Periodic Fasting:

Repair your DNA, Grow Younger, and Learn to Appreciate your Food

Cristian Vlad Zot

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Note to the reader (disclaimer)

The information from this book is intended to describe the possible benefits of therapeutic fasting. However, if you decide to treat your illnesses, do it under the supervision of your physician. Do not use this book as a substitute for professional medical care or treatment.

Every effort has been made to ensure that the information contained in the book is complete and accurate. However, the author is not engaged in rendering advice to the individual reader.

This book should not serve as a how-to guide for therapeutic, periodic, or intermittent fasting. If you decide to follow such endeavors, do it under the supervision of a qualified physician.

Periodic Fasting - Repair your DNA, Grow Younger, and Learn to Appreciate your Food

Copyright © 2015 by Cristian Vlad Zot. All rights reserved.

No part of this book or e-book may be used or reproduced in any manner whatsoever without written permission except in the case of brief quotations embodied in critical articles or reviews. For more information, contact the author at http://cristivlad.com

Table of Contents

Foreword......................................................................................................1

Introduction.................................................................................................3

Ch.1 - An Inborn Mechanism - How Life on Earth and Fasting Coevolved...................................................................................................15

Ch.2 - From the Middle Ages to the Early 20th Century....................29

Ch.3 - The Emerging Science of the Last Century...............................45

Ch.4 - Intermittent Fasting/IER and Prolonged Fasting:

Practical Insights........................................................................................65

Ch.5 - The Molecular Mechanisms of Fasting:

When Magic Happens at Cell Level and Below....................................79

Ch.6 - Recent Research in Fasting and Related Fields.......................105

Ch.7 - Fasting and the Emperor of All Maladies................................131

Ch.8 - My Personal Long-Term Fasting Experiment.........................145

Acknowledgements..................................................................................165

About the Author.....................................................................................167

References..................................................................................................169

Covers.........................................................................................................197

Foreword

Professor Richard David Feinman

Is there hope for nutrition?

              With the proliferation of meaningless statistico-epidemiologic studies and the media flipping back and forth between low-carb and low-fat, it is increasingly clear that individual dieters are on their own. We all have to sift through the mass of information and search personal accounts for authenticity.

              This book will be a great help for its emphasis on the value of fasting rather, as is so common, the warnings about the dangers of eating too much. Cristi describes the evolution of his thinking and behavior from early religious practice to the ketogenic diet and the values of the total-only water fast. The evolutionary perspective and the rather surprising story of fasting in the animal kingdom are well presented. The dental and anatomical evolution as well as social influences puts this in a broad perspective.

              In the end, the reader has an insight to the fast, how to get in and how to re-feed. Encouraging for most of us is the history of fasters in history including a discussion of Upton Sinclair who, like Cristi, gave us a blow-by-blow. Of current interest, of course, is how we are going to prevent and cure cancer and defy ageing with fasting and ketogenesis. There is a very good if maybe overly optimistic picture of the potential here and the drift of current as well as details of what to eat -- principles rather than recipes.

              In the end, this is a remarkably comprehensive view of fasting. Cristi is clear that neither the book nor the subject have final answers but researchers and individual dieters have a great place to start. 

Introduction

              At the time of this writing (Jan. 2015), I was already fairly intimate with the practices of periodic fasting and intermittent fasting. I had been doing it for more than 12 months. This book is not about religious fasting, though my childhood experience of fasting involves religious practices. It is the starting point of the book.

              From a very young age I was raised in the Christian-Orthodox religion. I lived with my grandparents in a small village in the north-western Romania until I was 5 years old and left to attend kindergarten in a nearby city. We used to go to church every Sunday.

              Christian Orthodoxy implies several religious fasts (abstinence from certain foods or total abstinence from foodstuff) throughout the year. The two biggest fasts are The Christmas Fast and The Easter Fast.

              The Christmas Fast runs every year from November 15th until December 25th, while the Easter Fast is determined in a more complicated way, but both of them last approximately 40 days.

              Milder versions of fasting (according to Orthodoxy) imply not consuming animals or animal derived products every Wednesday and Friday. Tougher versions require the practitioner to refrain from these foods every day of the fast. It is similar to a vegan diet. On the extreme end of the spectrum, there are people who abstain from food consumption for the entire 40 days. They only drink water.

              As a child I found it very hard to believe that someone will not eat for such a long period of time. My grandparents were following the usual "Wednesdays and Fridays No Animal Products" protocol, so they suggested I do the same, which I did without much discomfort.

              My practice of religious fasting started becoming a challenge during a Good Friday (which is also known as the Black Friday, Easter Friday, or Holy Friday), the Friday before the Orthodox Easter [1]. My grandmother used to fast for the entire day, until nightfall. She didn't consume water either. She prayed various times throughout the day.

              When I was a young kid we had the spring holiday around the Easter Holiday. It usually lasted for two weeks: one week before Easter and one week after Easter (Orthodox Easter). I used to spend those vacations in the village. It was in my early teens when I decided to try to do the total fast of The Good Friday.

              As the Good Friday went by I started becoming more aware of what I was doing. The burden of not eating was starting to take a toll on me. As my glycogen stores were getting depleted, hunger kept increasing. By 3 P.M. I was practically 'starving'. It was a battle with myself, but I had succeeded. I was able to fast until dusk, when I had a small protocol-friendly meal.

              Then I did it again next year, and the year after, and so on. Even though I was hungry, I kept distracting myself with chores that had to be done around the house. The evening meals usually consisted of French fries, a salad, and some white bread spread with margarine and jam. It was totally different than my current dietary regimen.

              The focal point of my religious experience was 2004. It was November 13th, the Saturday before the official beginning of that year's Christmas Fast. I was in high-school.

              I decided to try to keep the entire fast (water + allowed foods). It was tough because besides staying away from the restricted foodstuff (animal and animal derived products), I also had to stop smoking (I was a heavy smoker back then), stop drinking, stop using bad language, refrain from sexual activities, and start praying everyday.

              One cannot imagine the burden all those limitations had put on my shoulders. I went through a period of deep inner change. I learned more about my self than ever before. The first two weeks of no-smoking made my life experience miserable. Then it got easier.

              And I had achieved it. Even though it was contrary to my current nutritional beliefs, it was a success. I lost a lot of weight, which I gained it all back immediately after finishing the fast. My hunger and cravings were reduced (notice, it was a high-carbohydrate diet in which processed vegetable oils were not a commodity, but a staple). I believe my caloric intake was decimated compared to the period prior to the fast.

              The saddest part was that once the fast was over, on Christmas Eve, I jumped back all-in: started smoking again (even though I didn't feel the urge, but I wanted to do it), started going out and partying like crazy, and started consuming alcohol again...

              Flash-forward to 2013. At the end of September I was 3 years in of a normal weight, given that throughout my entire life I was overweight (not obese). I wanted to change something in my lifestyle because I felt I could not lose the last few pounds of fat from my mid-section. I really wanted to have visible abs.

              I learned about the ketogenic diet and I immediately jumped on the wagon. 2 months in and the results were amazing.

              A ketogenic diet is characterized by the presence of ketone bodies (aceto-acetate, beta-hydroxybutyrate, and acetone) in the blood (and urine, to a certain extent) as a result of a specific dietary approach or a fasting protocol.

              In a ketogenic diet the majority of energy intake (calories from food) comes from fat, a small to moderate part of energy comes from protein, while a very small part of energy comes from carbohydrates. It could be something in-between:

- 60% fat, 25% protein, 15% carbohydrates.

- 90% fat, 8% protein, 2% carbohydrates.

              The variations are limitless, but the key point behind a ketogenic diet is that it has to lead to the creation of ketone bodies (made in the liver as byproducts of fat metabolism). The purpose of their presence is to supply energy to the brain and other tissues and cells throughout the body in the context of low-carbohydrate (glucose) supply.

              As one increases the intake of carbohydrates and protein and reduces the intake of fat, the metabolism is switched to burning sugar (glucose) predominantly. Conversely, ketosis (in a ketogenic diet) is the state when the metabolism is fueled predominantly by ketones and fatty-acids.

              An unwanted situation is when both ketone bodies and glucose are in higher levels in the blood. This is known in the medical literature as diabetic keto-acidosis and it is usually seen in people suffering from Type 1 Diabetes.

              When it comes to my personal experience, I can say that I never fell off the wagon ever since I started my ketogenic journey at the end of September 2013. Yet, I designed a lot of variations for my nutritional approach, for my workout approach and for other interventions that came along. I made a lot of mistakes. There were times when I over-consumed food and times when I did not eat at all.

              And as I began to adapt to this new way of eating, I felt that my hunger and cravings went away. Prior to my ketogenic journey I was eating ~3 times a day with 1-2 snacks in-between. I find it difficult to do that now because I am mostly never hungry, which is why I switched to eating twice a day with an evening snack every now and then.

              Sometimes I was so driven in by my work that when I looked at the clock it was already 5 P.M. and I hadn't eaten anything all day.

              A couple of weeks into the keto-lifestyle, and the beginning of the religious Christmas Fast was approaching rapidly. It was the early of November 2013. And I decided that I will try to fast on Wednesdays and Fridays according to my religious protocol (no animal products) but also according to the ketogenic protocol. What was it left for me to eat then?

              The answer: nuts, avocadoes, dark chocolate, lemon juice, pumpkin, greens, coconut derived products... It went extremely well. I usually ate at ~5-6 P.M. each Wednesday and Friday. I was not able to consume my required daily energy intake in one meal. I did lose weight but I maintained my muscle mass, probably because I did a lot of strength training in a fasted state. I will often mention my experiences and experiments throughout the book.

              The Christmas Fast went fine and I was very satisfied with the results. So I considered "why not keep doing this protocol for the Easter Fast?" which usually starts at the end of February or the beginning of March.

              In April 2014 I was already some weeks-in the Easter religious fast doing my keto-friendly fast. I decided I wanted to go hardcore. I felt that I could do a total fast (only water) for a couple of days.

              Researching if and how people do this, I was astonished and a bit disturbed. There was little to no science behind it (my search skills were somewhat poor at that time). I wanted good knowledge on the bio-chemical implications of what I was about to do. I wanted to know the risks.

              It was probably then when I decided I had to carefully research this matter in the following months. At that moment I decided I had to write something about it in a more scientific manner. Most of what I was reading was about successful stories of people fasting for 7, 10, 20, 30 or even more days but with very little scientific explanation.

              Of course, I may not have looked into the right direction. Maybe the science was hidden somewhere or maybe my search tools were not good enough to access it. I was barely scratching the surface, as you'll see in the rest of this book.

              What I was about to do was called water fasting or total fasting. I found out about the special clinics throughout the world where people fast for health purposes. I found out that some people may have to consume a bit of sodium (salt) everyday, while many others do not consume anything but water. But that usually happens under strict medical supervision.

