Intermittent Fasting & Autophagy Fasting Timeline

Most people know intermittent fasting (IF) as a means to shed off body fat way faster than usual dieting methods. IF indeed is one of the most effective weight-loss strategies, allowing calorie deficit without malnutrition. In my case, I lost 26pounds after only 14 days of fasting, but have also done extensive intermittent fasting. But the benefit of practicing IF isn’t limited to just weight loss! Through IF, you can “reset” some of your bodily functions through the process of “cellular-recycling” called autophagy, which fasters commonly refer to as the period in which your body is “self-cleaning.”

What is autophagy?

Derived from the Greek word autóphagos, which means “eating of self,” autophagy refers to the physiological process wherein the cells in our body are degraded to serve as building blocks of other cells or sources of energy. Simply put, autophagy is the recycling of old, damaged proteins, microbes, and cell organelles to build new tissues and cells.

This whole process promotes efficient use of energy and mediates damage control because it removes damaged or non-functional proteins and organelles in our body, which is why it is also viewed as a “self-cleaning” process of the body. This self-degradative process is like hitting two birds with one stone! The importance of autophagy in prolonging our lifespan is seen in how it can actually protect cancer patients from the toxicity of chemotherapy via triggering stem cell regeneration. Autophagy can also help in the prevention of diseases like cancer, neurodegeneration, diabetes, and other autoimmune diseases.

Through cycles of fasting (as done in IF), dormant stem cells are induced to a state of self-renewal that allows immune system regeneration, leading to stronger immunity and protection against cell degeneration. Research shows that fasting cycles can change the signaling pathways in our body to favor the generation of blood and immune system cells. And so, fasting was used to help cancer patients lower their white blood cell counts and counter the toxicity of chemotherapy.

What’s even greater is that fasting is a ketogenic process, and as your reserved fats are burned, ketones are produced. In this study, evidences have shown that the production of ketones during fasting can selectively starve tumor and cancer cells. Since you won’t be supplying your body with any calories/glucose when fasting, cancer and tumor cells, which are glucose-dependent, will starve and die. On the other hand, normal cells are able to use ketones for energy!

Therefore, when you fast, you’re not just clearing out old, damaged proteins and cell organelles via induced autophagy, but you’re also stimulating the production of growth hormones, new immune cells, and ketones!

How to induce autophagy

Fasting can strongly induce autophagy, which is why it is one of the benefits that you can glean from IF. When your body is in a state of nutrient deprivation, autophagy promotes the survival of cells until nutrients are supplied to your body again.

When in a starved state, your body will try to be more energy-efficient by recycling cells that are not needed or are damaged rather than creating new ones. Through fasting, your body will be forced to use up stored glucose, fats, and even damaged cells and proteins through autophagy. This is how fasting can significantly lower your weight alongside giving you a better immune system.

However, if you’re in a well-fed state and there are a lot of available nutrients in your body, autophagy is limited only to parts needing recycling. One of the key regulators of autophagy is the target of rapamycin (mTOR) kinase, a major player in nutrient sensing and regulates cell growth. This kinase is regulated by nutrients, hormones, and growth factors. Depending on what is present, the activity of mTOR is affected. One example of this is insulin; insulin goes up during feeding because it regulates the entry of glucose into cells. The mTOR activity is actually increased by the presence of insulin because it indicates that nutrients are present.

Therefore, when nutrients are abundant, mTOR pathways are activated, favoring cell growth and division and inhibiting autophagy. At this state, autophagy is ongoing only in basal levels in some cells to maintain cell structure and integrity.

On the other hand, when there is nutrient deprivation, the adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) is activated. The AMPK senses the low ATP (i.e., low energy) levels within your body and inhibits TOR kinase. This repression of mTOR pathway makes way for the activation of autophagy, favoring the recycling of old cells rather than creating new ones.

To sum it up, this is what happens:

  • Well-fed state –> nutrients are present –> insulin mediates glucose entry to cells –> mTOR pathway recognizes insulin and glucose and is activated in metabolic tissues –> autophagy is repressed
  • Fasting –> calorie restriction & low ATP –> AMPK activation –> mTOR activity is reduced/inhibited –> autophagy is induced

Autophagy fasting timeline – when does it start?

