Metabolic Autophagy

by Siim Land

  As fasting continues, the liver starts to produce ketone bodies which are derived from our own fat cells. Lipolysis (breakdown of stored triglycerides in the adipose tissue) and ketogenesis increase significantly due to fatty acid mobilization and oxidation.

  Ketosis can occur already after 2-3 days of fasting. Triglycerides (molecules of stored body fat) are broken down into glycerol, which is used for gluconeogenesis (creation of new glucose) and three fatty acid chains. Fatty acids can be used for energy by most of the tissue in the body, but not the brain. They need to be converted into ketone bodies first.

  Figure 21 The stages of energy usage during fasting

  Ketosis is a metabolic state in which fat is the primary fuel source, instead of glucose, and can be achieved either through fasting or by following a ketogenic diet. Fasting induces ketosis very rapidly and puts the body into its more efficient metabolic state. The more keto-adapted you become the more ketones you’ll successfully utilize. At first, the brain and muscles are quite glucose dependent. But eventually, they start to prefer fat for fuel.

  Ketone bodies may rise up to 70-fold during prolonged fasts[122]. After several days of fasting, approximately 75% of the energy used by the brain is provided by ketones. This also allows other species, such as king penguins, to survive for five months without any food[123].

  Figure 22 While fasting, glucose drops and ketones soar

  Protein catabolism decreases significantly, as fat stores are mobilized and the use of ketones increases. Muscle glycogen gets used even less and the majority of our energy demands will be derived from the adipose tissue. This can be accomplished by following a well-formulated ketogenic diet as well, which actually mimics the physiology of fasting almost entirely.

  The Krebs cycle is a sequence of reactions taking place in our mitochondria that generate energy during aerobic respiration (a fancy way of saying breathing normally). When glucose enters this metabolic furnace it goes through glycolysis, which creates the molecule pyruvate. In the case of fatty acids, the outcome is a ketone body called acetoacetate, which then gets converted further into beta-hydroxybutyrate and acetone.

  Figure 23 The Krebs Cycle That Works Like the Furnace of Your Metabolism

  The difference between pyruvate and ketone bodies is that the latter can create 25% more energy. On top of that, the by-products of glycolysis are advanced glycation end-products (AGEs), which promote inflammation and oxidative stress[124][125], by binding a protein or lipid molecule with sugar. They speed up aging[126] and can cause diabetes.

  Fasting VS Caloric Restriction VS Starvation

  An important notion is to distinguish fasting from starvation. One is voluntary, deliberate, and intentional (i.e. with a purpose), the other is involuntary and forced upon. It’s like the difference between suicide and dying of old age. Abstention from food is the art of manipulating our metabolic system and can be done for many reasons. Malpractice might look like the person is starving, but if done correctly it’s very healthy and good for you. You just have to know how to balance it with sufficient anabolism and get enough essential nutrients. This book teaches you that.

  Starvation is a severe deficiency in energy intake. The body doesn’t have access to essential nutrients and is slowly wasting away by cannibalizing its vital organs. It’s a gradual process of degradation that’s often characterized by the skinny-fat look or the bloated stomach called kwashiorkor which is caused by insufficient protein even in the presence of sufficient caloric intake.

  Caloric Restriction reduces calorie intake without causing malnutrition or starvation[127]. You’re simply consuming fewer calories needed to maintain your body’s current energy demands. This will make you burn your stored fat and also lowers the body’s overall metabolic rate, down-regulated reproductive hormones, thyroid functioning and promotes gluconeogenesis. The difference between caloric restriction and starvation is that when calorically restricted, your body still gets access to the energy it needs to maintain its daily energy demands. It’s just that those energy demands have adapted to be lower and more efficient in terms of energy gained per calorie.

  Fasting is a state of metabolic suspension in which you’re not consuming any calories. Despite that, your body is still nourished and gets the energy it needs. This happens by shifting into ketosis, in which you’ll be burning your body fat almost exclusively.