              I also learned about a carefully conducted study when one person went 382 days without food. It was in the 1970s. The patient weighted-in 456 pounds (~207 kg) and weighted-out 180 pounds (~82 kg), losing 276 pounds (~125 kg) during his fast. Five years after the fast and the patient had been able to maintain a steady weight around 196 pounds. He was free of ill symptoms during and after the fast. I wrote about this experiment on my blog [2]. That was the time I knew it was all possible.

              Since I lacked the kind of supervision which the patient had, I wanted to reduce the risks as much as possible. I was going to start my fast on Sunday evening and try to keep it for at least 50+ hours. I was to consume a bouillon cube in a glass of hot water everyday to mitigate mineral loss, take 1 multivitamin-multimineral pill everyday, and, of course, consume plenty of water.

              I considered myself being fairly keto-adapted, so hunger and cravings were not a problem. To be keto-adapted is to have built proper enzymatic support to efficiently run a predominantly fatty-acid metabolism. It is also to have higher mitochondrial biogenesis (creation of mitochondria, the powerhouses within your cells) for this purpose.

              Keto-adapted individuals can (in my opinion) exercise in all energy states (both aerobic and anaerobic), from a low intensity to a very-high-intensity protocol without any disadvantage (many times with more advantages) compared to professionals or athletes that are not keto-adapted.

              Contrary to popular belief, the process of efficient keto-adaptation can take months of staying under strict ketosis, and this often can come (mostly in the first few weeks) with some inconveniences (general weakness, fatigue, light-headedness, constipation, and others). Many of these drawbacks can be avoided.

              However, regaining performance in short-burst very intensive exercises, heavy lifting, and other HIT (high intensity training) protocols can take more than 6 months, 1 year, or (sadly) more than that. The 3-week period of strict ketosis that's being advocated throughout the media may work for most folks not wanting to achieve high-performances in sports. I talked about this topic in much more detail in my previously released books Ketone Power and The Testosterone Protocol.

              In my case, in April 2014 (after 6 months of strict ketosis) I was already able to efficiently do my heavy lifting routines and also do fairly well in my kickboxing training (I had a down-fall for a couple of weeks as I began the high-fat way of life). Once the body starts adapting to primarily burning ketones and fatty acids, muscles can do that too. I believe that protein requirements fall much lower than those defended by main-stream media and current research when muscles can use ketones and when the body uses protein more efficiently.

              That is a possible reason why I did not lose muscle mass. I did not have any pre/post precise measurements of body composition because the DXA scanner that I was using had not been calibrated properly and it was outputting bogus results.

              I was able to fast from Sunday evening to Friday evening; 50 hours have turned into 5 days. I engaged in vigorous exercise every day. I had two heavy-lifting sessions: the first on Monday and the second on Wednesday. I did calisthenics (body weight exercises) the other 3 days.

              When people engage in total fasting and they come from a background where their metabolism is primarily supported by glucose, they have a certain amount of glycogen (stored glucose) in their liver and muscles that should provide fuel for a limited amount of time in the context of not eating.

              Glycogen stores can usually get depleted in ~12-24 hours (sometimes even more). The major short-coming is that as they get depleted, the person will feel withdrawal symptoms associated with the lack of glucose intake (in the form of carbohydrates). Excessive (obsessive) hunger, lack of energy, headaches, and crankiness are few of the symptoms present when the metabolism tries to switch to using fatty acids primarily.

              However, when the body is already adapted to using fat, it may not experience glucose withdrawal and the switch between eating and fasting may not be perceived. When I switched from eating to fasting, I didn't feel any of the symptoms because I was fairly keto-adapted.

              But it was tough psychologically. It was then that I understood the deep connection we have with our food. It was then that I understood the way we take everything for granted. It was then when I understood that we are being bombarded with low-quality foods everyday, 24/7. We eat like zombies (without thinking)....

              We mostly eat habitually and not because of real hunger. And this could spill into disaster given the inappropriate hormonal context, when the food that you eat keeps fueling a false hunger. You will read more on this topic throughout the book.

              At the end of the second day of my water-only fast, on Tuesday, I had a migraine. I suspect that my body was shifting into survival mode (total lack of food). For a non-keto-adapted person, I also suspect this step would be more difficult to overcome.

              When I woke up on Wednesday morning everything was fine and the headache was gone. But, even though I was not hungry, I felt that something was missing. Think about it, 99.99% of us eat a lot and we do it every couple of hours. If you don't do it for a couple of days it may start feeling odd. It is an experience you have never been through.

              I did not have too much time to become conscious of that. I was busy, I was writing for my first book, I had a lot of stuff to do outside my desk, and I also had to workout.

              There was no hunger. I did consume water frequently but I did not get obsessed with the importance of water consumption as many folks do. I did not have problems during my workouts, and I did not feel like I was going to black-out. In fact, I felt that my workouts were even better in the fasted state with no prior/post workout supplements. Many would consider this as heresy.

              Interesting and necessary to point out is that I had to go to the bathroom (stool) every day. I was amazed of the consistency and the amount of waste that can stay inside our bowels for such a long period of time. From my research, I understand that stool volume and discharge frequency will gradually decrease as the fast undergoes.

              Another aspect that will be discussed in the book is the refeeding strategy because one has to understand that after a prolonged fasting, there has to be a strategy of gradually introducing food back-in. This is however not necessary if one follows an intermittent fasting protocol, similar to what I've been doing for more than a year now.

              When I stopped my 5-day fasting that Friday evening of April 2014, I decided not to gradually re-feed. But I was careful on what I ate first. I started with an avocado and a freshly squeezed lemon. Two hours later I had some nuts (2-3 oz. or 60-90g). I felt fine. I was following both my religious and my dietary protocol; it was empowering. Then on Saturday I started eating more.

              During my water fast I lost about 2kg or 4.41 pounds, some of which may have been water, fat, and some muscle tissue. Muscle breakdown may have contributed to a very small percentage of the daily energy needs, but the net muscle breakdown could have been close to zero due to my keto-adaptation status (muscles use ketones efficiently; ketones come from fat) and due to the workouts that I did.

              At some point in this book, I will talk about how during fasting, human metabolism can create "sugar" from "fat" and how muscle loss is minimized during fasting, as long as the body has sufficient fat tissue and as long as other health parameters are fairly decent.

              When one does not want to allocate a lot of time to go to the supermarket to buy food, drive home, prepare meals, cook them, clean the dishes, they will invariably have more time for other ventures. During my 5-day fast I spent time on learning about the molecular implications of fasting. I learned what happens when the body focuses on DNA repair, maintenance processes, and waste removal. I learned about cell rejuvenation.

              I learned from Professors Thomas Seyfried [3] and Valter Longo [4] that if one engages in 7-10 days water fasting once a year, this would almost completely reduce the risk of tumor overgrowth and cancer.

              After I finished my water fasting, I purposed to engage in intermittent energy restriction (intermittent fasting) everyday for as long as I can. IER/IF (in my case) is not eating 16-20 hours and then eating during the remaining 4-8 hours. It is not about nutrition deficiency. Paradoxically, it is about nutrition richness and nutrition optimization which is most of the time done in a calorically restricted way.

              It implies calorie restriction automatically because I would have to force myself to eat at least 2,500 kcals in 4-8 hours, as per my minimum daily requirements in non-workout days and more during the days I workout. I rarely do it. I've been able to adhere for one year (and counting) without feelings of deprivation, without hunger and cravings, mostly because I can burn fat efficiently.

              IER/IF and water fasting are two subjects that will heavily be discussed in this book, both from a research perspective and a personal perspective. We'll start with some history. Then we'll try to observe what happens at sub-cellular and DNA levels when someone fasts.

              We'll also discuss about the benefits of fasting from a disease-curing perspective and as a preventive approach. We'll refer to the hormonal implications, potential dangers and the pitfalls of fasting, the possible hunger and cravings issues, and many other barriers that can appear.

              This book is different mostly because I try to measure things from an evolutionary approach with past and current medical research at its core, and more importantly because my experiments have been conducted over a keto-friendly-keto-adapted background (my personal touch). I will show you how I combine a well formulated low-calorie ketogenic diet with intermittent fasting and, sometimes, with prolonged fasting to increase the quality and, possibly, extend the longevity of my life.

Cristian Vlad Zot                                                                         9.1.2015 09:14             

Chapter 1

An Inborn Mechanism - How Life on Earth and Fasting Coevolved

              World population, according to a census from 2013, is ~7 billion people. In the same year, the number of malnourished people was ~1 billion. Paradoxically, the number of overfed people grew to reach ~1 billion as well.

              We are most likely experiencing a shift of paradigm in terms of food policy, as it is elegantly explained by Professor Michael Boschmann, the Head of Research at Franz Volhard Research Center in Berlin [5]. More people are going to be overfed than undernourished.

              How did we get here? How did we come to a time of consuming too much, too frequently, and too metabolically deranging foodstuff, when food was supposed to be thy medicine, as per Hippocrates' saying?

              According to Mattson et al. (2014), eating three meals and a few snacks everyday is not normal from an evolutionary perspective [6]. Taking a closer look at other species in the wild and at unaltered hunter-gatherer societies, one could rarely see conditions of diabetes, cardio-vascular disease and obesity. For the typical human ancestor food was probably scarce and it was "primarily consumed during daylight hours, leaving long hours of overnight fasting."[6].

              Fact or fiction, Professor Michael Boschmann (2013) explains that during lifetime, the nutritional needs of a typical 71 kg person are [5]:

~7 tons of carbohydrates (that's ~7,000 kg or ~15,432 pounds)

~0.4 tons of minerals (that's ~380 kg or ~838 pounds)

~2.8 tons of fat (that's ~2,840 kg or ~6,261 pounds)

~2.4 tons of protein (that's ~2,400 kg or ~5,291 pounds)

~39 tons of water (that's ~38,350 kg or ~84,547 pounds)

              The numbers sum up to ~52 tons (or ~114,640 pounds) of nutrients that cycle through the body in a lifetime. Add another ~10 million liters of oxygen (O2) and these figures would be the equivalent of 5-6 big loaded trucks.

              Professor Boschmann (2013) estimates that a moderately overweight individual would add an additional big loaded truck of nutrients to the equation [5]. Various unconfirmed sources report similar figures.

              If a normal person uses that much foodstuff and if the moderately overweight consume significantly more, it would be reasonable to consider what would happen to one's health and longevity if the consumption could be reduced without affecting the perception and quality of life of a human being. Eating less may increase longevity.

              It would also be interesting to investigate the quantity of nutrients that early humans consumed throughout their life. Some reserved conclusions could be withdrawn if we take a look at the feeding cycles of other species in the wild.

Fasting in the Animal Kingdom

              The regular feeding pattern that human beings adopt everyday is not reflected by animals in the wild. Animals do not consume 3 meals + snacks everyday. They most likely feed irregularly, when there is food available, and sometimes according to a specific circa rhythm. This could be circadian (daily cycle), circatidal (tidal cycle), circalunar (lunar cycle), and/or circannual (annual cycle). The implications of each of these cycles go beyond feeding patterns and encompass processes like breeding, hibernation, migration, hormonal regulation, sleeping patterns, and others.

