Metabolic Autophagy

by Siim Land

  Intermittent fasting promotes clearance of pathogens and infectious bacteria and helps to heal the gut in mice infected with salmonella[176].

  Fasting protects the gut against the negative effects of stress[177], such as inflammation. Fasting activates cAMP, which further activates genes that promote intestinal lining integrity and strength[178]. The cognitive benefits of fasting on the brain will also improve your mood and improve stress resiliency which protects against leaky gut again.

  Intermittent fasting promotes white adipose tissue browning and reduces obesity by shaping the gut microbiome[179]. The gut microbiota influences adipose tissue browning and insulin sensitivity[180] by signaling the browning of white fat into brown fat[181].

  Caloric restriction and weight loss increase the number of beneficial bacteria in the gut called Bacteroidetes[182]. Obese people have less of these bacteria than lean people. Caloric restriction enriches phylotypes in the gut that are positively correlated with increased lifespan[183].

  Fasting and time restricted feeding heal the gut by giving your intestines rest from breaking down food. Digestion requires about 25% of the calories from each meal. Being in a fasted state promotes anti-inflammatory cytokines and cellular autophagy that instigate healing.

  Fasting also increases the activity of the migrating motor complex (MMC), which is a mechanism that controls stomach contractions in a cyclical manner over 2 hour periods[184]. The MMC cleans out the GI tract and helps to eliminate undigested food particles. It’s regulated by feeding/fasting hormones such as ghrelin, serotonin, cortisol, and somatostatin. Eating inhibits MMC and not eating increases it. If you have longer breaks in between meals then you’ll digest and assimilate your food much better and prevent any kind of small intestine bacterial overgrowth or SIBO.

  Another study found that time restricted feeding restored a variety of beneficial strains of bacteria in mice[185]. Fasting has been shown to improve symptoms of irritable bowel syndrome (IBS) as well[186].

  A group of researchers from MIT found that fasting for just 24 hours boosted the regeneration of gut stem cells in young as well as old mice[187]. One of the scientists Omer Yilmaz said:

  This study provided evidence that fasting induces a metabolic switch in the intestinal stem cells, from utilizing carbohydrates to burning fat.

  Indeed, fasting activates a group of transcription factors called PPARs, that turn on genes involved with fatty acid metabolism. Another aspect of it has to do with shifting into ketosis that reduces inflammation and supports healing of the gut. However, fasting may cause some gut issues if done wrong.

  Fasting and eating at night may lower your sleep quality. Some species of bacteria like Enterobacter aerogenes are sensitive to melatonin (the sleep hormone), which influence circadian rhythms[188]. A disruption in circadian rhythms can disrupt the microbiome and thus negatively affect metabolic health[189]. That’s why it’s important to not overeat at night. Chapter XXII talks about circadian rhythms and fasting.

  Prolonged restrictive diets may cause a lack of microbial diversity. The gut microbiome can respond to changes in diet very fast and thus restructure the microbiome according to that. Short-term consumption of either fully animal or plant-based diets alter the gut microbial status, which can cause trade-offs in carbohydrate or protein metabolism[190].

  Fasting decreases the size of some digestion organs like the small intestine and liver, which can lower the capacity to consume food[191]. That’s why you may find it more difficult to eat as much as you did before when breaking your fast. However, these organs will regrow themselves quite rapidly and they’ll become more functional afterward.

  All of these issues are easily solvable and can be fixed with simply adjusting your fasting schedule.

  It might seem that, because of not eating, fasting will destroy all the healthy bugs in your gut and lead to autoimmune disorders in the future. However, this is not the case.

  In a study on mice, scientists found that intermittent fasting didn’t wipe out bacteria in the gut or destroy their diversity. Instead, intermittent fasting actually improved bacterial diversity[192]. This probably has to do with the life extension benefits of dietary restriction found across all species. When the bacteria are faced with mild starvation or fasting they live longer and promote energy efficiency through diversity.

  Fasting promotes the diversity and dynamics of the microbiome, which is determined by feeding and fasting cycles of the host[193]. At the same time, it will still starve off some of the pathogens, viruses, and bad bacteria.