  Fasting doesn’t equal starvation because your body is in a distinct metabolic state. Being fasted and fed is quite binary – even small amounts of food will shift you into a fed condition.

  Fasting isn’t entirely the same as caloric restriction either because you can be consuming fewer calories but still not enter into a fasted state.

  During World War II, they conducted a study called the Minnesota Starvation Experiment[128] on a group of lean men who reduced their calories by 45% for 6 months[129]. Their diet consisted of primarily carbohydrates which comprised 77% of total calories and had very little protein to mimic starvation conditions. After the experiment, the men showed a 21% reduction in strength, decline in energy and vitality. One of them started having dreams about cannibalism. This is critical. Very little protein and essential nutrients which promotes low satiety and catabolism of muscle. Prioritizing nutrient density and adequate protein makes a reduced calorie intake more tolerable. They ate potatoes, cabbage, macaroni, whole wheat bread while still maintaining their active lifestyle.

  Figure 24 The Minnesota Starvation Experiment

  The men in the Minnesota experiment were put under severe caloric restriction that resulted in starvation-like symptoms. Even though they were very malnourished, they weren’t fasting because of still eating a significant amount of carbohydrates that kicked them out of ketosis.

  Daily caloric restriction decreases metabolism, so it’s easy to presume that this would be magnified as food intake drops to zero. However, this is wrong. Once your food intake stops completely (you start to fast), the body shifts into using stored fat for fuel (ketosis). The hormonal adaptations of fasting will not occur by only lowering your caloric intake. In the case of being fasted, your physiology is under completely different conditions, which is unachievable by regular eating.

  Malnourishment happens when there is not enough nutrition to be found i.e. you go on a weight loss diet and restrict calories. While fasting, the organism is almost never fully deprived of essential nutrients, unless you lose all of your body fat. These fuel sources are mobilized from internal resources.

  To prevent malnutrition and starvation, while restricting calories, you want to establish ketosis and autophagy as soon as possible. Even consuming small amounts of food will put you into a fed state. It doesn’t matter whether you eat 200 calories or 1000, you’ll still be shifted out of a fasted state.

  That’s why intermittent fasting is a lot better than caloric restriction. If you’re feeding yourself, but in inadequate amounts, then your body will most definitely perceive it as scarcity. This will decrease your metabolic rate and creates a new set-point at which you can lose weight that’s lower than previously. You’ll be causing more damage than good. If you do it the wrong way, you’ll end up like someone from the concentration camps.

  Fasting isn’t a mechanism of starvation because your metabolism will be altered. This shift won’t occur entirely if you continue consuming food, even when you’ve reduced your calories to a bare minimum. It’s actually a lot healthier way of losing weight, as you’ll be burning only fat, not muscle. When on a restrictive diet you’ll never make the leap and to keep your energy demands at a balance you begin to cannibalize your own tissue. When in a fasted state, this can be circumvented.

  Instead, fasting is one of the best ways of escaping the hedonic treadmill and becoming immune to the ebbs and flows of nutrition. Not only will it improve your overall health but makes the relationship with food better. In the next chapter, we’ll talk about what the benefits are.

  Chapter III

  Why Intermittent Fasting


  “If a man has nothing to eat, fasting is the most intelligent thing he can do.”

  Hermann Hesse

  Intermittent Fasting (IF) is quite well documented in science as well as history as an amazing dietary strategy with many health and anti-aging benefits.

  Hippocrates, the father of modern medicine, said: “To eat when you are sick, is to feed your illness”. He recommended abstinence from food or drink for almost all of his patients.

  Before Hippocrates, the infamous Greek god Hermes Trismegistus, or Thoth the Atlantean in Egypt, said to have invented the art of healing. He used fasting to clear his mind to unveil the secrets of the cosmos by cleaning his body and purifying his mind.