              To clear things up, circa rhythms (often times seen as circadian rhythms) refer to various biological rhythms that are shaped by environmental cycles. The circadian (daily) cycle refers to biological processes that occur under 24-hour regularity. One of the master controllers of the circadian cycle is the light/dark periodicity. For example, in healthy adult men, peak testosterone production usually occurs between 8 and 10 A.M. everyday. That is one of the reasons I always do blood samples for Testosterone at this time of the day. Similarly, melatonin secretion usually starts increasing between 8 and 10 P.M. everyday.

              Circatidal rhythms are regulated by tidal periods (~12.5 hours each), circalunar rhythms are regulated by lunar cycles (~29.5 days each), while circannual cycles take place with an annual regularity. Important to point out is that much of the life on Earth is sustained chrono-biologically [13]. We will discuss more about this concept later in the book.

              Cherel and colleagues (1988) studied the physiology and biochemistry of long-term fasting in geese and in penguins [7]. One thing they've noticed is that these birds do not become lethargic or inactive as a result of long-term fasting. Yet, they decreases energy expenditure by lowering both the metabolic rate and their locomotor activity.

              During prolonged fasting, these birds undergo through 3 phases. The first one is an adaptation phase marked by drastic reduction in protein catabolism and an increase in fat oxidation. It is when the body switches from glucose to fat and fat derived byproducts (ketone bodies) as primary metabolic substrates.

              Phase II is the "economy" phase, as the researchers wanted to name it. It is the on-going weight (primarily fat) loss phase during which more than 90% of energy expenditure derives from fat, keeping protein catabolism at minimum. Under optimal conditions, phase II may last until the body fat stores become drastically depleted.

              The shift between phase II and phase III occurs in the context of extremely reduced body fat which can be used for fuel. But in phase III, the body starts breaking down protein at an accelerated pace. It is until a certain point reversible, if re-feeding occurs. Phase III is critical because the body starts becoming alerted, NPY (Neuropeptide Y) secretion increase dramatically triggering hunger [7], making the subject (animal) seek for food as its top priority. Phase III is the starvation phase. A similar tri-phase context is observed for other species in the wild.

              In a related study, Cherel et al. (1987) observed the physiological changes in King Penguin chicks that can fast for up to 5 months, experiencing a decrease of ~70% in body mass. Phase III of their fast is marked by increased uricacidemia (sign of protein breakdown) and decreased ketonemia (sign of ketone production) [8].

              Very much alike birds, bears sometimes fast for up to 7 months. They do not eat or drink anything during their hibernation. It is interesting to address the metabolic adaptations occurring in bears prior and during this circannual (yearly cycle) habit. One thing to note is that they maintain their core body temperature in the range of 32 - 35 °C, unlike other hibernating mammals that lower their body temperature significantly.

              Prior to hibernation they undergo a fattening period, consuming ~20,000 kcals/day and developing insulin resistance. This is a mechanism allowing for immediate deposition of body fat, which is present in many species (in humans too). Bears developed a mechanism to recycle protein during hibernation, which in combination with shivering thermogenesis (allows for muscular contractions) drastically minimizes protein catabolism.

              According to Stenvinkel et al. (2012), hibernating bears should be of great interest to the nephrologist (kidney specialist) as they do not consume water or food for months, they do not urinate, and they remain immobile. Yet, they awake from hibernation with low blood urea nitrogen levels (marking reduced protein breakdown), strong bones, and healthy lean mass. During hibernation, contrary to popular belief for humans, they show increased testosterone production [10].

              Other evidence of fasting from hibernating species can be seen in Madagascar lemurs [11] (that hibernate in tropical climates with temperatures sometimes higher than 30 °C or 86 °F), ground squirrels, marsupials, rodents, butterflies, insectivores, etc [12].

Early Life on Earth

              While life on Earth is thought to have emerged ~3.5 billion years ago (that is 3,500,000,000 years ago), primates and hominid species have only been around for a couple of millions of years. One has to consider the scale of things for a greater comprehension of evolution, life, and biochemical processes [14].

              Evidence on primitive life forms, such as bacteria kept in a stationary phase for a prolonged period of time, shows how they are highly dynamic even after months of incubation. Finkel and Kolter (1999) studied the evolution of microbial diversity during prolonged starvation by incubating E. coli in culture systems where no nutrients were added [20].

              They observed how 10-day-old cells (starved) are much more dynamic compared to cells in fresh overnight cultures. What is more interesting is that cells from 20-day-old cultures outcompeted cells from 10-day-old cultures; and the same applies for 30-day-old cultured cells that outcompeted 20-day-old cultured cells. They conclude by saying that: as batch cultures age under starvation conditions, they develop beneficial mutations allowing microbial diversity to evolve. Hence, they are being conferred competitive advantage [20].

              Moving on to more complex life forms, yet still very old, starvation and dietary restriction studies made on Drosophila (fruit fly) show how these model organisms develop a greater resistance to desiccation (extreme dryness) and oxidative stress, concomitantly with experiencing prolonged development and increased lifespan [21]. There is still much to learn about many of the mechanism behind such adaptations during the survival mode.

              Many studies are currently conducted on Drosophila because some of the conclusions can be partially extrapolated or used in regards to other organisms closer to the human species, ultimately trying to use the latter conclusions as insight or hypotheses for human studies.

              One of the reasons for which these studies are feasible is that the lifespan of Drosophila is on average, 30 days. Their genome has been fully sequenced, it contains ~15,000 genes, and ~75% of the known human disease genes resemble similar genes in these fruit flies [22]. And, most importantly, they are easily grown in the lab. Now, let us move higher into the chain.

Early Hominid Species

              Even though the first hominid species, according to current research, is thought to be The Sahelanthropus, who lived in Central Africa about 7 million years ago, more data is available on The Australophits, who are also known as The Australopithecus [15]. Australopiths lived in Africa between ~4.2 to ~1.5 million years ago.

              In his fascinating book, The Story of the Human Body, Daniel Lieberman, a paleoanthropologist at Harvard University, describes how these amazing creatures had relatively short legs, long-arms, large faces and wide waists [16]. From a personal perspective, their physical appearance proves (to a certain extent) how they've adapted their primate structures to live on the ground compared to earlier species that mostly lived in trees.

              I also consider The Australopithecus as the pre hunter-gatherer species because their upper body size was much larger (and elaborated) compared to their lower body size. With hands bigger (and longer) than their feet, they were mostly adapted to digging for roots and tubers and to grabbing fruit. They had flat feet, which made them less adapted to moving faster (i.e. to hunt, migrate, escape predators, etc) [16].

              In Lieberman's own words, they may have occasionally consumed meat probably by scavenging "since being slow and unsteady bipeds likely made them ineffective hunters" [16]. Nothing may be for certain with regards to what they ate. It was more likely that whenever they found food that was either high quality (nutrient rich and energy rich - meats, fat, honey, nuts, etc) or fallback food (leaves, stems, seeds, and/or fruit), they would eat until they had to move to another location [18].

              In another study, Henry and colleagues (2012) examined the diets of Australopithecus sediba, one of the latest species of the Australopithecus family, who were found at the archeological site of Malapa, in South Africa. Researchers suspect that this species lived approximately 2 million years ago, just when the Homo species was beginning to emerge [23]. 

              The specimens studied were 2 subjects (smaller sample size may be seen as a drawback). Researchers extracted plant phytolits from their teeth and they also considered stable carbon isotope data, as well as dental micro-wear texture data to make speculations on their possible diets. Unlike earlier Australopithecus species (3-4 million years ago), these 2 subjects consumed almost exclusively a C3 diet [23].

              Carbon isotopes help determine whether species ate C3 resources, which can be tree derived, certain herbs, shrubs, as well as animals eating these foods, C4 resources which can be tropical grasses, sedges, and animals eating these foods, or a combination of C3 and C4.

              Au. sediba mostly consumed C3 foods that may have included harder foods, dicotyledons (ex: wood, leaves, fruits, bark) and monocotyledons (ex: sedges and grasses) [23]. Basically the diet of one of the latest Australopiths resembled both the diets of chimps and earlier Australopiths and it also included aspects of the diets of early Homo, such as Homo erectus and P. robustus.

              In the rare cases when they were able to eat copiously, insulin was a life saving factor. It allowed them to pack food as fat tissue through the process of lipogenesis, the same tissue that would later provide them with energy when food was scarce [17]. I'll get into more details on this topic later.

              I wonder how many of them survived and how their physiology may have been different than ours to allow them to thrive. Maybe the mechanism of insulin resistance has been improved throughout their existence, but it has not been perfected. After all, evolution is a non-stop process. I have some doubts that, as being predominantly gatherers, they could eat so much to trigger insulin resistance efficiently. Maybe this is one of the reasons they have become extinct.

              As Australopiths left the scene of evolution, a newer species started appearing approximately 1.9 million years ago in Africa. They were the Homo erectus species ('erectus', from Latin, meaning 'up-right'). Unlike the Australopiths, Homo erectus started migrating across continents, they evolved as more prolific hunters, but they were also gatherers because they did not find wild game in all the places that they migrated to.

              Differences could be observed in the physiology of Homo erectus. These made the species more suited to move faster and on greater distances (short toes, full-arch in their feet, longer legs, etc) [19].  Having feet acting like springs allowed them to evolve into good hunters, which in turn gave them better access to more energy dense foods.

              From what has been studied so far, the mean brain size of some Australopithecus was 478 cc. In contrast, earliest Homo species had larger brains, with an average of 700 cc, suggesting cooperative breeding, as well as a wider access to energy rich foods and a possible carnivore diet [24]. However, these facts alone do not shed light on the feeding rhythmicity of the species.

              Perhaps, as one study points out, early hominids ate a lot of fish due to its availability all year around. Steward (1994) refers to the fish remains found in many early hominid sites [25]. Perhaps, as Strait (2014) suggests, they ate many insects, given they were widely available and they serve a substantial source of protein [26].

              Or perhaps they mostly focused on food sources that came from fat, as these were able to provide energy for longer periods of time. An interesting study conducted by Ben-Dor et al. (2011) correlates the disappearance of the elephant in the Levant (an area in S-W Asia) with the increased energy needs of the Homo erectus [27].

              According to the researchers, as elephants disappeared (i.e. could have been hunted), early hominid species needed to hunt significantly smaller pray that were also faster [27]. It is not the same thing to hunt (or be chased by) an elephant (big tank of fat and protein) or to chase a wild boar or a rabbit. They had to maintain an adequate fat content in the diet to be able to thrive.

              The hunting process could last for hours or days in a row and the body of these early hunters would most likely be in ketosis. The certainty of being in ketosis increases if the hunting process lasts for more than 24 hours (enough time for glycogen stores to become depleted and for the metabolism to switch from primarily using glucose to primarily using fatty acids and ketones). I assume they did not carry around energy bars in their pursuit for energy-dense-energy-rich food sources (i.e. big mammals).

Higher Energy Needs <=> Higher Brain Size?

