Below you can find:
- What Happens During Fasting?
- What Is the Timeline of Changes During Fasting?
- Where Does Each Fasting Method Lie on the Fasting Timeline?
- What Interrupts the Fasting Timeline?
- What Can You Eat While Fasting Without Losing the Benefits?
- Fasting Goals – What Does the Research Say?
- Enhancing Longevity and Healthspan
- Making New Stem Cells
- Enhancing Autophagy
- Treating Cancer
- Summary: The Takeaways
Fasting Part 1 is an introduction to fasting. It described each of the different fasting methods and how to fast.
If you haven’t read Fasting Part 1, you can get caught up with it here (link coming soon!). That will help you prepare for what you’ll learn here in Fasting Part 2.
Below you will learn the timeline of fasting and how this applies to different fasting goals.
Check out the Summary Takeaways section at the end to see how fasting fits your specific goals. Then come back and grab all the details and references to go over with your doctor. That way you’ll be fully prepared and get the most from your fast.
Use the Fasting Optimisation App to find the best fasting method for you. It comes with a detailed step-by-step plan to guide you along the way.
What Happens During Fasting?
At its core, “fasting” describes different methods of calorie restriction. Calorie restriction is the research term for reduced food intake.
As you saw in Part 1, the fasting methods differ in how much, how long, and how often they restrict calories.
The calories you normally eat come from carbohydrates, fats, and proteins. When you fast, you deprive your body of these fuels. This forces your body to pull from its fuel reserves.
- Carbohydrates come from glycogen, the body’s storage form of carbohydrate
- Fats come from your body fat stores
- Amino acids mainly come from the proteins in your muscle
As you’ll see below, glycogen is used first as your body adapts to using fat as your main fuel source. Then protein is consumed to maintain your blood glucose levels.
Many people worry about losing muscle during fasting. It is true that you lose some protein during a fast, and your muscle is the main source of this protein.
But the amount of protein you consume during a fast is surprisingly small. You’ll lose an estimated 1.1-1.2 lbs of protein during a 7-day fast.
To put this into perspective, people can lose 5 lbs or more during a week of fasting. This means only ~20% of weight loss comes from protein if you fast for a week.
Your body taps into these fuel reserves as hormone levels begin changing. Hormones are chemical messengers that carry signals throughout the body.
Insulin, glucagon, insulin-like growth factor 1 (IGF1), and growth hormone are some of the major hormones affected by fasting. These hormones are described in more detail later.
These hormones control large-scale changes during fasting, like what you see in the mirror. They also control small-scale changes, like what happens at the cellular level in your body.
What Is the Timeline of Changes During Fasting?
Studies on prolonged fasting paint the clearest picture of the fasting timeline.
Your hormones and metabolism change considerably within just one week of fasting.
A week of fasting may seem like an eternity without food. When you compare it to a normal 15-hour eating window, i.e. eating from 7 AM to 10 PM, an entire week of fasting can seem like a very long time.
But people have been studied during fasts lasting much longer than one week. In general, the first week of fasting establishes the major changes to hormones and metabolism that continue during longer fasts.
Falling Back onto Fuel Reserves
During fasting, your body’s liver glycogen is tapped first. Glycogen is a storage form of carbohydrate which consists of long, branched strings of glucose.
Your largest glycogen stores are found in your liver and muscle cells. But during fasting, only your liver’s glycogen is used to control your blood glucose level. This is because your muscle cells can’t make the enzyme glucose-6-phosphatase. This enzyme is necessary to release glucose into the bloodstream.
Another organ, your pancreas, controls how liver glycogen is used during fasting.
Your Pancreas Controls Your Carbohydrate Reserves
When you eat carbohydrates like bread or rice, they are converted into glucose and this increases your blood glucose level. When your blood glucose level rises, your pancreas secretes the hormone insulin into your bloodstream.
Insulin shuttles excess glucose out of your blood and into cells throughout your body. These cells can then use the glucose or store it as glycogen. In this way your liver and muscle are basically large glucose “sinks”, as liver cells and muscle cells can store lots of glycogen.
When you stop eating carbohydrates, your pancreas secretes glucagon into your bloodstream. Glucagon stimulates your liver cells to break down glycogen and this raises your blood glucose levels. You can see this illustrated in Figure 1 below.
Figure 1. The effect of insulin and glucagon on liver glycogen.
Altogether, the hormones insulin and glucagon both come from your pancreas and play “tug-of-war” on your liver glycogen. The ratio of insulin to glucagon will determine who wins. This ratio tells you whether glucose is going into or coming out of the liver.