As mentioned, autophagy is actually happening within your body but only at a basal level. It is constantly occurring in all cells to degrade misfolded proteins and damaged cellular components. Autophagosomes and lysosomes are the cell organelles that work hand in hand to remove these damaged parts of the cell. Without this process, diseases may develop due to lack of housekeeping within the cells and abundance of damaged proteins. Bear in mind that mTOR is a negative regulator of autophagy and favors cell proliferation or growth; if there is no autophagy, excessive cell growth due to mTOR may occur, and this may lead to tumor growth. In the brain, dysfunctional autophagy leads to accumulation of damaged proteins, which may lead to neurodegenerative diseases.

So far, I have been only sharing with you the pros of autophagy. However, anything excessive is bad for your health. Excessive autophagy and fasting can lead to heart failures, muscle wasting and weakness, and chronic nutrient deprivation. This is why fasting must also be practiced with caution. So, in my opinion, if you already managed to experience the benefits of fasting and autophagy, it’s time to wind it down and go back to feeding, supply your body with glucose to turn off autophagy. Thus, it’s important to know the timeline of intermittent fasting and when autophagy kicks in as a nutrient mobilization system instead of just cell housekeeping process.

Stages of intermittent and prolonged fasting

Stage 1: 0-12 HOURS OF FASTING

At this stage, your body is still operating as usual, breaking down available glucose from the food that you consumed within the day. If ever there are excess glucose, it is stored away for later use as glycogen and fat reserves. This process of growth, wherein our body uses up available nutrients/glucose for energy and muscle growth, is an anabolic process.

Stage 2: 12-24 HOURS OF FASTING

During this stage of fasting, your body is switching to catabolic processes, which is the breaking down stored energy reserves. Your body taps into stored glycogen first and breaks it down into glucose. Your body will continue to break down glycogen until it reaches the normal blood glucose level of around 70-120 mg/dl.

Once your body has depleted all the available glycogen reserves, you’ll feel hunger due to fluctuations in your ghrelin (hunger hormone) and leptin (satiety hormone) levels. This is your body telling you to eat; it induces the feeling of hunger, so you’ll be urged to eat. However, this feeling will pass as you get further into the fast!

It’s also important to note that doing a 12-hr fast in between feeding can reverse the symptoms of prediabetes through increased insulin sensitivity! In this study, within five weeks of IF with a 12-hr feeding period, obese men with prediabetes showed improved insulin sensitivity, a significant drop in insulin levels, lowered blood pressure, and a significant decrease in appetite.

This is also the time where your body starts to switch to another metabolic pathway for energy production: ketogenesisResearch shows that between 12-36 hours, your body will start to break down fat after you’ve depleted your glycogen reserves, producing ketone bodies that will act as your body’s main energy source. This is why IF typically involves fasting for 12 hours or longer.

However, if you have plenty of glycogen reserves, ketogenesis might not occur until you’ve reached the 24-hour mark or more. The longer you do IF, the faster you’ll be able to reach this stage (as early as 12 hours)!

Stage 3: 24-48 HOURS OF FASTING

As your body continues to produce ketones as its fuel, your ghrelin levels will continue to decline. Since you’re still not introducing glucose to your body, insulin levels also decline. With lowered ghrelin and insulin levels, you’ll feel less hungry, and it’ll be easier to continue with your fast.

This is also where autophagy starts to kick in. The factors that can induce autophagy are now present at this stage: low insulin levels, nutrient deprivation or no glucose/glycogen availability, and increased ketone concentrations. The AMPK signaling pathway is activated, and the activity of mTOR is reduced, allowing autophagy to start. In this study, autophagy was detected in human neutrophils after 48 hours.

Stage 3: 48-60 HOURS OF FASTING

At this stage, ghrelin secretion starts to level off, resulting in less frequency and intensity of hunger pangs. The total ghrelin secretion on the 3rd day of your fast is even lower compared to days 1 and 2, as shown in this study, because your body is continuously using the other pathways to generate energy (e.g., ketogenesis). Even after refeeding, you’ll find that your appetite is easier to control, and you won’t get hungry often!