              While the Australopith weighed around ~44 kg (97 pounds) and had an average brain weight of 485 g (1.07 pounds), early Homo (up to Homo erectus) weighed on average 57 kg (126 pounds) and had an average brain weight of 805 g (1.77 pounds). This could also be a potential explanation for the availability of higher energy foods. Yet, this does not provide clear insight on the frequency of eating of these early species [27].

Adapted from Ben-Dor et al. (2011) [27].

              Researchers speculate that to support the increasing energy demands, Homo erectus gradually upped fat intake to more than 45% of total calories (~3,500 kcals), while still consuming ~28% raw plant calories (carbohydrate and fibre rich sources) and ~27% protein calories. They suspect that early Homo sapiens reduced total caloric intake to ~2,400 kcals, concomitantly with reducing fat intake to ~33% [27]. I personally find it difficult to accurately assess the amount and type of food sources they used for feeding.

              In other well conducted studies, researchers were reserved in drawing a conclusive line in terms of macronutrient partitioning, total calories, and the feeding cycles of Australopiths and early Homo. They do highlight the possible change in dietary adaptations as early Homo emerged. They base their conclusions on analysis of incisor size, teeth micro-wear texture and complexity, as well as occlusal morphology [28, 29].

              Their findings suggest (to a certain extent) a shift toward consuming foods requiring more incisal preparation and molar shearing, such as tough-plants or animal-based foods. When it comes to increased meat eating or using tools in food preparation, Ungar and colleagues (2006) are quite confident about a stronger correlation between the two [29].

              There are several Homo species between Homo erectus and Homo sapiens sapiens (the modern man). Homo heidelbergensis, Homo neanderthalensis, and Homo rhodesiensis are only three of them; however, the only remaining one seems to be Homo sapiens sapiens (H. sapiens).

              Until a few years ago it was strongly believed that the modern human appeared ~200,000 years ago somewhere in Africa and only much later they migrated outside Africa [30]. There are various theories that try to explain how modern humans emerged. One of them is The Multiregional Evolution Theory hypothesizing that we are the product of gene flow among Asian Homo erectus, European Homo neanderthalensis and African Homo erectus ergaster [31]. I love the thought of being, partially, a Neanderthal.

              Another theory, with its basis in mtDNA analysis (mitochondrial DNA analysis), supports a "Single African Origin" where all modern humans are derived from a single woman who lived ~150,000 years ago [32]. Mitochondrial DNA is widely used in human evolution and ancestry studies because it is inherited maternally only, it does not recombine and it mutates faster compared to nuclear DNA, making it the appropriate tool for relating individuals to one another [32].

              We still do not have a very clear picture of how hominid species evolved and migrated across continents, but given the adaptations observed in each species and ultimately in modern humans, one can make certain inferences on food supply, rhythmicity of feeding, as well as reproductive capacity.

Empathy, Social Aspects and Collaborative Food Procurement

              Some theories and fair logic would focus on the social perspective of Australopiths, early Homo and modern Homo. Australopiths were predominantly foragers and gatherers and it is thought that they did not organize themselves in groups or tribes. They did not have to cooperate for hunting and they may have not been developed enough (in terms of brain size) to support cooperation. They were in-between late primates and early Homo species, but their feeding patterns may resemble, to a higher extent, a vegetarian approach.

              From both social and feeding perspectives, Homo erectus and later Homo species (including H. sapiens - us) developed hunting habits possibly because of their bigger brain size, but it could also be the other way around. They may have had bigger brain size because of the higher energy content of their feeding. One thing has to be kept in mind: these processes took place over thousands and hundreds of thousands of years; each small adaptation could have lasted a very long period of time.

              I would suspect a strong correlation between social behavior (tribal or group organization), brain size, and food supply. Increased brain size and the development of the neocortex would provide the context for a greater interconnectivity between individuals, which would also provide support for hunting. Primitive language is also thought to have existed in early Homo habilis. Whenever high-energy food is available (from prey) it would feed the energy needs of the individuals [31].

              Another aspect of increased social behavior, this time in Homo sapiens, is the first evidence of burial [31]. In time, all of these contributed to developing higher-order organizations (tribes, villages, towns), led to fewer migrations, and it eventually served as the basis of primitive agricultural societies.

Higher-order Societies

              Settling down, forming families, living in villages, raising farm animals, and cultivating the land may have allowed for a steadier and more stable supply of food throughout the entire year. Even though this may not seem the perfect context, it comes to my mind to relate to my personal story as a young kid in the village of my grandparents. I remember that we used to rely on grain crops, corn, and the backyard garden for food supply. We raised chicken, ducks, gees, turkeys, pigs and cows.

              This was the time when my grandparents were still strong and active. Daily duties consisted of feeding and taking care of farm animals, as well as working the land. Corn was (to a certain extent) used to feed the chicken once or twice a day, while the rest of the time they were running free on the field eating grass and worms. Pigs were also left loose during the day and sometimes I had to take care of them. It was one of the jobs I hated most.

              My grandparents used hay (dried clover, dried alfalfa, and/or dried grass) to feed the cows during wintertime, while during the summer they were left loose to eat fresh grass. We had a lot of work with their chow: mowing the grass, letting it dry in the sun, turning it on the other side to get dried, then taking it back home and storing it for the winter time. Most of the work was not mechanical, it was pure labor. Looking back, I miss those times. Life was simple.

              From a feeding rhythmicity perspective, we ate twice or three times a day: first thing in the morning and late in the evening. This was convenient during spring, summer and fall time because we worked the land all day long. When we had to go to a farther land site we carried supper with us. It was the most enjoying experience to eat in the field at the shelter of a big tree in a hot summer day.

              One can imagine the type of food we ate. Every day we had soup and some grain based second course, often times pasta, potato and cheese pie, potatoes, bread spread with margarine and jam (sometimes with lard and jam), and so on. We also consumed eggs from our chickens and milk, cheese and other home made dairy products from the cows. Once or twice a week we had a meat based meal, usually on Sundays, and sometimes once during the weekdays.

              From a macronutrient perspective this is a carbohydrate rich feeding protocol. I am inclined to say it was not detrimental to our health as long as we kept processed products from our dinner table (and we mostly did), but it could have been better.

              It would not be unsafe to correlate this with the way of life of early humans living in agricultural societies approximately 10,000 years ago. Such living allowed for eating everyday at least once or twice. This does not mean that everybody did the same. Many may have, but many have not. One could only consider the different societal classes that were existent from the very beginning: the poor may not have had the same "luxury" to eat twice or three times a day.

              Even with the agricultural way of life on our shoulders for ~10,000-11,000 years, we were doing mostly fine. People did not suffer from modern diseases until concentrating in big cities in the late 19th century, which is why I can consider my early life in the village as being quite healthy, given the type of food and the frequency of eating. I was a bit overweight but I was not obese. And most of the folks were not obese either. We were active, we did not have too much EMF radiation (electromagnetic field radiation), we did not have too much exposure to artificial light, and we slept well. The picture is quite different in a modern city life.

              That is one of the reasons I think that such a short-period of time of 10,000 years is not sufficient for a proper adaptation of the human species to all the changes we have implemented in our lives (especially the frequency with which we eat) given that as a species we have a background of ~2 million years.

              When very small adaptations accumulate over thousands of years, when the last 150 years translates to multiple significant changes into our lives, and when 10,000/2,000,000 years is 0.005 or 0.5%, one can understand the gravity and the poor situation of current human health.

              Recent decades brought us various enormous improvements regarding the quality of our lives. We can cure multiple diseases that killed thousands of people a couple of hundred years ago, yet we are living in a world-wide epidemic of obesity and diabetes. We can efficiently use antibiotics to save lives, yet we prescribe them for simple viral infections; we overuse them. We can use technology to communicate in real time with anybody on the other side of the globe, yet we are constantly bombarded by EMF radiation. And I could keep on and on...

              As a society, we have to find ways to leverage on the advantages and mitigate the issues. The same goes with feeding cycles. I'm not saying that everybody should immediately jump into 7-day water-only fast or they should do Intermittent Fasting everyday for the rest of their lives. What I'm suggesting is that, when appropriate, one can use these tools strategically and do it in a very enjoyable manner. In the next chapter we will travel through time from the Middle Ages to the late 19th century to see some IF and total fasting experiments.

Chapter 2

From the Middle Ages to the Early 20th Century

I am not so simple as not to know that, as I was born, so I must die; but the natural death that I speak of does not overtake one, until after a long course of years; and even then, I do not expect the pain and agony which most men suffer when they die.

Luigi Cornaro

              It would be common rationality to suspect that prehistoric humans and many early societies did not follow a frequent feeding cycle similar to the one of the 21st century human. They, most likely, did not consume 3 meals and 7 snacks every day (please excuse my ironic tone).

              To support such claims, there has been evidence of people practicing energy restriction (intermittently, periodically, and/or prolonged) from the times of Socrates and Plato, through Middle Ages, and up to the early 20th century [33]. In our present days, many folks have started coping with such practices (i.e. 5:2 Diet) but when we are referring to prolonged fasting, many still cannot separate it from its religious connotations.

              As a stand-alone science field, integrating fasting with other techniques to support disease treatment and prevention, we are still scratching the surface, as this is viewed mostly controversial. But I will discuss conventional vs. functional medical approaches later in this book.

              As we have previously seen, feeding cycles may have been irregular for primitive hominid species. They may have also had a circadian factor, implying feeding in light cycles and resting during dark cycles.

              Remember, these early humans were most likely eating energy rich food whenever they were able to hunt, while the rest of the time they may have been feeding on lower energy foods or fasting, given the circumstances. The situation has probably changed as hunter gatherer tribes have settle down into villages and towns and started cultivating the land.

              Yet, there is evidence that some folks have deliberately practiced energy restriction and fasting even when agricultural societies emerged.

Seneca's Letters

              Take, for example Seneca, who lived between ~4 B.C. to ~65 A.D. In his letters to Lucilius he often urged for "laying down the law to the soul, and bit it be alone in refraining from pleasures just when the whole mob has let itself go in pleasures" [34].

              This appears in his Letter XVIII where he is consternated that Saturnalia (a Roman holiday in December) which was previously celebrated in a more reserved fashion, has now become an opportunity for most people to go into excessive drinking and eating. "Once December was a month, now it is a year" highlights the importance that people attribute to this festival lasting from Dec. 17th to Dec. 23rd. He advises Lucilius that "it shows much more courage to remain dry and sober when the mob is drunk and vomiting" [34].

              Seneca goes into details:

"Set aside a certain number of days, during which you shall be content with the scantiest and cheapest fare, with coarse and rough dress, saying to yourself the while: "Is this the condition that I feared?"[34].

              In these words one may see that foodstuff restriction is not carried out for the sake of ailment alleviation alone (in fact, he does not even mention fasting as a cure), but to prove oneself that sobriety and modesty (through a minimal lifestyle) can bring as much joy as the life of a wealthy (financially) person would bring. Moreover:

"Let the pallet be a real one, and the coarse cloak; let the bread be hard and grimy. Endure all this for three or four days at a time, sometimes for more, so that it may be a test of yourself instead of a mere hobby.