During a normal day of eating, this overall process helps to keep your blood glucose levels at a certain set point. Unless you’ve eaten within the last few hours, your blood glucose is probably ~5 mM (~90 mg/dL) right now.
It works like a thermostat. When your blood glucose rises, insulin comes out and brings it back down again. When your blood glucose falls, glucagon comes out to bring it back up again.
During fasting, insulin levels progressively drop as glucagon levels rise. This means glucagon wins the tug-of-war on liver glycogen. You can see this in Figures 2 and 3 below.
Figure 2. The levels of insulin and glucagon during fasting.
Figure 3. The insulin:glucagon ratio during fasting.
Your liver holds an estimated 70 grams of glycogen. This tug-of-war on liver glycogen allows it to last 2-4 days during prolonged fasting.
As you can see in Figure 4 below, blood glucose levels drop to a new set point below 70 mg/dL during this time.
Figure 4. Blood glucose levels drop during fasting.
What about Hypoglycemia?
Hypoglycemia has very uncomfortable and potentially dangerous symptoms. The mild symptoms of hypoglycemia include nervousness, sweating, and increased heart rate and blood pressure.
Surprisingly, non-diabetic people who are fasting are protected against the symptoms of hypoglycemia. The high levels of ketone bodies in their blood are believed to be responsible for this. Ketone bodies are the breakdown products, or metabolites, of fat.
Studies found that non-diabetic people who fasted for >6 weeks did not show symptoms of hypoglycemia, even at incredibly low blood glucose levels. But this does not mean it’s impossible to become hypoglycemic during fasting.
Certain medical conditions such as insulinoma and glycogen storage diseases can cause hypoglycemia during fasting. Type 2 diabetics who take blood glucose-lowering medications are also at risk for hypoglycemia during fasting, even if they eat food on their fasting days.
Type 1 diabetics are at risk for both hypoglycemia and hyperglycemia during fasting. Because of this volatility in blood glucose levels, there is not enough research yet to recommend any fasting method for type 1 diabetics.
Fasting Puts You Into Ketosis
The buildup of ketone bodies in the blood is called ketosis. In fact, the ketogenic diet was developed to mimic fasting since they both put you in ketosis.
As you run out of liver glycogen, your body taps into its fat reserves and begins creating ketone bodies. Blood levels of free fatty acids and ketone bodies increase during fasting.
Following a ketogenic diet for at least 4 weeks may help with fasting. One reason for this is because your body adapts to using less glucose within 4 weeks on the ketogenic diet.
You can see in Figure 5 below that as blood glucose falls, levels of free fatty acids and beta-hydroxybutyrate rise in the blood. Beta-hydroxybutyrate is the predominant ketone body your body makes while fasting.
Figure 5. How blood levels of glucose, free fatty acids, and beta-hydroxybutyrate (BHB) change during fasting.
Your blood glucose set point drops during fasting, but it does not drop to zero. This means new glucose needs to be made during fasting.
New glucose is generated during fasting through a process called gluconeogenesis. Just like the name gluco-neo-genesis implies, new (neo) glucose (gluco) is generated (genesis) during fasting. As noted earlier, some gluconeogenesis comes from the amino acids of protein during fasting.
Some gluconeogenesis also comes from glycerol during fasting. Glycerol is the backbone of triglycerides, which is your body’s main storage form of fat. Triglycerides get broken down into fatty acids and glycerol. The fatty acids can then be converted into ketone bodies and the glycerol can be converted into glucose.
So, some muscle protein does get broken down during fasting. As mentioned earlier, total protein breakdown amounts to only ~1.1-1.2 lbs during a 7-day fast. This means it is not a major concern during fasting. You can see a timeline of protein breakdown in Figure 6 below.
Figure 6. The estimated breakdown of protein per day during fasting.
To help put things into perspective, an obese person may carry ~750,000 calories of fat but only ~30,000 calories of protein on their body. If they relied heavily on protein for fuel during fasting, they could not safely fast for very long. But obese individuals like this have safely fasted for several months. One obese man even fasted for 382 days!
In summary, fat becomes the primary fuel source for the body during the first week of water-only fasting. Afterwards, the size of the fat reserves determines how long a person can safely fast before breaking down too much muscle.
The Growth Hormone/IGF1 Axis
Growth hormone and IGF1 are two hormones which control the growth of the body. You may have heard of them before in the context of childhood growth or muscle growth.
Growth hormone is normally released during the night while you sleep, though it can also be released during the day.
Growth hormone signals your liver to produce IGF1. IGF1 then triggers pro-growth mechanisms throughout your body. This is called the growth hormone/IGF1 axis.