Furthermore, an increase in human growth hormone (HGH) levels at this stage, which promotes growth and muscle strength and improves weight loss and metabolism. This study involved nine men who went on a 48-hour fast that resulted in a five-fold increase in the HGH production rate. Also, insulin drops to its lowest level after 54 hours, allowing your body to become more insulin-sensitive.

Stage 3: 60-72 HOURS OF FASTING

This is where autophagy kicks up a notch. As shown in this study, after fasting for 72 hours or more, your body does not only degrade old, damaged cell organelles/proteins via autophagy, but it’s also undergoing stem cell-based regeneration! Your body is now generating new immune cells because there is a reduction in insulin-like growth factor 1 (IFG-1). This leads to further repression of mTOR pathway and promotion of stress resistance, self-renewal, and regeneration of stem cells.

Of course, refeeding stage is just as important as fasting. A sudden influx of calories may cause serious problems like heart complications. To know about how I break my fast properly, check out this article!

When does autophagy start & when does it peak?

It is impossible to measure autophagy by itself since you can’t just take a peek inside a cell of a live human and see what’s happening in it. Studies on autophagy measurement are still limited to mice and cultured cells, and through this, researchers have managed to measure autophagy by measuring the “autophagy flux” instead. This is a process wherein the degradation of autophagic structures is measured by taking samples at multiple time points.

In humans, the expression profile of autophagic pathway-related genes was created by getting peripheral blood samples as they did in this study. The researchers measured autophagic activity in neutrophils (our bodies’ most abundant white blood cells) to determine when autophagy peaks during fasting, and it was found out that it took 4 days to significantly increase autophagic activity in humans. In this study, it took 72 hours for a 30% increase in one of the autophagic markers, LC3-II.

These are all complex processes that require fully equipped research labs to carry out. Therefore, it’s not feasible for us to constantly measure autophagy while fasting. However, we can use previous studies conducted in clinical trials of humans as a basis to know whether autophagy is happening. Also, you can estimate at which degree of autophagy you’re in by finding out whether your body is undergoing catabolic process via getting your blood tested to get your insulin to glucagon ratio (IGR) and computing for your glucose ketone index (GKI). Reduced IGR promotes catabolism and fat loss, which can mean your body is undergoing autophagy. A low GKI means high levels of ketosis, which is a sign of ongoing autophagy. Check this article on how to compute for your GKI.

There are signs that may indicate that autophagy is ongoing as a nutrient mobilization process that you can easily look out for, and through recognizing such signs, you can pace yourself and determine when to stop fasting.

Signs of autophagy

  • Low blood glucose and insulin levels
    • Having low blood glucose and insulin levels is one of the first results of fasting. When your blood sugar drops to about 70 mg/dl (on average), the body responds by raising cortisol, growth hormones, and ketones. This reaction promotes the breakdown of fats and ketosis, which induces autophagy.
  • Higher ketone levels
    • As mentioned, fasting is a ketogenic process, and this induces autophagy. Having elevated ketone levels indicates that your body is burning its stored glucose and fat via ketosis and autophagy.
  • Reduced or loss of appetite
    • Fasting does not only lower insulin levels, but it also lowers ghrelin, which is the “hunger hormone” that stimulates appetite. When your body is already using up its reserved fats via ketosis and recycling old, damaged cells via autophagy, it no longer needs outside sources of glucose. This leads to lowered secretion of ghrelin.
  • Weight loss
    • Of course, if you’ve been burning up reserved fats, you’ll lose weight. However, this is not an immediate result and therefore should not be what you look for at first to know if you’re undergoing autophagy or not. It might take three days or a week for you to see significant weight loss. But if it happens, it generally means that you’ve been successful at reaching autophagy. Read my article here to know how much fasting has helped me reduce my weight.
  • Improved skin health and immune system
    • As mentioned, autophagy promotes stem cell regeneration and delays aging in some cases. You might notice that your skin has been clearing up whenever you practice intermittent or prolonged fasting; it’s because autophagy is also triggered in the skin fibroblasts upon fasting. However, take note that this may vary from person to person since other hormones and stress level can influence the presence of acne.