Then, I assure you, my dear Lucilius, you will leap for joy when filled with a pennyworth of food, and you will understand that a man's peace of mind does not depend upon Fortune; for, even when angry she grants enough for our needs."[34].

              I interpret this as a call to experiencing the richness of life by removing or reducing much of the comforts that they had. Living on pennyworth of food for a certain number of days, wearing coarse cloak and sleeping on a hard pallet will allow one to be satisfied with the minimum and will bring infinite joy when granted with access to a wealthier living.

The Temptation of Jesus

              Then, we can all recollect the writings of the Bible, in Matthew 4:2, about the Temptation of Jesus:

"Then Jesus was led up by the Spirit into the wilderness to be tempted by the devil. And after He had fasted forty days and forty nights, He then became hungry."[35]

              It may be out of context to start talking about the biochemical implications of this situation. Clearly, Jesus may have run out of His fat reserves and the increased NPY secretion (Neuropeptide Y) may have triggered hunger. This is often seen in successful prolonged fasting experiments on obese or overweight people, who by the time their adipose tissue gets depleted they become hungry. This is when re-feeding should be implemented. This is when starvation starts. This topic was partially discussed in Chapter 1 and will be addressed in more detail in later chapters.

              Jesus may have been an extraordinary human being for achieving such austerity. Great teachers from other religions have embraced fasting as a common practice as well. Buddhists have been using it as a method of self control, while followers of the Islam adopt it in the month of Ramadan as one of the five pillars of their faith.

              Slightly moving away from religious practices, I want to elaborate on one of the earliest written self experiments on fasting and prolonged caloric restriction.

The Nobleman from the 15th Century

              It is the personal journey of Luigi Cornaro, a 15th Century nobleman from Italy who, at the age of 35, after a near-death experience started doing caloric restriction daily for the rest of his life [36]. It was this deliberate practice that allowed him to live a quality life past 100 years. Some records show that he lived between 1464 and 1566, clocking at a vibrant and respectful 102 years of age [37].

              Nevertheless, it is extremely interesting when one can read his claims about the soundness of his health, his vitality and high energy levels in his 90s, how he had the mental clarity to start writing (he was a writer) immediately after consuming food, how he, compared to his siblings, was better equipped to manage difficult emotions, and so on.

              Even though he started doing calorie restriction when he was in his mid-thirties, he only started writing about it when he was ~80 years old. It startles me when I encounter such examples of courage, boldness and initiative from elder folks.

              Another lesson of boldness comes from Grandma Moses, who lived most of her life at a farm raising children and doing housekeeping. In her late 70s, after her husband died, she started painting. She lived to 101 (1860 - 1961) and her paintings had been sold for millions of dollars [38].

              Luigi Cornaro journalized his long-life experiment in a book called How to Live 100 years - Discourses on the Sober Life, originally written in Italian as Discorsi [36]. There are 4 Discourses written over a period of 20 years, from his early 80s until his late 90s. Luigi's basic principle was to consume no more than 350g of foodstuff and 414 ml of wine per day. His diet included bread, meat, egg yolk, and soup.

              The first of his discourses resembles similar ideas to Seneca because he mentions about his contemporaries who eat and drink as much as they please and then they render themselves useless at the ages of 40 or 50, "burdened with strange and painful infirmities...while I remain so sound and hearty at the age of 81" [37].

              In his early life, due to his lifestyle, Luigi may have suffered from colic and gout, "a stomach generally out of order...and a perpetual thirst" [37]. One of the leading physiologic philosophies of this man was that he should allow himself no more food than his stomach can easily digest, often times leaving the table at the point of feeling good but not full or satiated.

              His practice somehow relates to Hara Hachi bu, a Japanese technique instructing people to eat until they are 80% full [40]. In his own words, he: "always rose from the table with a disposition to eat and drink more" [36]. Of course, the ambition of this book is not to promote constant hunger or to live a miserable life.

              There may be no purpose of living a lengthy life if one is always hungry. You will later learn how to leverage upon the benefits that Luigi felt. I will show you how you can combine long-term ketosis, fasting, and calorie restriction. Adopting this combo (given that other factors of health are considered close to optimal) one's hunger and cravings may be reduced to minimum.

              There are some well studied anatomical implications of not eating until you are stuffed and are no longer able to breathe normally. There may be a delay between the communication of some hunger regulating factors and the brain, especially CCK (cholecystokinin) and leptin [39, 40]. The logic behind the Japanese technique is robust because if one always eats to total satiety (until stuffed), the volume of the stomach will be in a constant accommodation state (always increasing).

              It took Luigi almost a year until he started feeling entirely free from all his ailments. Some other strategies that he implemented are:

"I have carefully avoided, as far as possible, all extreme heat, cold, extraordinary fatigue, interruption of my usual hours of rest, and staying long in bad air" [36].

Dear Luigi, you would be surprised of the modern human who almost 365 days a year prefers living in a cozy environment, sleeps poorly, and breathes an air that is dozens of times more polluted than yours.

              As years went by, word spread about Luigi Cornaro's approach to life. He claims to have been visited by "many of the learned doctors of this university, as well as physicians and philosophers" who were very familiar with his age, life, and manners [36].

              As a nobleman, he devoted sufficient time for intellectual endeavors. Reading and writing were two of his most important activities. In his own words [36]:

"Moreover, they know in what manner I spend my time, so as never to find life weary: I pass my hours in great delight and pleasure, in converse with men of good sense and intellectual culture; then, when I cannot enjoy their company, I betake myself to the reading of some good book. When I have read as much as I like, I write; endeavoring in this, as in other things to be of service to others; and these things I do with the greatest ease to myself, living in a pleasant house in the most beautiful quarter of this noble city of Padua."

              To support his temperate and frugal living, he often mentioned great people from history who led a similar life, such as: Plato, Cicero, Socrates, "and many other great men of former times, whom not to tire the reader I forbear naming; and, in our days, Pope Paul Farnese and Cardinal Bembo; and it was that reason they lived so long" [36].

              Living in the 15th century makes Luigi smarter than many followers of the conventional medicine today [36]:

"...he who thus lives, cannot be sick, or but seldom, and for a short time, because, by regular living, he destroys every seed of sickness, and thus, by removing the cause, prevents the effect..."

              If the reader is not aware, conventional (modern) medicine mostly focuses on treating the effects of illnesses rather than shooting for the root causes. One receives insulin to reduce blood sugar instead of consuming foods lower in sugar so that insulin may be less required.

              One is given statin drugs to unnaturally and unsafely reduce cholesterol levels instead of promoting an internal environment where fats and cholesterol are used when they are mostly needed. One is being prescribed antibiotics for simple viral issues. And so on. Conversely, functional medicine may be closer to a more optimal approach to wellbeing.

              At 86 years of age, Luigi writes that "all my senses have continued perfect, and even my teeth, my voice, my memory, and my heart. But what is still more, my brain is clearer now than it ever was" [36]. He goes on by saying that he can jump into writing immediately after meals, as his understanding is never clearer and he never feels drowsy. In Discourse 2, we are given another glimpse into his diet [36]:

"I eat as follows: bread, panado, eggs (the yolk), and soups. Of flesh meat, I eat kid and mutton. I eat poultry of every kind; also of sea and river fish. Some men are too poor to allow themselves food of this kind, but they may do well on bread (made from wheat meal, which contains far more nutriment than bread made from fine flour), panado, eggs, milk, and vegetables."

              We often may think of our ancestors as being less intelligent compared to the modern man. Yet again, the wisdom of a teacher from the Middle Ages cannot stop amazing me. I do not judge the type of food he ate. It may not matter as much given that he calorically restricted. It may not matter the bread and the panado he consumed because as an active man, he was mostly using the nutrients of his diet, at the same time allowing low or no inflammatory processes to occur. But I wonder if he could have lived even longer if he would have further optimized his lifestyle.

              In Discourse 3 [36]:

"My Lord, to begin, I must tell you, that being now at the age of ninety-one, I am more sound and hearty than ever, much to the amazement of those who know me."

              Luigi continues by saying that he often spends 8 hours every day on writing treatises on subjects useful to mankind and he spends many more hours walking and signing. He was a very faithful man, which often proved to be a grounding factor to many. Believing in a higher power can provide the equilibrium and, at the same time, the fuel for living a passionate and action-driven life.

              The ending of Discourse 4 happens in the same note [36]:

"I solemnly assure all mankind that I really enjoy a great deal more than I can mention, and that I have no other reason for writing, but that of demonstrating the great advantages, which arise from longevity, and such a life as I have lived.

I desire to convince men, that they may be induced to observe these excellent rules of constant temperance in eating and drinking, and therefore, I never cease to raise my voice, crying out to you, my friends, that your lives may be even as mine"

              Thanking Luigi, I say that the time has come for me to build upon his life-long experiment by studying and practicing caloric restriction, and, at the same time, optimizing (as much as possible) the nutritional protocol so that it can encompass nutritious-rich-energy-rich foods.

              Along with other protocols, my purpose is to reduce hunger and cravings, reduce ailments to minimum, and paradoxically increase energy levels, mental power and overall the quality of living a long life.

The Fasting Cure of Upton Sinclair

              Jumping through time until the early 20th Century, I will introduce the experiments of Upton Sinclair on periodic and prolonged fasting.

              Upton Sinclair was a highly productive American writer who lived between 1878 and 1968 (died aged 90). He wrote approximately 100 books on various different topics. One of his passions regarded diet and health and some of his books were on this topic. He experimented with fasting, he wrote a lot about it in newspapers and he got hundreds of letters from readers whom wanted to try fasting as a means to cure their illness conditions [41].

              Some other folks wrote to him how they were motivated to fast after reading his articles; they shared their experiences in great detail and thanked him for his careful guidance. Upton condensed all these letters along with his own experience in a book entitled The Fasting Cure [42]. As I have done with Luigi Cornaro's life-long calorie restriction journey, I will further describe and interpret Upton's book along with quotes from it so you get a better picture of the fasting practices from the early 1900s. 

              Upton's book was born out of necessity. He needed a reference that people can read and have their questions answered quickly so that he would not have to answer fasting letters every day for the rest of his life. He starts by describing his personal experience with fasting [42]:

"I cannot take any case but my own, because there is no case about which I can speak with such authority."

              Both Luigi and Upton focused on their personal experiments; they considered that nobody knows one better than himself. Luigi mentioned his discovery of better tolerance to fresh red wine compared to older red wine. He claimed that no doctor would have been able to tell him that, because no doctor would have lived so close to him to be familiar with his life in such detail.

              To that I draw a very big exclamation mark: be careful with following general recommendations. Our DNAs even if they are 99% the same, individual gene expression is different. It only takes a single switch (mutation) in a base pair (SNP - single nucleotide polymorphism) to make a person very different from another. I would urge you to practice with strategies, observe and optimize.

