells of your  heart, skeletal muscle, and brain, when glucose isn’t readily available. Did you know that your brain uses up some 60% of your glucose when your body is in the resting state? During intermittent fasting, ketone bodies generated by your liver partly replace glucose as fuel for your brain as well as other organs. This ketone usage by your brain is one of the reasons that intermittent fasting is often claimed to promote mental clarity and positive mood – ketones produce less inflammatory products as they are being metabolized than does glucose, and they can even kick-start production of the brain growth factor BDNF! Ketones have also been shown to reduce cellular damage and cell death in neurons and can also reduce inflammation in other cell types

By 18 hours, you’ve switched to fat-burning mode and are generating significant ketones (Anton et al., Obesity 2018). You can now begin to measure blood ketone levels above your baseline values. Under normal conditions, the concentration of ketones in your plasma ranges between 0.05 and 0.1 mM. When you fast or restrict the carbohydrates in your diet, this concentration can reach 5-7 mM. You can help accelerate ketone production with some heart-pumping exercise! For example, intermittent fasting combined with running cause rewiring of nerve cells in the brain which leads to improved learning and memory in lab animals

As their level in your bloodstream rises, ketones can act as signaling molecules, similar to hormones, to tell your body to ramp up stress-busting pathways that reduce inflammation and repair damaged DNA for example.

Within 24 hours, your cells are increasingly recycling old components and breaking down misfolded proteins linked to Alzheimer’s and other diseases (Alirezaei et al., Autophagy 2010). This is a process called autophagy. 

Autophagy is an important process for cellular and tissue rejuvenation – it removes damaged cellular components including misfolded proteins. When your cells can’t or don’t initiate autophagy, bad things happen, including neurodegenerative diseases, which seem to come about as a result of the reduced autophagy that occurs during aging.  Intermittent fasting activates the AMPK signaling pathway and inhibits mTOR activity, which in turn activates autophagy. This only begins to happen, however, when you substantially deplete your glucose stores and your insulin levels begin to drop.

Intermittent fasting is one way in which you can increase autophagy in your cells and possibly reduce the effects of aging. A 2019 study with 11 overweight adults who only ate between 8 am and 2 pm showed increased markers of autophagy in their blood after fasting for around 18 hours, compared to control participants who only fasted for 12 hours. A second study detected  autophagy  in human neutrophils starting at 24 hours of fasting.  In a third study, skeletal muscle biopsies of healthy male volunteers who fasted for 72 hours showed reduced mTOR and increased autophagy. In mice deprived of food, autophagy increases after 24 hours and this effect is magnified in cells of the liver and brain after 48 hours.

But intermittent fasting is not the only way to enhance the ability of your cells to recycle old components. Some of the known benefits of exercise for overall health have to do with increased autophagy. For example, autophagy induced by exercise delays the progression of heart disease by giving the heart better quality cell parts and reducing oxidative damage.

Exercise, just like intermittent fasting, inactivates mTOR, which increases autophagy in many tissues. Exercise mimics the effects of going without food for an extended period: It activates AMPK as well as autophagy-related genes and proteins. 

In mice, endurance exercise increases autophagy in the heart, liver, pancreas, fat tissue, and brain. In humans, autophagy increases during high intensity exercise, including marathon running and cycling.

Learn more about autophagy in this blog post and in these free mini-courses:

What is autophagy?

Why is autophagy good for your health?

peak growth hormoneBy 48 hours without calories or with very few calories, carbs or protein, your growth hormone level is up to five times as high as when you started your fast (Hartman et al.,1992).

Part of the reason for this is that ketone bodies produced during fasting promote growth hormone secretion, for example in the brain. Ghrelin, the hunger hormone, also promotes growth hormone secretion. Growth hormone helps preserve lean muscle mass and reduces fat tissue accumulation, particularly as we age. It also appears to play a role in mammalian longevity and can promote wound healing and cardiovascular health.

minimum insulinBy 54 hours, your insulin has dropped to its lowest level point since you started fasting and your body is becoming increasingly insulin-sensitive (Klein et al., 1993).

Lowering your insulin levels through Intermittent fasting has a range of health benefits both short term and long term. Lowered insulin levels put a brake on the insulin and mTOR signaling pathways, activating autophagy. Lowered insulin levels can reduce inflammation, make you more insulin sensitive (and/or less insulin resistant, which is especially a good thing if you have a high risk of developing diabetes) and protect you from chronic diseases of aging including cancer.

By 72 hours, your body is breaking down old immune cells and generating new ones (Cheng et al., 2014).

Prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations. IGF-1, or insulin-like growth factor 1, looks a lot like insulin and has growth-promoting effects on almost every cell in the body. IGF-1 activates signaling pathways including the PI3K-Akt pathway that promotes cell survival and growth. PKA can also activate the mTOR pathway (and, of interest, too much caffeine during a fast may promote activation of PKA).