  Time-restricted feeding has been shown to prevent weight gain, improve gut diversity, and circadian cycling of the gut microbiome in mice despite being fed a pro-obesity diet[194]. Mice who were allowed to eat the same diet ad libitum whenever they wanted got obese and sick.

  All living organisms have built-in circadian clocks that connect them with the day and night cycles. The microbiome functions like a signaling hub in communication between you and your environment[195].

  In the 2017 Annual Review of Nutrition, it was said that prolonged intermittent fasting has sustained improvements in health and they may be caused by benefits on circadian biology, the gut microbiome, and better sleeping patterns[196]. Intermittent fasting already has so many health benefits on your metabolism, body composition, cognitive functioning, and longevity but it’s a win-win for your gut microbiome as well.

  Part of the reason taking care of your gut is so important has to do with how the microbiome affects your cognitive functioning. Over 70% of your serotonin – the feel-good hormone – gets produced in the gut and all the other circadian rhythm-related processes are also linked with that.

  Science has now discovered that microbial life inside living organisms has played a crucial role in shaping the evolution of said organism. In fact, the mitochondria are descendants of bacteria that millions of years ago developed a co-existence with our ancestral bodies. This has led to the suggestion of the concept of a Microbe-Gut-Brain (MGB) Axis[197].

  The MGB Axis is this network of biochemical signaling between the gastrointestinal tract (GI) and the central nervous system (CNS). It includes the enteric nervous system (ENS), the endocrine system, the hypothalamic-pituitary axis (HPA), the autonomic nervous system, the vagus nerve, the endocrine system, and the gut microbiome[198].

  Figure 29 The Gut Brain Microbiome Axis

  Your immune cells, muscle cells, cells of the gastrointestinal tract are all mediators of the neuro-immuno-endocrine system that are influenced by both the brain and the gut microbiome. In fact, it’s been thought that the microbiome plays a much more influential role in the state of your being than the brain[199].

  It’s like a super-complex ecosystem that consists of trillions of microorganisms and bacteria. The ’thing’ you call ’I’ is literally comprised of this collective consciousness of many living organisms and cells inside your body. Hence the importance of taking care of your gut and mitochondria with fasting.

  Fasting and Fat Loss

  Fasting is also the healthiest and easiest way to reverse obesity. Before you can burn fat, you have to first “release” the fatty acids into your bloodstream through a process called lipolysis. Then they get transported to the mitochondria where they’ll be oxidized into energy. See Figure 30.

  During rest, our muscles start to use more fatty acids for fuel. When fat burning increases so does the amount of Uncoupling Protein-3 in our muscles. As little as 15-hours of fasting enhances the gene expression for UCP-3 by 5-fold[200]. We’ll be using ketones to feed our lean tissue more effectively.

  Figure 30 The process of burning stored body fat - low insulin raises cAMP, which leads to lipolysis that releases free fatty acids for the mitochondria to burn off as heat

  Contrary to popular belief, intermittent fasting doesn’t slow down the metabolism but actually increases it by 3.6% after the first 48 hours[201]. Even further, 4 days in, resting energy expenditure increases up to 14%. Instead of slowing down the
metabolism, the body revs it up and puts it into higher gear. This is probably caused by increased adrenaline so that we would have more energy to go out into the savannah and find some food. The scarcer calories become the more detrimental it is to succeed in hunting.

  People think that if they skip breakfast the body will hold onto its own body fat and store every calorie in the next meal. Think about it. Does your body really think it’s starving after not eating for a day or is it simply your primal mind playing tricks on you?

  In a fasted state, we actually become more efficient with the food we eat, instead of storing it all. With the lack of calories, especially carbohydrates, we become more insulin sensitivity[202], meaning that we need less of it to lower our blood sugar levels back to normal. Fasting can actually reverse insulin resistance and reduces overall blood sugar levels.