              Upton spent his childhood without having too many cares in the world. In his own words [42]:

"I spent my boyhood in a well-to-do family, in which good eating was regarded as a social grace and the principal interest in life.... It was not considered fitting for children to drink liquor, but they had hot bread three times a day, and they were permitted to revel in fried chicken and rich gravies and pastries, fruit cake and candy and ice-cream... I was an active and fairly healthy boy; at twenty I remember saying that I had not had a day's serious sickness in fourteen years."

              Then he started developing summer colds as he began his writing career. Upton gave little to no importance to it, but as years passed by this condition always came back. A tooth nerve extraction (root canal) was one of his most miserable experiences as it kept him in bed for a week "with chills and fever, and nausea and terrible headaches" [42].

              After overcoming his illness, he took some measures of precaution: he lived in open air as much as possible (something that Luigi Cornaro also gives reference to), he exercised everyday (walking, tennis, boating, and swimming), he did not work and he did not allow himself to become stressed. But, all his efforts were mostly in vain because "at the end of the year's time my general health was worse than ever before" [42].

              One day Upton heard the story of a woman who during her life suffered from "sciatica and acute rheumatism; from a chronic intestinal trouble which the doctors called "intermittent peritonitis"; from intense nervous weakness, melancholy, and chronic catarrh, causing deafness." and who was, until recently, a bed-ridden invalid. She was the same woman to join him on horseback riding up Mount Hamilton in California. To his amazement, the woman claimed that when she took the ride she "had not eaten a particle of food for four days previously!" [42].

              This was the first real encounter of Upton with the practice of fasting. Seeing the changes which this woman went through, he decided he would try to fast for a couple of days.

              As one might suspect, it was not easy in the beginning. Upton felt the same disturbing hunger I felt when I tried doing my first Good Friday fast. The difference is that he kept going, and as he depleted his glycogen storage, hunger started melting away. In day 5 he did some walking and also began doing some intellectual work. To his surprise, "I read and wrote more than I had dared to do for years before" [42]. His sleep was not affected. However, each day around noon he would feel weak (possibly due to decreasing cortisol levels). He mitigated this phenomenon with a massage and a refreshing cold shower.

              To eliminate the fears of those considering that not eating for a longer period of time will lead to stomach trouble from the acid secretion, Upton explains that after the first hunger ceases (glycogen being depleted) secretions come to a halt as well, and the food assimilation process, which is a big consumer of energy, goes out of business. The body then starts house-cleaning, focused on a multitude of regenerative processes, including DNA repair. These will further be detailed in subsequent chapters.

              He advises people to do enemas (injecting certain fluids into the lower bowels through the rectum) and bathe daily; and most importantly drink copious amounts of water. This provides additional support to the process of detoxification and rejuvenation.

              These practices may sound obscure, but these folks were not crazy. Later research shows how coffee enemas can increase the activity of glutathione S-transferase in the liver by 700%. This enzyme is responsible for fighting free-radical damage [43].

              Upton lost a total of 17 pounds during his 12-day fast. Most of the pounds were lost during the first 4 days - that is 15 pounds. I suspect this has a lot to do with glycogen depletion and water loss, and much less with fat loss. During the next 8 days he claims to have lost only two pounds (that is ~900g). I suspect that much of this subsequent loss would be from fat mass.

              Upton broke the fast with some orange juice. This is a very common practice among experienced fasters (people who fast a lot). But it is not the main protocol of breaking the fast and reintroducing food that I describe later when I talk about prolonged fasting. Upton kept on juicing for the first two days (the juice of ~12 oranges), then he switched to the milk diet (a glass of milk every hour, or so, for 3 days). He describes an extraordinary sense of inner peace on the milk diet, "as if every weary nerve in the body were purring like a cat" [42].

              During the first 24 days after his first fasting experience, Upton gained a total of 32 pounds. It is also intriguing to observe this trend of post-fast huge gains in the letters people were sending him. Most of them saw this as a successfully completed process and this is totally different from what many modern practitioners would say.

              As he gained back weight, his desire for physical work increased ravenously. In his own words [42]:

"Now, after the cleaning-out of the fast, I would go into a gymnasium and do work which would literally have broken my back before, and I did it with intense enjoyment, and with amazing results. The muscles fairly leaped out upon my body; I suddenly discovered the possibility of becoming an athlete."

              Not only that, but he also discovered that most of his allergies went away. He was now able to consume acid fruits, bananas, and peanut butter with no trouble. It would be engaging to research the changes in the microbiota in people who fast for 5 days or more.

              Throughout time he did more prolonged fasting experiments. As he became more experienced he started writing articles in big publications. And people began sending him letters, some of them were testimonials, others were questions, and many of them were thank you notes.

              One letter features a young man, severely injured in a train wreck. He suffered from typhoid, bronchitis, pleurisy, and pneumonia. He decide to experiment with fasting because he was very weak. When he was healthy he weighted 186 pounds. Now he was 119 pounds and on the brink of suicide. He was able to fast for 6 days; after fasting, he gained additional pounds (went up to 146 pounds) and became much healthier. He started playing tennis and succeeded walking 442 miles in 11 days, which I find astonishing.

Other success stories, in Upton's own words [42]:

"I know one man who reduced his weight from 365 pounds to 235. I know one little girl whose spine was bent in the shape of a letter U lying sideways, and who, by means of fasting and a diet of fruits exclusively, has come four inches nearer to straightness in a few months. She has the complexion of perfect health, and is rapidly recovering the use of arms and legs, which were paralyzed years ago."

              Another letter is from an anemic school teacher who had a big goiter and was constantly the victim of colds and headaches. She fasted for 8 days and she cured herself from all her ailments. She modified her lifestyle and started consuming ~1,200 kcals a day mostly from fresh fruit.

              I also found a trace-back to the spiritual and/or religious connotations [42]:

"Holy Writ says that Moses fasted 40 days, and to prove to his congregation that one did not have to be superstitious to believe some of these Old Testament tales, Rev. J. E. Fitch, at the age of 80, fasted fifty days; and instead of losing flesh towards the last part of his fast actually gained in weight. He is as vigorous to-day as he was at 21."

              This particular story makes me think of the Christian monks from the convents in my country who often fast for many days in a row, consuming only pure water. They appear active, vibrant and many of them live well into their 90s.

              In another letter, an individual claims to have lost interest in food from the very first day. His tongue remained coated throughout the fast (sign of toxic elimination) and his breath was offensive even to himself. He lost voice timbre and resonance. In his letter he does not mention the duration of his fast but he provides details about his re-alimentation strategy: orange juice for the first two days, milk diet and orange juice in day 3, and solid food starting day 4.

              A particular letter from the end of the book caught my attention [42]:

"Tarbox, whose letter I enclose, on the thirty-seventh day of her fast, her tongue was perfectly clean and she had natural hunger, and she was well on the way to recovery from the terrible cancerous growth and condition in which I found her. Since Mrs. Tarbox' cure, I have had several other cases of cancer cured through fasting."

              Many of these people used the same or a similar strategy to Upton's, possibly because they have implemented the protocol outlined in his newspaper articles:

- they took alternate hot and cold showers,

- they bathed daily,

- they had enemas,

- they drank copious amounts of water,

- they drank some warm water to stimulate peristaltic movement (for bowel discharge),

- they watched how the coating and the color of the tongue changes,

- they stayed in fresh air and they walked a lot,

- they engaged in vigorous physical training after fasting was over.

              Upton kept track of 277 fasting experiments. The average number of days of prolonged-fasting was 6. However, 90 people were able to fast for 5 days or more, 51 people were able to fast for 10 days or more, and 6 people were able to fast for 30 days or more. 109 people wrote to him, out of which 100 reported benefits while 17 reported no benefits (I'm not sure about his math though...). Those who reported no benefits almost all were fasts of only 3 or 4 days. This implies a certain correlation between the duration of the fast and the benefits that are experienced.

              Even so, in his opinion, longer fasts would mostly seem fitted to those suffering from chronic diseases (rheumatism, Bright's Disease, Cirrhosis, and cancer, to name a few). I believe that by "longer" he refers to fasts that last for more than 10-15 days. Hence, I would cautiously regard 6-10 day fasts as fairly safe.

              Unlike Luigi Cornaro, Upton did not advocate for calorie restriction or fasts lasting 2 or 3 days because he regarded them hard to attain to. One of his motives was that in prolonged fasting, the first two days are the hardest because hunger may be persistent, same as it may happen in calorie restriction under a certain nutrition protocol.

              In prolonged-fasting, one can often observe severe cases of hunger suppression. Upton points out to the story of a lady who began fasting three days before Christmas and finished it three days after New Year's, while at the same time she cooked food for her family. In further chapters I will try to elaborate a protocol that allows people to fast for shorter durations and to combine calorie restriction with fasting in a manner in which hunger is not a problem.

              One of the reasons I was so keen into providing as much insight as possible from Upton's writing is that because of his exposure to so many cases of fasting and due to his personal experiments, his words, explanations, observations, and conclusions carry tremendous gravity and insight for me. What brings even more balance into his approach is that he did not embrace a particular type of diet: either of meat eating or vegetarianism.

              He did not consider that people should regard pigs and chickens as their brothers, hence not kill them. He experimented with meat-only diets same as he did with the milk-only diet from the re-feeding period of some of his fasts. However, he was not a big meat eater and he consumed it every now and then.

              If it were for me, I would quote the entire book that Upton wrote in the early 1900s. But that may not be considered fair use. What I can do is to highlight its importance as a sound reference guide for the uninitiated faster (person who fasts) written in a simple and easily understandable language.

              I will leave Upton's wealth of knowledge on fasting with a remarking quote [42]:

"Starvation consists in denying food, either by accident or design, to a system clamouring for sustenance. Fasting consists in intentional abstinence from food by a system non-desirous of sustenance until it is rested, cleansed, and ready for the task of digestion. Food is then supplied."

              Now that you are regarded with some decent knowledge on the practices of fasting and caloric restriction, I will start elaborating on the science and focus on the studies conducted in the 1900s, especially on those lead by George Cahill in the '50s and '60s, one of the brightest minds in the field.

Chapter 3

The Emerging Science of the Last Century

              I am particularly fascinated by the emerging research of the 20th century especially because many studies have been carefully considered and well designed. Ethics was still a deciding factor in most studies, but it was not as strictly controlled as it is today.

              Subjects were allowed to fast for indefinitely prolonged periods of time and total fasting in obesity experiments was not such a buzz as it is today. Of course, things did not work well in a number of studies. Some subjects have died; however, if one investigates the circumstances in which these individuals were fasting, as well as the complications that occurred throughout the experiments, this may have been predictable. Think about it, an obese individual may not have the most appropriate biochemistry to undergo such an impacting strategy.

              But on the other side of the spectrum there were also these lean individuals who decided to try total fasting for healing, detoxification and rejuvenation purposes. As I previously mentioned, I can easily relate to the Christian-Orthodox monks from my country whom most often do caloric restriction and fasting altogether.

              The experimental study that I am about to analyze starts by giving reference to various successful fasts in the 19th and in the 20th century. Unsurprisingly, here we meet Upton Sinclair once again [44]:

"Upton Sinclair, better known for other literary works, wrote extensively on the health benefits of fasting."