During fasting, the growth hormone/IGF1 axis becomes muted. Growth hormone levels peak more often during fasting and the total growth hormone release is higher than normal. But instead of increasing like growth hormone, IGF1 levels drop during fasting.
Figure 7. How IGF1 levels change during fasting.
This observation for growth hormone seems rather strange considering its pro-growth effects. You probably don’t think about “growth” being an important part of fasting. Why would growth hormone stay elevated when a person is fasting?
Growth hormone helps regulate fuel use during fasting. High levels of growth hormone are necessary to increase fat breakdown during fasting. Growth hormone also promotes the liver to release more glucose into the bloodstream. This helps deplete the liver glycogen reserve more quickly as the body shifts to fat metabolism.
So, growth hormone goes up during fasting and this promotes a switch to fat metabolism. This surprisingly does not increase IGF1 levels, which instead drop during a prolonged fast.
Where Does Each Fasting Method Lie on the Fasting Timeline?
The fasting timeline in the graphs above outlines the key changes in hormones and metabolism which take place during fasting. Each of the fasting methods will come with at least some of these changes.
To get an idea of how the fasting timeline relates to each fasting method, you can imagine two different states of the body when it comes to food:
- Anabolism is the building up of complex structures like glycogen and muscle protein. When your body is in an anabolic state, it is building these structures.
- Catabolism is the breaking down of these complex structures. When your body is in a catabolic state, it is breaking down structures like glycogen and muscle protein.
The effect of insulin and glucagon on glycogen illustrates this well. Figure 8 shows this below.
Figure 8. Anabolism and catabolism control the size of glycogen in the liver.
Fasting promotes catabolism. This means fasting puts you into an overall catabolic state where complex structures are broken down.
Since fasting promotes catabolism, the catabolic state will be called the Fasted State from now on. The anabolic state will be called the Fed State.
Each fasting method has its place. The fasting method which is best for you will depend on a couple of factors:
- How deep of a Fasted State do you need?
- Do you need to take food/medication to make sure your fast is safe and successful?
The Fed And Fasted States
Among the hormones discussed in the fasting timeline above, insulin and IGF1 are hormones of the Fed State. Insulin stimulates the buildup of glycogen, muscle protein, and triglycerides. IGF1 stimulates the buildup of muscle protein.
These hormones of the Fed State decrease during prolonged fasting.
On the other hand, glucagon and growth hormone are hormones of the Fasted State. Glucagon stimulates the breakdown of glycogen and muscle protein. Growth hormone stimulates the breakdown of glycogen and triglycerides.
These hormones of the Fasted State increase during prolonged fasting.
You can think of a Fasted State as a “rest period” from food and growth.
Type 2 diabetes is a great example of this. Entering a rest period from food is helping treat and potentially “reverse” type 2 diabetes. Entering a rest period periodically may even prevent diseases like type 2 diabetes.
Also, studies on stem cells suggest that a rest period can allow old cells to die off while stem cells expand in number. Then entering a Fed State after this rest period allows the body to make use of the new stem cells.
Studies like these are discussed in the “Fasting Goals” sections below. As you’ll see, the depth of your Fasted State will depend on your fasting goal.
It is not simple to track hormone changes during a fast. But the Fasted State comes with a drop in blood glucose levels and a rise in blood ketone body levels. Glucose and ketone bodies are easy to measure using an over-the-counter blood meter.
This means you can gauge your Fasted State by tracking these blood measurements.
Which Fasting Methods Have The Deepest Fasted States?
The depth of your Fasted State depends on how much you restrict calories and for how long you restrict calories.
You can think of this as a spectrum.
On one end of the spectrum is TRF. The fasting window is short (<24 hours) and there is no calorie restriction. So TRF has the shallowest Fasted State.
On the opposite end of the spectrum is prolonged fasting. The fasting window is long (≥72 hours) and calories are completely restricted. So prolonged fasting has the deepest Fasted State.
The other fasting methods fall somewhere in the middle.
For modified fasting, the number of days you choose to restrict calories will determine the net calorie deficit for the week.
On a weekly timeline, alternate-day fasting and modified fasting can both result in calorie deficits. This is certainly true of alternate-day fasting, which fully restricts calories on up to four days of the week.
So, between these two methods, alternate-day fasting has a deeper Fasted State than modified fasting. Placing the 5-day and 8-day fasting mimicking diets (FMDs) on the spectrum is a little more difficult.
The 5-day FMD and 8-day FMD both involve prolonged calorie restriction of ≤50% calories/day. This means they each have deeper Fasted States than modified fasting or alternate-day fasting. This must be true for the 8-day FMD as it has a lower calorie limit.