  There’s no reason to be concerned about malnutrition during fasting because our fat stores can deposit almost an infinite amount of calories. The main issue is rather micronutrient deficiencies. Potassium levels may drop slightly, but even 2 months of fasting don’t decrease it below a safe margin. Magnesium, calcium, and phosphorus remain stable because 99% of them are stored in our bones. The man who fasted for 382 days maintained such a lengthy fast with no harmful effects on health thanks to taking a simple multivitamin. That’s all you need to survive for that long.

  Fasting and Growth Hormone

  Another anabolic mechanism that gets increased is human growth hormone (HGH). After 20-24 hours of fasting, it does so by 1300-2000% (See Figure 31)[203]. It not only promotes tissue repair, body composition, and metabolism but also preserves youthfulness.

  Figure 31 Fasting increases Growth Hormone Exponentially

  Growth hormone plays a key role in the metabolism of all macronutrients. Its normal secretion fluctuates throughout the day and increases significantly during the first hours of sleep at about 11-12 PM.

  After 3 days of fasting, HGH increases dramatically in non-obese individuals, but flats out after day 10[204][205]. In obese people, there is little to no reported rise after fasting from 14 to 38 days [206]. Hypothetically, this happens as a response to preserving lean tissue. I would suggest that beyond that point the body simply becomes extremely well keto-adapted and reduces both the overall energy demands as well as increases the efficient use of ketones as fuel.

  What goes hand in hand with HGH is insulin-like growth factor (IGF-1). It’s one of the major growth factors in mammals which together with insulin is associated with accelerated aging and cancer. Just 5 days of fasting can decrease IGF-1 by 60% and a 5-fold increase in one of its principal IGF-1-inhibiting proteins: IGFBP1[207].

  Potential Side-Effects

  There may also be some negative consequences to fasting. Headaches, dizziness, lightheadedness, fatigue, low blood pressure and abnormal heart rhythms are all short-term. Some people may experience impaired motor control or forgetfulness. But these are all symptoms of withdrawal, not fasting. Because most people rarely get to use their own body fat for fuel, they become too dependent on glucose. It’s like an addiction that makes them crave more sugar.

  When I first started practicing intermittent fasting I experienced some feelings of hypoglycemia but nothing serious. I simply got a bit lightheaded whenever I stood up too quickly. After going on a ketogenic diet those signs have disappeared completely. Any mental hindrance is caused by an inner energy crisis. Once the body adapts to utilizing fat for fuel, the brain will accept ketones and will also reduce hunger.

  Fasting may cause some flare-ups of certain medical conditions, such as gout, gallstones or other diseases. This is yet again not because of fasting directly but because of the overall high amounts of toxins in the body. The adipose tissue is more than a caloric pantry. It also stores poisons and infections that we digest. Once you start breaking down triglycerides, those same toxins will be released into your bloodstream again and need to get flushed out. There may also be some nervous stomach, irritable bowel of diarrhea. That’s why fasting is an effective detox tool, as it cleanses the organism completely.

  In comparison to all of the empowering health benefits of fasting, these few side-effects are minute and not guaranteed. They may or may not happen. What’s certain is that they will be alleviated after time.

  Why then have we been lead to believe that fasting is bad for us? Medical doctors and supplement companies all preach the consumption of 6 small meals a day. Why? I’m not going to be pointing any fingers or calling anyone out but simply put: there’s no money to be made from healthy people who fast. How do you prescribe a pill of fasting that’s completely free?

  Intermittent fasting is truly the 80/20 dietary strategy in terms of improving your overall health and life expectancy. Unfortunately, it’s never been implemented that thoroughly in the long-term. There aren’t many people I can think of who’ve practiced time-restricted feeding over the course of decades, starting even from early adulthood.

  When I first started I was 18 and I still have many years ahead of me. Although I’m still in my 20s at the moment, I don’t feel like I’m getting any older. Of course, I stick to a consistent exercise routine, eat only healthy food, get enough sleep, and do other biohacks but I attribute most of my wellness to intermittent fasting. The reason I started with this pursuit towards optimizing my health and wellness had to do with my family background. My grandmother had three husbands who all died to metabolic disease. To not leave my close ones in a heartbroken state, I want to take care of myself and those around me.