  Plutarch said: “Instead of using medicine, rather, fast a day.” In Ancient Greece, consuming food during illness was thought to be unnecessary and even detrimental, since it would stop the natural recovery process. There was also a widespread belief, that excessive food intake could increase the risk of demonic forces entering the body. Perhaps obesity and slothfulness so many are plagued by today?

  The Greeks believed that abstention from food improved cognitive abilities as well. Pythagoras systematically fasted for 40 days, believing that it increases mental perception and creativity. He also wouldn’t allow any of his students to enter his classes unless they had fasted before. So did Plato, Socrates, and Aristotle – all of the great philosophers. They frequently abstained from food intake for several days.

  This would seem reasonably effective, as the only way for a hunter-gatherer to end their starvation was to get smarter and more efficient at chasing game. Toolkit complexity is linked with increased hunting and fishing practices[130], as traps and toggle-headed harpoons require more intelligence to make than simple digging sticks. Unlike plants, animals run away and if you want to eat them, you have to come up with better ways of catching them. This ever-imposed stress on hunting societies was probably one of the major driving forces behind the development of our species.

  Fasting’s been written about in many myths, legends, and religious texts as well. Christianity, Judaism, Buddhism, and Islam all instruct abstention from food in some shape or form. Similar teachings are preached in philosophical, moral and tribal codes. It’s commonly thought of as a definite way of creating a communion between God or other divine deities. The only religion that prohibits fasting is Zoroastrianism, because of its belief that such asceticism will not aid in strengthening the faithful in their battle against the sources of evil. But intermittent fasting has extremely empowering effects, which actually make the practitioner stronger, healthier and sharper, especially mentally. Those traits are useful for battling everything.

  Siddhartha by Herman Hesse is a story of Gautama Buddha that talks about his life and path towards enlightenment. In the book, he is a monk and beggar who comes to a city and falls in love with a famous seductress Kamala. He makes his move on her, but she asks: “What do you have?” One of the well-known merchants challenges him as well: “What can you give that you have learned?” Siddhartha answers the same way in both cases, which leads him to ultimately getting everything he wants. He said: “I can think. I can wait. I can fast.” What does it mean?

  I can think: You possess good judgement and you’re able to make good decisions.

  I can wait: You have the patience and perseverance to play for the long-game without expending unnecessary effort.

  I can fast: You are capable of withstanding difficulties and challenges. Fasting trains you to control your physiology and makes your mind more resilient.

  These three traits are extremely useful for living life according to your own terms. This book will teach you how to cultivate all of them.

  The Sumerian epic hero Gilgamesh sought to find immortality to revive his fallen companion Enkidu. He traveled the landscape for months and walked through the darkest of caves until he reached a sage. During his entire journey he hadn’t eaten anything – day and night - and was thus considered enlightened and worthy of receiving a small potion from the Fountain of Eternal Youth. It didn’t help him though, because it got stolen by a serpent while the man was sleeping. He reached immortality nonetheless, as his people kept telling his story and carried his achievement through centuries.

  For health, fasting has been advocated by many, even since the Middle Ages. Luigi di Cornaro was a Venetian aristocrat living at the 15th and 16th century. By the age of 40, he had gathered severe illnesses thanks to excessive eating and drinking. No medication or physician was able to help him and his days seemed to have been numbered. However, there was one doctor who, contrary to popular practice, suggested periodic strict abstinence from food. Cornaro survived and rid himself from all his diseases. When he was 83 years old, he wrote his first treatise Tratatto de la Vita Sobria (A Treatise of Temperate Living) and died at the age of 102. Talk about a comeback!

  The Swiss-German doctor Paracelsus was also in favor of this. He said: “Fasting is the greatest remedy, the physician within.” In the medical community, Paracelsus is famous for revolutionizing the medical sciences, by utilizing empirical observations from nature, rather than referring to ancient texts. He also gave zinc its name, calling it zincum and noted that some diseases are rooted in psychological conditions. For all of his patients, he advised intermittent fasting. Not something you see in today’s doctors who would much rather prescribe drugs.