If you consider prolonged fasting as eight days of water-only fasting, then the spectrum of Fasted States looks like Figure 9 below.
Figure 9. The spectrum of Fasted States.
Do You Always Want The Deepest Fasted State?
So, because prolonged fasting has the deepest Fasted State, shouldn’t everyone just do that? What is the purpose of these other fasting methods?
Not necessarily. As discussed in the Fasting Goals section below, a deep Fasted State is useful some of the time. You don’t always want to stay there.
Also, some of the benefits of TRF relate to the circadian rhythm. The circadian rhythm is a daily variation in certain physiological markers like hormone levels. The idea here is that your eating habits are normally out of sync with your circadian rhythm, and TRF helps correct this.
This makes TRF the ideal starting place if you have never fasted before. You can get used to shallow Fasted State and get a more tuned circadian rhythm by following TRF.
This will also help you gain the confidence to try the methods with deeper Fasted States. Succeeding at one fasting method is better than giving up after failing at another fasting method.
If you are on medication which requires food, then you’ll want to use a fasting method which lets you eat every day.
This is especially true if you are on a medication which lowers your blood glucose levels such as metformin, insulin, and sulfonylureas. Even with modified fasting, type 2 diabetics on these medications can get hypoglycemia.
The type of medication and the dose are important to consider when fasting. You should always discuss a strategy with your doctor before beginning any fasting method.
What Interrupts the Fasting Timeline?
In general, it is best to limit your food intake during your fasting window to no-calorie beverages.
This includes coffee, tea, saltwater/bouillon, and even flavored no-calorie beverages. In fact, you lose electrolytes during prolonged fasting, so replacing them periodically is a good idea. Salty water and magnesium supplements are good for replacing electrolytes.
Remember that insulin and IGF1 are hormones of the Fed State. The higher they go, the more they take you out of your Fasted State. That can interfere with your fasting goals.
What Affects IGF1 Levels?
Studies on fasting and calorie restriction suggest that IGF1 levels are increased mostly by protein and carbohydrates. Fat does not have as much impact on IGF1.
Overall calorie intake is important here as well, as a low-calorie intake will not stimulate IGF1 very much during fasting.
For example, after a 5-day fast, a healthy person at 150 lbs (68 kg) could eat 68 g protein and 750 calories total for three or four days without rebounding their IGF1 level.
Even the 5-day FMD, which allows for a similar amount of calories and much less protein, drops IGF1 levels by 24%.
So, what does this mean for your fast? This suggests that very low amounts of protein (<<68 g) and total calories (<<750 kcal) can be taken during your fasting window if necessary.
What Affects Insulin Levels?
Foods rich in protein and/or carbohydrates also stimulate insulin release. This means that eating foods rich in carbohydrates and/or protein during a fast will take you out of your Fasted State.
Fat has little effect on insulin. This means fat is a better choice than carbohydrates or protein when fasting.
Certain fibers do not impact blood glucose or insulin much either. In fact, high-fiber foods impact blood glucose and insulin less than their low-fiber counterparts.
What Can You Eat While Fasting Without Losing the Benefits?
You want to minimize foods which take you out of your Fasted State. This means you should minimize foods which increase your blood glucose, insulin, and IGF1.
Foods high in fat and fiber and low in protein and non-fiber carbohydrates (e.g. avocados) are ideal if you need to eat while fasting.
If you have a blood glucose/ketone monitor, you can check on your Fasted State after eating something.
To do this, measure your blood glucose and ketone bodies before you eat the food item. Then measure again one hour after eating it.
If your glucose goes up and/or your ketone bodies go down, then the food item increased your insulin and should be avoided.
When in doubt, consider these questions:
- How does the food item impact your blood glucose and insulin levels? Aim for foods high in fat and fiber and low in protein and non-fiber carbohydrates.
- How much of each food item do you want to consume while fasting? In general, high-carbohydrate and/or high-protein foods will increase your insulin. If you eat enough of them, they will also increase your IGF1 levels.
Table 1 lists foods that people often want to take while fasting. It can help you answer the questions above when you want to eat something during fasting.
Table 1. What to expect from foods during fasting. References for each item are included where available.
|Category||Item||Blood Sugar Triggered?||Insulin Triggered?|
|Exogenous Ketone Bodies||MCT Oil||No||Slight|
|C8 MCT Oil||No||Slight|
|Drinks And Liquids||Coffee (Black)||No||No|
|Almond Milk (Unsweetened)||Possibly||Possibly|
Fasting Goals – What Does the Research Say?