  By subtracting from your life and applying positive restriction with fasting you will actually gain exponentially more freedom and results. It would be unwise to not take advantage of such a simple yet powerful strategy as simply not eating. Instead of looking for another shortcut or trying to find the next magic supplement that will increase your lifespan, you can just stop eating for a while and see how your body reacts.

  IF is one of the central cornerstones of Metabolic Autophagy because one of the few known ways of actually activating this procedure requires fasting. There are a few nuances to it but you’d get the biggest bang for your buck if you were to just fast. The next chapter will delve a bit deeper into the physiology and mechanisms of this process.

  Chapter IV

  What We Know About Autophagy So Far

  „Life lives on life.

  This is the sense of the symbol of the Ouroboros - the serpent biting its own tail.

  Everything that lives lives on the death of something else.

  Your own body will be food for something else.

  Anyone who denies this, anyone who holds back, is out of order.

  Death is an act of giving.“

  Joseph Campbell

  In the early 1990s, a Japanese biologist Yoshinori Ohsumi was studying the transport of ions and small molecules in the cells’ vacuole, which is a membrane-bound organelle in the cell. At that time, most of the other scientists were researching the plasma membrane and considered the vacuole just a garbage can with not much importance.

  Cell differentiation requires a lot of protein degradation. Dr. Ohsumi decided to study the lytic function of the vacuole to observe any morphological changes in cells undergoing such degradation. He used a microscope to look at vacuolar proteinase-deficient mutant cells, which cannot sporulate as normal cells do when under conditions of nitrogen starvation. After 30 minutes of observation, he saw many vesicles appearing and accumulating in the vacuole. From the bunch, he identified formations of some autophagosomes, which sparked his interest in starting to research autophagy in yeast.

  In 1991, one of Dr. Ohsumi’s graduate students was observing some mutant yeast cells under a microscope and found the first autophagy-defective mutant named APG1-1, which is now called ATG1. ATG is an abbreviation of autophagy-related gene or autophagy-related protein[208]. In total, the researchers discovered 14 ATG mutants. Except for ATG1, all of the ATG genes turned out to be novel genes with their amino acid seque
nces not being very clear. Eventually, Dr Ohsumi’s lab realized they had an entirely new pathway in their hands and published their results in the journal Nature[209].

  On the 3rd of October 2016, Dr. Yoshinori Ohsumi was rewarded the Nobel Prize in Physiology or Medicine for ‘discoveries of the mechanisms for autophagy.’ Ohsumi’s research is done in simple organisms like baker’s yeast but the autophagy-related pathways have been found to be similar to autophagy in mammals as well.

  Part of the reason why intermittent fasting is such a powerful thing for longevity has to do with how it primes the body to heal itself from within. This chapter will delve deeper into the mechanisms and benefits of autophagy.

  What Is Autophagy

  Autophagy or autophagocytosis in fancy science language translates from the Ancient Greek word autóphagos which means self-digestion or ‘eating of self’.

  Autophagy is a metabolic process during which cells disassemble and remove their dysfunctional components. You’re basically recycling cellular debris and taking out the trash.

  Initially, it was thought that autophagy was a hormonal response to starvation, but recent research has shown autophagy to have several other roles in biology. There are many benefits to autophagy, such as reduced inflammation, improved immunity, prevention of genotoxic stress, anti-aging, suppression of cancerous tumor cells, and elimination of pathogens.

  Compromised autophagy pathways will lower the body’s ability to eliminate and heal the organism from inflammation, accumulation of toxins, and parasitic infections. Inability to cause autophagy makes rats fatter, less active, have higher cholesterol and impaired brain function[210].

  The word ‘autophagy’ was coined at the Ciba Foundation Symposium on Lysosomes in London 1963. There, one of the scientists, Christian de Duve, who is a 1974 Nobel Prize Laureate and the discoverer of the lysosome, proposed the term autophagy to illustrate how lysosomes self-eat themselves[211]. That process is called macroautophagy but there are several types of autophagy that basically describe the same thing.