Autophagy & loose skin

Your skin may improve upon practicing IF due to autophagy being activated in skin fibroblasts. Mild sagging of the skin can be remedied by combined efforts of autophagy, healthy eating, proper skincare routine, and exercise to tighten up the skin.

What about moderate to extreme weight loss? Does autophagy prevent the formation of loose skin? Yes and no. It may depend on your skin’s elasticity or its ability to snap back after stretching. If you have fairly healthy skin with enough elasticity, you have a high chance of not needing any skin-removal surgery even after a huge weight loss journey.

Dr. Jason Fung, a nephrologist who specializes in fasting, also said so in an interview, “We have anecdotal cases where people have lost 120, 130 pounds, and they said their skin also shrank.” He postulates that during fasting, your body might also harvest the excess fats and proteins from the skin, which may aid skin tightening. However, this may be a case-to-case basis since we all have different bodies.

Rapamycin & autophagy

The mammalian target of rapamycin (mTOR) signaling pathway is affected by a multitude of hormones that signal which physiological process must be favored or turned on. Depending on what hormones or signals are present in your body, some genes are turned off and some are turned on. One example of this is how mTOR is activated when it senses nutrients with the help of insulin. And another example is how AMPK activation inhibits mTOR, inducing autophagy to ensure that the cells within our body adapt to nutrient deprivation.

However, calorie restriction via fasting (AMPK activation) is not the only thing that can inhibit mTOR. In clinical setups, rapamycin is used to repress mTOR activity and promote autophagy.

The mTOR is a kinase that operates as two distinct protein complexes: mTORC1 and mTORC2. The mTORC1 is rapamycin-sensitive, while mTORC2 is not. Numerous clinical trials and research made use of the sensitivity of mTORC1 to rapamycin to inhibit mTOR and activate autophagy, in order to increase cancer/autoimmune disease patient lifespan, and prevent aging by boosting stem cell-based regeneration. Since mTOR favors cell growth, rapamycin is also used to inhibit tumor growth and to prevent rejection of organ transplants because it represses mTOR and inhibits cell cycle progression.

As of now, many novel strategies are being developed to induce autophagy via caloric restriction and rapamycin, in order to find an anti-aging drug to further improve human life expectancy.

Does caffeine promote autophagy?

Studies have suggested that caffeine intake leads to an increase in autophagy. However, it’s important to note that observations were done on mice and not on humans. The closest to human clinical trials was this study, which was conducted on cell culture of human neuroblastoma cell line to investigate the protective effects of caffeine against neurodegeneration. Results showed that caffeine-induced autophagy protects human neuronal cells from neurotoxicity, thereby preventing neurodegeneration. In my opinion, you should take this result with a grain of salt and wait for the results of series of clinical trials instead before consuming caffeine to increase autophagy during your fast.

Some of my own thoughts as well as the conclusion

This concludes our discussion about intermittent fasting and autophagy! If you want to know more about what happens to your body during fasting and how to take advantage of your hormones for a successful fast, check out my 3-day water fast and prolonged fasting articles!

Water fasting is really a tool I have come to love myself. Whether you are looking to lose some weight, or you’re doing it for longevity purposes, it’s something I think most people would find truly revolutionizing to try out. After doing my own initial 3 day fast, it became apparent just how crazy it is to think about that we’re generally reliant on 3 meals every single day, and most people additionally do a serious amount of snacking on top of that as well. It was kind of a surprise just how easy it turned out not to eat for several days straight, and the mental clarity that I experienced was incredible.

Besides that, I have started incorporating in a lot of OMAD in my life, which I find vastly beneficial. For one, I do appreciate the simplicity of not spending the entire day eating, and the freedom it brings to limit my eating to an hour per day. It’s also easy to do for weight loss and won’t require that you refrain from being part of the various social activities around you.

REFERENCES:

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  15. https://aminoco.com/blogs/health/autophagy-loose-skin

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