As you’ll see below, guidelines for some of the major fasting goals are clearly defined by research on humans.
But this is not true for all the fasting goals. Some of these goals have only been demonstrated in animal models so far.
For some of these goals, it is still possible to create reasonable guidelines based on animal models. As discussed above, markers of the Fasted State help to compare the fasting timelines for humans and other animals.
Some of the major fasting goals are explained below. For each goal, the relevant fasting methods are outlined in detail. These details are also summarized in the Takeaways section at the end.
Enhancing Longevity and Healthspan
Increased longevity is often considered the Holy Grail of benefits from lifestyle interventions.
Many expect this benefit from fasting. After all, animals like nematodes and rats see longevity benefits from calorie restriction and fasting.
Nematodes and rats are separated by over 900 million years of evolution! There must be something about this type of restriction that is inherently good for longevity.
But even if fasting does increase human longevity, it would be difficult to measure. Longevity studies in humans are not practical due to the necessary time and resources.
If lifespan is the “years in your life”, then healthspan is the “life in your years.” Healthspan is a way to refer to healthy aging, i.e. how many years you can live without the burden of disease.
Markers of healthspan are much easier to measure in humans than lifespan.
Increased longevity was found in fasting rats as early as 1946. These rats fasted at least one day a week. Rats who fasted every one in three days had the best combination of healthspan benefits and increased longevity.
This fasting method is most similar to alternate-day fasting in humans. You can see an illustration of alternate-day fasting in Figure 10 below.
The 1946 study on fasting rats looked at breast tumors as a marker of healthspan. These tumors were assessed in female rats in the control and fasting groups. The female rats who fasted every one in three days developed smaller tumors than the control group. These tumors also appeared later in life than tumors in the control group.
Figure 10. One week of the alternate-day fasting method.
The Fasting Mimicking Diet (FMD) and Prolonged Fasting
The FMD improves the healthspan of mice. Like the rat study above, this includes a decrease in the number of mice with tumors. It’s important to note here that the FMD for mice is different than the FMD for humans.
For mice, this version of the FMD is four days long and begins with ~50% of normal calories on Day One. Then the mice eat ~10% of normal calories on Days 2-4.
For humans, this version of the FMD is five days long with ~1090 calories on Day One and ~725 calories on Days 2-5.
If you follow a 2000 calorie/day diet, this means you’d eat ~53% of your normal calories on Day One and ~36% of your normal calories on Days 2-5.
You can see that the mouse FMD has a deeper Fasted State than the human FMD based on the % drop in calories.
As you saw in the fasting timeline graphs, ketone bodies serve as a marker of the Fasted State. Levels of ketone bodies increase ~10-fold in mice at the end of their FMD cycle. In humans, this increase is only 3.7-fold.
To see ketone body changes like the mice, you would need to fast for at least two days.
IGF1 serves as marker of the Fed State and goes down while fasting. IGF1 levels decrease by ~45% in mice by the end of their FMD cycle. In humans, IGF1 levels decrease by only 24%.
To get IGF1 levels to drop by 45% like the mice, you would need to fast for at least 2-3 days. There is a large variation in how people’s IGF1 levels drop during a fast though, so this may take as long as 5 days.
Another important difference in the mouse and human FMDs is how often they are performed. In this study, mice repeated the FMD every two weeks once they hit middle age. The humans in this study followed the FMD once a month for only three months.
This is not to say the 5-day FMD is useless for humans. In humans, three months of the 5-day FMD improves several biomarkers which can predict disease. If you have biomarkers trending in the wrong direction, the FMD can be useful to get you back on track.
But to get some of the same healthspan benefits that mice get from the FMD, three days of fasting would be a good place to start.
Using a 3-day fast once per month for three consecutive months may be even more beneficial than the current 5-day FMD method. This is based on the changes in blood glucose, ketones, and IGF1 levels. But there is no study that has tested this yet.
Alternatively, you could also modify the FMD to focus your calories on high-fat and high-fiber foods. The human 5-day FMD method includes carbohydrates and protein which take you out of the Fasted State.
An avocado-based FMD is described on The Quantified Body podcast which you can find here. This will be referred to as the Ketosource Method from now on. Some results from one cycle of the Ketosource Method show an even deeper Fasted State than the mouse FMD. You can see a breakdown of the published FMD and the Ketource Method in Figure 11 below.
Interestingly, IGF1 levels dropped by 44% in the Ketosource Method. This suggests that one cycle of the Ketosource Method is at least equivalent to one cycle of the mouse FMD.