              Further, on non-obese persons doing prolonged fasting [44]:

- Dr. Tanner who reportedly fasted for 40 days in 1880 [45, 46].

- Alexander Jacques did a 30 day and a 40 day fast in 1887 and another 30 day fast in 1888 [46].

- Signor Succi completed at least 32 fasts of 20 days or more [47]; he also completed longer fasts during 1890 (40 and 45 days) [48].

- F. Penny, M.D. completed a 30 day fast in 1905 [49].

              And, on fasting for weight loss in obese subjects [44]:             

              Drenick and colleagues [50] had obese subjects undergo fasts lasting for up 117 days, while Thomson et al. (1966) [51] supervised fasts of 139, 236 and one lasting 249 days. The longest recorded fast was that of a 27 year old obese man and it lasted 382 days, resulting in the loss of 125 kg. I have discussed about this medically supervised world record in the introduction of the book [52]. They also mention fasting for the treatment of convulsions, referencing two studies, one dating back to 1910 and found in a 1963 paper [53] and another one from 1921 [54].

              It is beyond the scope of the book to go into the details of all these medical experiments and individual stories, which is why I provided clear references to them. And many can be accessed for free online. I wanted to mention them and detail some of them so that the practice of prolonged fasting is not further seen as some controversial, unachievable and religious endeavor, but on the contrary, if well conducted, it can be a powerful tool to repair and rejuvenate the body from DNA level and above. I will go into more details for the very recent research on prolonged and intermittent fasting.

Lean Subject - 36 days without Food

              And now, to stay in line with the chronologic flow of the book, I want to get into the specifics of the n=1 (includes one research subject) study from the 1980s (which provided the plethora of historical medical reference from above).

              I have been fairly interested into describing and interpreting this study because it has been well conducted and it is widely cited, it includes ~170 references, and it links back to many total fasting, calorie restriction and intermittent energy restriction studies from the early 1900s (as you have seen). It makes a good starting point of research. Later in this chapter, I will focus on the studies conducted by George Cahill, one of the brightest scientists of starvation, fasting, and calorie restriction.

              Kerndt and colleagues (1982) meticulously supervised a 41 year old non-obese man of 68.6 kg (~151 pounds) and 172 cm tall (~5.7 feet) who decided to undergo a 40-day water-only fast. This person was a member of a religious community and he was to carry his fasting experiment in strict anonymity in the confinement of the monastery he was part of.

              The researchers updated him on all the possible negative outcomes and complications that his experiment may turn to; they agreed that he can terminate the fast at any time he wants and/or upon medical recommendation. This guy had been an ovo-lacto-vegetarian for the preceding 24 years. His diet was prohibiting the consumption of meat products. He was mostly consuming vegetables, eggs, milk and related products.

              The subject was able to fast for only 36 days out of the initial target of 40 days because he developed profound weakness and postural hypotension and this interfered with his daily activities. He lost 15.7 kg (~35 pounds) and he kept on losing weight during the first two days of realimentation. The total loss was 16.6 kg (~36.6 pounds).

              He initially lost 0.9 kg/day (~1.98 pounds) during the first 5 days, but then it gradually decreased to 0.3 kg/day (0.66 pounds) after the third week. I suspect the initial increase in weight loss during the first 5 days was from glycogen and water mostly, as the body gradually adapted to using fatty acids and ketones predominantly.

              In this and in similar experiments conducted by Ancel Keys and colleagues in the 1950s [55], researchers could observe decreasing pulse rates that reached an average of 35 beats/min 13 weeks into the starvation or semistarvation experiments. The situation may be a bit different when we are talking about lean subjects, as in this experiment [44].

              After all, the duration of the fast (other factors considered optimal) may be tightly dependent on the volume of bodyfat. One thing to note is that initial water intake was 2 liters/day (~68 oz) for the first 3 weeks, which then decreased to 1 liter/day (~34 oz) throughout the rest of the experiment.

              In the next table you can observe the fluctuation of different biomarkers before, during, and after the fast [44]:

Adapted from Kerndt and colleagues (1982) [44]

              Insulin levels seem to have dramatically dropped during the first few days of the fast, while glucose remained mostly constant in the 70 mg/dL range. Glucagon increased and it reached peak levels in day 33. I suspect it may have a lot to do with higher gluconeogenesis. Remember, this subject was fairly lean and his body fat may have dropped drastically in the last few days of the fast. If he had kept going, he may have reached the point of no return, as once the body fat is depleted, the survival mechanism switches to burning muscle and even organ tissues (starvation).

              Growth hormone levels, as seen in many other experiments increased significantly. In day 26 growth hormone levels were ~14 times the values from prefast and postfast periods. Total lipids and triglycerides remained fairly constant suggesting their active involvement in the metabolic picture.

              Kerndt and colleagues (1982) thought that glycerol, the by-product of TAG hydrolysis, can contribute significantly as a non-protein-derived precursor to gluconeogenesis, along with lactate and other substrates [44]. They also considered that protein-derived-amino-acids contribute about 10-15% of the gluconeogenic needs in the early days of fasting. In my interpretation, this means that even though muscle breakdown occurs, it may not be significant. And as the fast is prolonged, the further increase and efficiency of fatty acid and ketone metabolism may reduce protein catabolism, which is often seen in long-term fasting experiments.

              I have to be really clear and straightforward about this. Starvation is different from fasting! Fasting refers to abstaining from nutrients in order to help a system (body) focus on detoxification, repair, rejuvenation, and maintenance. The end point of fasting (when fasting should be ceased) is when body fat stores are low. This is where fasting turns into starvation.

              In starvation, when there is not sufficient fat to fuel the metabolism efficiently, the body turns to burning muscle and organ tissue extensively. It is a gradual and sometimes irreversible process. You will later see that lean people can water-only fast for 30-40 days or even longer without ever reaching starvation. Turn back a few pages to the end of Chapter 2 and please reread about the difference between fasting and starvation.

How do you know when you are crossing from fasting to starvation?

              In prolonged-fasting (under optimal conditions) one never feels hungry. The general state of wellbeing is mostly elevated. But as bodyfat stores get critically low, real hunger emerges, as NPY and other hunger regulating factors increase their activity, urging the person to start consuming food. Almost none of the experienced fasters reach this point. Thomas Seyfried approaches this concept in a recent (March 2015) lecture on calorie restriction, ketogenic diets, and cancer [46].

              To support an efficient fat-burning mechanism, researchers observed a decrease in total nitrogen urinary excretion from 10-12g per day in the first week to 5-7g per day after week three [44].

              Lipolysis (breakdown of triglycerides) and ketogenesis increase significantly during the first couple of days of fasting, while serum ketone bodies gradually rise over the first 3-4 weeks. Subsequently, researchers note a decreasing muscle ketone uptake by 75% as prolonged fasting progresses and as muscles start relying more on free fatty acids (which is an optimal mechanism only when insulin level is low).

              The rise in growth hormone levels (which peaked in day 26 in our study) are not similar to growth hormone levels in obese individuals fasting from 18 to 38 days.

              Thyroxine (T4) levels in this subject were 5.9 µg/dL before fasting, decreased to reach 4.9 µg/dL in the 36th day of the fast, while they measured 4.4 µg/dL 12 days after the fast ended. Normal values are between 4.5 - 12.5 µg/dL. Measuring T3 (triiodothyronine - active thyroid hormone) levels would have been more accurate, but as researchers point out: during prolonged fasting T3 levels fall but clinical hypothyroidism does not develop, as TSH levels remain mostly unchanged.

              Under normal feeding conditions and when carbohydrate intake is consistent (regardless of source), it has been noted that T4 is converted to the active T3, which is responsible for many reactions inside the body. As noted by many, including Perera and Marikar (2014), during caloric restriction, fasting, IF/IER or in similar circumstances, T4 is converted into the inactive rT3 (reverse T3) and hypothyroidism will not developed. I described the widely misunderstood low-T3 levels on my blog [243]. Steve Phinney and Jeff Volek also wrote an insightful post on the topic as of March 2015 [244].

              However, resting energy expenditure, body temperature, blood pressure, and heart rate may decrease [56]. This scenario is not indicative of a diseased state, but more likely (I would say) of a preservation state.

              In the following table, one may observe mineral fluctuations in our lean subject who fasted for 36 days [44]:

Adapted from Kerndt and colleagues (1982) [44]

              Serum Sodium levels decreased slightly but remained in the normal range mostly throughout the fast. There was a significant decrease between days 33 and 36 (from 134 mEq/l to 122 mEq/l). Since the subject was lean when he started the experiment, I suspect his bodyfat may have been depleted during the last days of fasting, and together with the reduced blood pressure these should have served as signs to stop the fast.

              Potassium, Magnesium, Calcium and Phosphorus levels remained in the normal range. Uric acid, as previously specified, increased significantly during the first period of the fast, but it was reduced during the last part of the fast.

              What I find most surprising is the 3.5 fold increase in Zn levels. A similar phenomenon was observed in a 4 day fasting experiment in turkey poults [57] and in a 3 day water-only fasting experiment conducted on human subjects [58]. Some researchers link this increase in serum zinc concentration with the increased release of zinc from the muscle tissue as catabolism occurs, while more recent research (O'Halloran et al., 2013) views this mechanism with more complexity [59].

              From another perspective, Zinc participates as metal cofactor in the antioxidant defense system of the human body [63, 64, 65].

              Some complications can occur in prolonged fasting studies, as widely referenced by Kerndt et al. (1982). They can be non-fatal (headaches, nausea, cramps, weakness, acute gout, renal insufficiency, edema, oliguria, urate nephrolithiasis, anemia, alopecia, and others) or fatal (lactic acidosis, renal failure, small bowel obstruction, intractable ventricular arrhythmias, and others). Many of these conditions have occurred due to an improper health status prior to the fasting experiment and quite many occurred in obese and morbidly obese subjects, whom, as one can imagine, may not have the vibrant health of leaner individuals.

              In this study [44], the lean subject did not develop any of these symptoms throughout the fast. However, he had to interrupt his 40 day fast in day 36 due to the signals (low pulse, low blood pressure, etc) given by his body that "It should be over".

              To end the discussion of this experiment in a positive note, I want to highlight that, during fasting this subject, (others have reported similar findings) described feelings of euphoria:

"Others [51] have reported euphoria without total anorexia. Ketosis, which develops rapidly during fasting, was commonly believed to be responsible for the anorexia [60];

To explain the euphoria, Bloom [61] postulated that accumulation of aceto-acetic acid produces a mild intoxication similar to ethanol. Phillips [62] from studies in animals speculated that the accumulation of isopropyl alcohol in neural tissue might be responsible for fasting-induced religious, mystical or hallucinatory experiences."

              I often experience the euphoric states that some researchers link to ketosis. And during my 5 day total fasting experiment these states have increased significantly. However, they did not reach the point of religious revelations. Who knows? Maybe if I had kept on with my fast, I may have reached that point.