  In the mid-1800s, E.H. Dewey, MD published a book called The True Science of Living, in which he said: “every disease that afflicts mankind develops from more or less habitual eating in excess of the supply of gastric juices." Basically, consuming too much food too often, without letting the body repair itself. That’s why proper autophagy is central to longevity.

  Since the 20th century, as doctors became more knowledgeable about the human body, fasting became increasingly popular as disease treatment and prevention. Some methods lasted more than a month, allowing only the consumption of water, non-caloric beverages, exercise, and enemas. Other modified fasts allowed the intake of about 200 to 500 calories a day, which came from vegetable soup, broth, honey or milk.

  There have been many non-obese persons who have recorded their prolonged bouts of abstention from food. Alexander Jacques fasted for 30 days in 1887 and for 40 the year after[131]. An Italian professional faster, Signor Succi, said that he had done at least 32 fasts of 20 days or more, with his longest ones lasting for 40-45 days[132].

  For obesity, fasting has been used as an effective therapy for a long time. Overweight patients have been put on fasting regimens of up to 159, 200 and 249 days[133]. The longest recorded fast lasted for 382 days (1 year and almost 1 month). In 1965, a 27-year old obese man Angus Barbieri from Scotland asked doctors to help him to fast as long as possible. He lost 125 kg (275 lb) in the process by going from 375 lb to 100 lb[134].

  Figure 25 Angus Barbieri fasted for 365 days and lost 275 pounds

  However, the average person in the Western world hardly experiences the sensation of real physiological hunger nor do they enter a fasted state. This is a shame as it will not only prevent them from getting all the benefits but also make them more fragile and dependent on their illusory food.

  What I’m going to be doing now is go through all the physiological benefits of fasting and how it’s going to affect your health. Starting with the most important component of the cell.

  Fasting and the Mitochondria

  The key to keeping mitochondria healthy is to maintain energy homeostasis and remove dysfunctional cellular components that are causing inflammation.

  Time-controlled fasting prevents mitochondrial aging and deterioration. It can also promote the longevity of mitochondria by eliminating the production of reactive oxygen species and free radicals by dysfunctional organelles.

  The study we mentioned earlier on nematodes in the journal Cell Metabolism specifically found that fasting and caloric restriction substantially increased the lifespan of nematodes by promoting autophagic mitochondrial fissi
on-fusion dynamics[135]. One of the scientists William Mair said:

  Our work shows how crucial the plasticity of mitochondria networks is for the benefits of fasting. If we lock mitochondria in one state, we completely block the effects of fasting or dietary restriction on longevity.

  Building new mitochondria is also critical for keeping yourself youthful and energized throughout your lifetime.

  Mitochondrial biogenesis is the process of building new mitochondria through the activities of certain metabolic regulators such as PGC-1α[136] and AMPK[137]. AMPK produces new mitochondria and controls mitophagy as well.

  The key to growing new mitochondria is to signal the body to produce energy under energy depletion and in stressful environments. This causes cellular crises that need to be compensated for by building new power plants.

  Fasting increases AMPK which promotes fatty acid oxidation which produces ketone bodies[138]. The mitochondria run a lot better on ketone bodies because they can get into the mitochondria faster via the electron transport chain and they’ll yield more ATP than glucose.

  Fasting increases FOXO proteins, which regulate longevity through the insulin/IGF-1 pathway and mitohormesis. FOXO1 and FOXO3 promote mitophagy[139].

  Fasting increases sirtuins. Sirtuins regulate fat and glucose metabolism in response to physiological changes in energy levels, thus they’re crucial determinants of energy homeostasis and healthspan of the cell[140]. SIRT1 regulates mitochondrial biogenesis and PGC-1α[141]. Suppressing SIRT2 restricts fatty acid metabolism, reduces mitochondrial activity, and promotes obesity[142]. SIRT3 is the major mitochondrial deacetylase and it protects against oxidative stress[143] through its anti-oxidant properties.