To get even more benefits, you could do two or more cycles of the Ketosource Method every month.
Figure 11. Different approaches to the 5-day FMD.
Time-Restricted Feeding (TRF)
The FMD was developed to mimic prolonged fasting. But it is not the first diet designed to do this. Over a century ago, the ketogenic diet was developed as a fasting replacement for the treatment of epilepsy.
Recent mouse studies on the ketogenic diet showed improved mid-life mortality and median lifespan. One key difference between these two studies is how they dealt with food intake.
Roberts, et al. controlled the calorie intake of mice, which means the researchers likely fed the mice at the same time every day. In this way, the median lifespan increase for these mice could have come from TRF.
In support of this, mice eating one meal a day have increased longevity and healthspan. This seems to be independent of what they eat or how much they eat.
As mentioned already, the fasting timelines for mice and humans are very different. There is no great way to compare these benefits for mice with potential TRF benefits for humans.
But there are some modest benefits for people following TRF.
For example, most people eat within a 15-hour window that extends into the night. Eating between 6 AM and 7 PM could prevent overeating and lead to weight loss.
An 11-hour eating window (13-hour overnight fast) is also associated with less breast cancer recurrence.
An 8-hour eating window shows some benefit for obese people and even for athletes.
Those with prediabetes or at risk for type 2 diabetes can see benefits from eating within 6 hours and 9 hours, respectively. In these cases, the eating window should begin in the morning (8-9 AM).
Making New Stem Cells
One of the most overlooked benefits of fasting is its effect on stem cells.
When you get an injury, stem cells replace the dead cells and regenerate the damaged area. But it is well known that this ability of stem cells decreases with age.
Hematopoietic stem cells, or stem cells of the blood system, illustrate this well.
The number of hematopoietic stem cells in mice increases as they age. But hematopoietic stem cells from aged mice are more defective than the same cells from young mice.
Water-only fasting for three days in mice improves the function of their hematopoietic stem cells.
This length of fasting causes the mice to create more stem cells. But unlike aging, in this case the new stem cells are more functional than the old stem cells.
This was evident from the ratio of blood cell types which looked more like young mice after fasting. In this way, fasting “rejuvenated” the blood systems of these mice.
These benefits are believed to come from a drop in IGF1 levels in the mice. At the end of a 3-day fast, IGF1 levels in mice drop by 70%.
You would need to fast for at least 5 days to get a similar drop in IGF1 levels. As stated earlier, people’s IGF1 levels drop at different rates during fasting. It could take as long as 9 days of fasting to see this drop in IGF1.
The Fasting Mimicking Diet (FMD)
The FMD also provides stem cell benefits to mice. This includes benefits to brain stem cells and stem cells found in the bone marrow.
Interestingly, certain organs shrink (kidney, heart, liver) in mice while they follow the FMD. These organs then return to their normal weights or heavier after the mice eat again for a week. There are also signs of organ and blood system rejuvenation following this re-feeding phase.
This highlights the importance of the re-feeding phase. Without entering back into this Fed State after the Fasted State, the mice would not be able to use their benefits from their Fasted State.
As discussed in the “Enhancing Longevity and Healthspan” section, the mouse FMD has a deeper Fasted State than the human 5-day FMD. But you can mimic the mouse FMD with water-only fasting for 3-5 days or by using the Ketosource Method as an FMD.
Figure 12. Where stem cell benefits fall on the fasting timeline.
Autophagy is the process whereby old or damaged cellular machinery gets recycled.
Autophagy is integral to many cellular functions, and a background level of autophagy is found in practically all cells. This means autophagy benefits come from ways to “enhance” autophagy, which already takes place to some degree.
Certain natural compounds which promote longevity in multiple species do so via autophagy. Mouse studies have also found that coffee and exercise enhance autophagy. Unfortunately, no studies have confirmed these findings in humans yet.
However, water-only fasting can enhance autophagy in both mice and humans.
Research suggests the timelines are different for each species. And that the timelines are also unique for different cells in the body.
Autophagy is difficult to address as a fasting goal. One reason for this is how complex autophagy is to measure.
As explained below, insulin levels are the best way to compare the autophagy timelines for mice and humans right now. There is a lot of interest in tracking autophagy in humans, so insulin levels could be one way to track this.
In mice, autophagy is enhanced in muscle cells after one day of fasting, and this is shut off by the hormone insulin. This suggests that insulin levels can be used to compare the animal and human timelines for autophagy.
After one day of fasting, levels of insulin in mice have dropped by 95%.