You might see where this is leading – pressing the brakes on IGF-1 and PKA through nutrient restriction and fasting can turn down cellular survival pathways and lead to breakdown and recycling of old cells and proteins. Studies in mice have shown that prolonged fasting (greater than 48 hours), by reducing IGF-1 and PKA, leads to stress resistance, self-renewal and regeneration of hematopoietic or blood cell stem cells. Through this same mechanism, prolonged fasting for 72 hours has been shown to preserve healthy white blood cell or lymphocyte counts in patients undergoing chemotherapy.

How to do intermittent fasting

If you are just getting started with intermittent fasting, we recommend slowly working up to your target fasting schedule over the course of several weeks or months.  Start by reflecting on your eating habits. Do you snack in between meals or after dinner? If so, try a 12-hour fast overnight. This means you finish dinner by 7 pm, for example, and don’t eat anything else until 7 am the next day. If you usually don’t feel the need to eat after dinner or between meals, try a 14-16 hour fast (For example, finish dinner by 6 pm and don’t eat again until 10 am the next day).  If you’d like to fast longer, add 1-hour increments every 5 days or so. Drink water to keep you both hydrated and distracted from hunger. If you need caffeine, drink unsweetened black coffee and tea.

31 daily challenges to get started with intermittent fasting

Intermittent fasting schedules to follow

There are many ways to practice intermittent fasting for weight loss. The following are some of the most popular schedules:

Time-restricted eating: This involves consuming all of your meals within a period of 4-12 hours in a day. For example, you could choose to have your meals and calories between 8 am and 6 pm. Limiting your calorie intake to daylight hours is called “eating with the sun”. Time-restricted eating is particularly beneficial if you eat your meals before sunset. Not only does this help you eliminate bad habits like late-night snacking, but it improves your sleep and blood sugar control. Over time, time-restricted eating can lower your blood sugar levels, make you more sensitive to insulin, and reduce your blood pressure. 

One-meal-a-day (OMAD): This involves packing all of your day’s calories in a single meal that you consume within 1-2 hours. A small study conducted by Dr. Jason Fung’s research group showed that fasting for 24 hours 3 times a week and eating only dinner on fasting days, eliminated the need for insulin in type-2 diabetic patients. This fasting approach also resulted in improved HbA1C, lower body mass index, and reduced waist circumference.

Alternate-day Fasting: This involves alternating between days in which you consume no calories and days in which you eat normally.  This way of fasting increases life span in rodents by 80%, possibly by decreasing glucose levels and regulating insulin. It also reduces the incidence of cancer in lab animals genetically predisposed to it. Alternate-day fasting is the most studied method of intermittent fasting in humans, and it’s been shown to lead to weight loss and to improve heart health, as it reduces circulating levels of LDL or ‘bad’ cholesterol.

The 5:2 “diet”: The 5:2 plan involves eating normally for five days each week and then fasting for the last two. For example, you might decide to fast Monday and Tuesday and then eat normally the rest of the week. You can also look at it as one 60-hour fast per week. Finish dinner at 6pm on Sunday night and don’t eat again until breakfast on Wednesday morning, for example.

What intermittent fasting schedule is right for you? Find out here.

How to break a fast

We almost forgot about the last and perhaps most important stage of intermittent fasting – the refeeding stage! It’s important to break your fast with a nutritious, balanced meal that will further improve the function of cells and tissues that went through cleanup while you were fasting. From Mark Mattson and colleagues at the National Institute on Aging:

“Upon refeeding, ingested carbohydrates* and glucose stimulate release into the blood of the incretin hormone glucagon-like peptide 1 (GLP1) from enteroendocrine cells in the gut. GLP1 enhances clearance of glucose from the blood by stimulating insulin release from the pancreas and increases the insulin sensitivity of cells. GLP1 crosses the blood–brain barrier and can act directly on neurons to promote synaptic plasticity, enhance cognition and bolster cellular stress resistance.”

*Update: This isn’t a recommendation to break your fast with lots of carbs and sugars, which may in fact lead to problematic blood sugar spikes. A few carbs can go a long way. It’s best to break your fast with a balanced meal including plenty of vegetables, plant fibers and plant fats, with healthy proteins and some whole grains or legumes if you choose. Avoid simple sugars and processed/packaged foods. Learn what works best for your body, and what you feel best eating following your fasts.

So what are you waiting for? Try fasting for 12, 16, or even  48 hours or more with the LIFE Fasting Tracker app! You’ll be rewarded with badges on your fasting arc that give you updates on your progress toward autophagy and cellular renewal! Talk to your physician before attempting fasts of 48 hours and longer.

food love.

Paige Jarreau, PhD

I am the VP of Science Communication for LifeOmic and an avid blogger. I'm interested in how scientists use social media to promote public engagement and health behaviors.

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