You would need to fast for at least 2 days to get this drop in insulin. However, older human studies suggest that a 95% drop in insulin does not happen during fasting. Of course, the starting point for insulin could also matter here.
For mice, this 95% drop in insulin could be a plateau. This means it could be the lowest insulin level possible for mice. In this case, the human equivalent would likely be 5 days of fasting.
In support of this, there are mixed signals for autophagy in human muscle cells after 3 days of fasting.
This could be because insulin has not dropped enough yet to enhance autophagy. Or it could be due to the difficulty in measuring autophagy and interpreting data for the protein p62.
Autophagy usually degrades p62. The muscle cells showed some signs of autophagy in this study, but they also had higher levels of p62.
A study on white blood cells found that autophagy might be enhanced in many types of human white blood cells within 4 days of fasting. But detailed testing was only carried out after one day of fasting. This detailed testing revealed that autophagy is enhanced in just one type of white blood cell (the neutrophil) in humans after one day of fasting.
In mice, autophagy is enhanced in all types of white blood cells within two days of fasting. Could these autophagy benefits have started earlier in the fast? The researchers did not check. So for now, there is no great way to compare autophagy timelines yet for white blood cells.
Taken together, insulin is the only trackable biomarker to use when comparing the human and mouse autophagy timelines.
So for now, these studies suggest that you would need to fast for at least one day to enhance autophagy in one cell type (the neutrophil). Extending the fast to 2 days probably enhances autophagy even more in neutrophils based on this sort of trend in mouse cells.
But based on the muscle studies and insulin levels during fasting, most likely at least five days of fasting are necessary to get autophagy benefits in multiple cell types. This is shown in the graph below.
Figure 13. Where autophagy benefits fall on the fasting timeline.
The Fasting Mimicking Diet (FMD)
There are signs of muscle autophagy benefits in mice following the FMD.
Mice following the FMD have decreased expression of the protein p62 in muscle. As stated earlier, p62 is degraded by autophagy.
However, this result was also seen in mice who had followed cycles of the FMD consistently for a long time. And the level of p62 in these mice on the FMD was similar to that of young mice not on the FMD.
This suggests that mice who regularly follow the FMD are more able to undergo muscle autophagy than normal mice of the same age.
Based on the role of p62 in tumor formation, this might also help explain why these mice had fewer tumors when they died.
Autophagy markers were not measured in humans in the study. And like the mouse study on muscle autophagy, the insulin levels for mice drop by ~90% during the FMD.
As stated earlier, this level of insulin is seen in humans after 5 days of fasting. This suggests that regularly fasting for 5 days could enhance your long-term autophagy benefits. In other words, it could ensure you maintain the ability to undergo autophagy as you age.
The use of fasting in cancer treatment is very controversial. This section is not intended to promote the use of fasting as an adjuvant to, or as a replacement for cancer treatment.
Nor is it intended to offer guidelines for treating cancer. It is intended only to serve as reference material which you can go over with your physician.
As mentioned above, the Fasted State comes with lower levels of the pro-growth hormones IGF1 and insulin. The Fasted State also comes with lower blood glucose levels and higher blood ketone body levels.
Insulin and IGF1 are both implicated in the development of cancer and in its progression. Inhibiting the pro-growth effects of these hormones is a major focus in cancer drug development.
Similarly, glucose metabolism is another target for cancer therapy. An estimated >90% of cancers show signs of enhanced glucose metabolism.
Studies suggest that cancer arises due to problems with cellular metabolism. And that these problems make cancer cells rely on glucose.
During fasting, normal cells can deal with a shift from glucose metabolism to ketone body metabolism. In fact, nearly 60% of brain metabolism shifts to using ketone bodies during long fasts.
Glucose levels as low as 0.5 mM (9 mg/dL) have been recorded during fasting without symptoms of hypoglycemia. This is only ~10% of a normal blood glucose level. This low blood glucose level would be fatal without the high levels of ketone bodies that come from fasting.
As stated above, lowering glucose and pro-growth hormones while increasing ketone bodies is a key feature of the Fasted State. This is believed to selectively harm cancer cells.
Mice with 70-80% lower IGF1 levels are more protected against the side effects of chemotherapy than normal mice. These mice also have better survival against melanoma. This is the IGF1 level reached by normal mice after fasting for three days.
Mice who fast for three days are also protected against the side effects of chemotherapy. Together, these studies suggest that a ~70% drop in IGF1 levels is beneficial for chemotherapy side effects and cancer survival.
As mentioned earlier, humans need to fast for at least 5 days to see this drop in IGF1 levels.
Have Cancer Patients Fasted for Five Days?
There are at least three studies on prolonged fasting in cancer patients. In each of these studies, the fasting period was right before and/or right after chemotherapy. Two of the studies were on the same group of patients.
None of the studies focused on fasting as a treatment for cancer. But each of them suggested that fasting can be safe for cancer patients undergoing chemotherapy.
In one of these studies, ten patients with various cancers fasted for 48-140 hours before and/or 5-56 hours after chemotherapy. On average, fatigue and weakness from the chemotherapy were better when the patients were fasting. None of the chemotherapy side effects became worse.
For some of the patients of this study, the effectiveness of their chemotherapy could be measured. In these cases, there were no signs that fasting prevented the effectiveness of chemotherapy against their cancers.
In the second study, 20 patients with various cancers fasted for 1-3 days surrounding chemotherapy. This fasting period allowed for up to 200 calories per day. The changes in glucose, ketones, and pro-growth hormones varied amongst the patients.
Like the mouse study mentioned above, there were benefits for white blood cells in patients who fasted for 2-3 days. Specifically, their white blood cells were protected against DNA damage from the chemotherapy.
The third study looked at the same group of patients as the second study. This third study also found that white blood cells were more protected in patients who fasted for three days compared to patients who fasted for one day.
Together, these three studies suggest that fasting can be safe for cancer patients and it can help with the side effects of chemotherapy. These studies also suggest that fasting for 2-3 days can help protect the immune system from chemotherapy side effects.
But it’s important to remember that these fasts were carried out under medical supervision. Malnutrition and muscle wasting are still some of the major concerns for the use of fasting in cancer treatment. More research is needed before a specific fasting method is proven safe and effective for cancer patients.
Summary: The Takeaways
The best fasting method for you is based on your specific goal(s), lifestyle, and any medications you currently take.
Use the Fasting Optimisation App to find the best fasting method for you. It comes with a more detailed step-by-step plan to guide you along the way.
Takeaways: How To Achieve Your Fasting Goals
- Weight Loss: Use alternate-day fasting to lose weight. This method has a high compliance rate and keeps you at a big calorie deficit for the week.
- Enhancing Longevity And Healthspan: Use 3 monthly cycles of the Ketosource Method (found here) to get disease markers under control. Use a 5-day fast in place of the FMD to add autophagy and stem cell benefits. Repeat as necessary if your blood markers start trending in the wrong direction.
- Enhancing Autophagy: A 1-day fast will enhance autophagy in one cell type (the neutrophil). Use a 5-day fast to enhance autophagy for multiple cell types.
- Stem Cell Self-Renewal: Use a 5-day fast to promote stem cell self-renewal. Depending on how IGF1 levels drop for you, this could require up to nine days of fasting.
- Treating Cancer: More research is needed to clarify the safety and efficacy of fasting in cancer patients. It is too early to set any takeaways for the role of fasting in cancer treatment.
- Treating Type 2 Diabetes: Use modified fasting so you can take your medications safely. Use more than two low-calorie days per week to lose weight more quickly. Add an early 6-9 hour TRF on top of this fasting method to get more benefit.
Takeaways: How To Prepare For Fasting
- Follow a ketogenic diet for four weeks before fasting. This will get you fat-adapted and make fasting easier.
- If you’ve never fasted before, follow TRF first to get a feel for it. This can be as simple as ending your last meal by 7 PM every day.
- If you take medications that require food, plan to eat foods high in fat and fiber and low in protein and high-glycemic carbohydrates.
- Use a glucose/ketone meter to check how foods affect you. This will help you pick out foods which can be safe for your fast if you need them.
Takeaways: Making Fasting Easier
- If the hunger is overwhelming, eat a small amount of high-fat/high-fiber food to help get you through. This includes avocados and MCT oil.
- Go for short walks to take your mind off the fast. Staying active will help ease the hunger until it passes.
Takeaways: Executing Your Fast
- Sip on saltwater/bouillon during the day to keep your electrolytes up. Avoid too much coffee as it will make you lose electrolytes more quickly.
- The re-feed after prolonged fasting is very important. Avoid high glycemic carbohydrates (e.g. fruit juices, candy, cereal, etc.) as you will be fat-adapted and not carb-adapted after a fast. Have a high-fiber shake as your first meal after the fast to prevent stomach issues.
- For the prolonged fasting re-feed, introduce solid foods slowly after the high-fiber shake. Solid foods high in fat and protein will satisfy your hunger and help you avoid overeating. Overeating will feel very uncomfortable as it brings on stomach issues and hiccups. Gradually increase your solid food intake over a couple of days as you feel more comfortable with it.