The other Facet of Ancel Keys and the 1940s

              A checkpoint of the 20th century with regards to food deprivation should be the 1940s. During this decade, the world renowned and badly famed Ancel Keys conducted experiments on semi-starvation. He was recently popularized in a negative fashion by the fans of low-carbohydrate dieting because of his Six and Seven Countries Studies, where he presented the data to misdirect the reader [69].

              Ancel Keys conducted research on the diets of people from 22 countries to observe the relationship between cholesterol intake and cardiovascular disease. He started publishing results as of 1955. In his findings however, he only presented data from 7 countries that proved a linear relationship (apparently causal) between the two parameters.

              When other researchers started accessing the same databases that Keys did, and when they plugged-in the data from all 22 countries, they observe no relationship between cholesterol intake and heart disease whatsoever [70]. But it was too late at that point, because the harm was made. Keys gained a lot of influence and may have participated in the fat phobia that emerged once his misleading study was out.

              But not everything about Ancel Keys should be bad. In fact he conducted well-informed studies during the 1940s on semi-starvation to gain "insight into the physical and psychologic effects of semistarvation and the problem of refeeding civilians who had been starved during the war" [71]. Together with his colleagues he wanted to provide efficient strategies for famine victims of the World War in Europe and Asia. The experiments are known under the name of The Minnesota Starvation Experiment and they have been published into two large books consisting of ~1,400 pages [55].

              According to Baker and Keramidas (2013) [72], during November 1944 Ancel Keys selected 36 male subjects between 20 and 33 years old to participate in a year long study that would mimic the conditions of people affected by the war. They were put on a control diet for the first 3 months. It was a good diet of ~3,500 kcals. The subjects were instructed to walk ~20 miles per week. Ancel Keys and colleagues purposed for a 25% bodyweight loss in the subjects.

              The hard part of the experiment was the semi-starvation phase that lasted for 6 months, between February and July 1945. The subjects consumed ~1,570 kcals of foods similar to the ones in Europe at that time, such as potatoes, bread, jam, sugar, cabbage salad, jello, oatmeal and macaroni and seldom some token amounts of dairy and meat products [72]. They mostly ate breakfast and lunch.

              The next part of the experiment consisted of a controlled rehabilitation period of 3 months, from July to October 1945, when the subjects were given between 2,500 and 3,500 kcals (different groups received larger or smaller amounts). The fourth part lasted for 8 weeks and it consisted of an uncontrolled rehabilitation period where the subjects could eat as much as they want. Some of them consumed 10,000 kcals/day.

              The most dramatic changes of these individuals have been observed during the semistarvation period. As they lost weight, their physical appearance degraded significantly. They lost strength, stamina, and sex drive. Their core body temperature decreased, as well as their heart rate. Many developed obsessive thoughts about food:

"Fatigue, weakness, and hunger were outstanding complaints. The marked reduction in strength and endurance was paralleled by a curtailment of spontaneous activity. The subjects moved slowly and cautiously; they climbed stairs one at a time. Coordination was affected and the men sometimes tripped over curbstones and bumped into objects which they intended to sidestep." [73]

              Attempts to suppress or substitute food were made by heavily using chewing gums, a lot of water, coffee, tea, and smoking. Some subjects consumed as much as 40 packages of chewing gums per day. They would chew gum until the last bit of sweetness and flavor and then discharge it. Researchers had to limit chewing gum use to two packages a day.

              Others consumed as much as 15 cups of tea and coffee per day. Researchers had to input restrictions on coffee and tea to as much as 9 cups per day (still quite a lot, if you ask me). Sugar was not used for sweetening the coffee but it was served during meals.

              When the semistarvation phase of the experiment started, subjects were allowed to spend time alone, but thereafter they had to be accompanied by a buddy if they had to attend events. So, they were under observation most of the time.

              The apparently increased level of detail that I put on this experiment pales in comparison with the 1,400 pages written to extensively describe it [55]. I would encourage further reading so that you can see for yourself how much interest is put on the behavioral changes of these men submitting themselves honorably to such traits [73].

              I cannot judge the ethics of the experiment or the contents of their diets. The purpose of the study is of far greater importance. Their diets appear to consist mostly of carbohydrates, many of them being refined carbohydrates. The control phase of the study shows that their satisfaction point with respect to this particular macronutrient partitioning protocol is somewhere at 3,500 kcals or beyond. I can then try to understand the immense and obsessive hunger they developed while at ~1,570 kcals/day on average.

              Consuming a diet of 1,570 kcals/day which come mostly from carbohydrates would stimulate hunger tremendously. Insulin, as we know, and as we will see later in the book, is one of the primary drivers of hunger, along with its interplay with other hunger regulating factors. These subjects were not efficiently tapping into their adipose tissue. They, most likely, never entered ketosis and this could provide an understanding of their significantly low-quality physiologic and psychologic states.

              This experiment, sadly and paradoxically, is the opposite of the successful prolonged water-only fasts that we have seen previously. These subjects felt much hungrier than an average faster would feel even in the first 24 hours of no eating. Of course, given the initial health and physical status of these subjects, they would not have been able to complete a 6 month water-only fast unless they had had a substantial amount of adipose tissue on hand, as well as decent health status.

              It took the subjects significant time and over-consumption of food even after the uncontrolled rehabilitation period to get back to their baseline. And many of them developed life-long habits and convictions with respect to food. Further, I will continue analyzing Cahill's research on prolonged-fasting and obesity, as well as the research of other bright minds from the 20th century.

On Obesity, Diabetes and other Fasting Therapies

              I think there are many reasons that prolonged fasting has become an active (yet, silent) area of research. Some of them could be: the discovery of insulin, the investigation of the mechanisms of diabetes, especially Type 1 Diabetes (ketosis vs. ketoacidosis), a possible treatment for obesity, as well as other disturbing conditions such as epilepsy.

              One of the researchers who dedicated his life to studying prolonged fasting and starvation was George Cahill Jr. (1927 - 2012). His first experience was as an intern in 1953 treating a young person suffering from diabetic ketoacidosis (often see in Type 1 Diabetes patients). He briefly describes his vast (multi-decade) career as [66]:

"I subsequently became extremely busy serving with a number of governmental agencies, bio-research institutes, scientific advisory boards (i.e., chairman of Merck’s), the National Diabetes Commission, the Nutritional Advisory Board of NASA, and others. I was offered several chairs of medicine and deanships, but my disregard for administrative minutiae persuaded me to remain a free agent. However, I did take on one major role, namely with the Howard Hughes Medical Institute (HHMI)."

              In 1970 he started teaching at Harvard Medical School. He did it until 1990 when he was awarded the emeritus status. He also taught classes at Dartmouth College. One of the early notable publications of Cahill was on adiposity and it contained more than 4,300 references [67]. In this handbook they clarified and/introduced many physiologic implications of adipose tissue dynamics, most importantly how TAGs (triglycerides) are hydrolyzed into glycerol and free fatty acids during fasting or when the subject is stimulated with epinephrine [68].

              Numerous researchers conducted experiments of prolonged fasting during the 20th century. But as we approach modern days, one can observe an increase in the strictness of the regulations regarding experimental studies, which is why prolonged fasting and some starvation studies have been regarded mostly unethical and sometimes unsafe. Nevertheless, we still have historical data providing wealth of information that can be accurate, inaccurate, and sometimes inappropriate.

              What I am trying to do is to dig into this research as much as possible without getting lost into too much detail and with the purpose of providing safer and most appropriate background for these practices.

              In one study, Cahill and colleagues [74] observed metabolic and hormonal changes in 6 normal subjects and 2 individuals suffering from Type 2 Diabetes. They fasted for 8 days. The initial average weight was 80kg and the average height was 176 cm. Average post-fast weight was 74.2 kg. All subjects lost more than 5 kg (~12 pounds) of bodyweight.

              In the 6 normal subjects blood glucose levels went from ~77 mg/100ml in day 0 to ~63 mg/100ml in the 8th day of the fast. Free fatty acid, acetoacetate and BOHB levels increased throughout the fast, marking an active participation of fats in the metabolic process. Nitrogen excretion increased in the first days and then gradually decreased. Insulin levels went from ~14 µU/ml in day 0 to ~8.3 µU/ml in day 8. And as we've seen previously, growth hormone levels increased almost 30 fold, from 0.3 mµg/ml in day 0 to 8.8 mµg/ml in day 5 and to 8.3 mµg/ml in day 8 [74].

              In the 2 T2D (Type 2 Diabetes) subjects, serum glucose levels went from ~98 mg/100ml in day 0 to 59 mg/100ml in day 8. Free fatty acids, Acetoacetate and BOHB (beta-hydroxybutyrate) increased throughout the fast. Insulin levels went from ~30 µU/ml in day 0 to ~24 µU/ml in day 8, while growth hormone went from 3.3 mµg/ml in day 0 to 25.0 mµg/ml in day 2 to 8 mµg/ml in day 7 and to 4.4 mµg/ml in day 8.

              While similar metabolic processes occur in normal persons and T2D patients, one can observe the differences in fasting glucose levels and insulin secretion, marking a less efficient blood sugar management in T2D patients. Baseline growth hormone levels in T2D have been 10 fold increased during the fasted state compared to normal subjects and much more increased as fasting undergoes. While both types of subjects (normals and T2D), show significant increase in growth hormone levels during the fast, the biggest increase was seen in T2D patients.

              During his early studies, George Cahill figured out that "the fuel substrate for brain could not continue to be glucose since gluconeogenesis from protein would consume so much muscle that long-term viability would be dramatically decreased." [66].

              He also pointed out that urinary nitrogen excretion in fasting subjects falls to ~4-5 g/day, while BOHB and acetoacetate contributes ~2/3 (66%-70%) to brain fuel, "markedly diminishing the need for muscle proteolysis to provide gluconeogenic precursors." [66]. In line with other researchers, Cahill noted that normal healthy adults may be able to survive 2 months of water-only fasting, while obese people could do it even longer, mostly due to the maximized use of fats and ketones in the metabolic equation.

              This is a totally different scenario compared to the semi-starvation studies of Ancel Keys when the subjects never adapted to burning fat efficiently. Semi-starvation (inappropriate caloric restriction) is much closer in appearance and mechanism to starvation (the real one). Fasting is like an oasis where the body takes a breath of clean and fresh air and takes some time off from digesting food.

              From what I've observed, Cahill and other researchers used starvation and fasting interchangeably. That's why in some quotations you will often see the use of starvation which I would translate to fasting. But, again, it is not the same thing.

              After conducting more experiments, George Cahill started giving precise details with regards to fuel metabolism during prolonged fasting:

"Hepatic glycogen contribution to blood glucose is essentially zero by the second or third day of starvation. Total splanchnic glucose production in several weeks’ starvation amounts to approximately 80 grams daily. About 10–11 grams/day come from glucose synthesis from ketone bodies, 35–40 grams from recycled lactate and pyruvate, 20 grams from fat-derived glycerol, and the remaining 15–20 grams from protein-derived amino acids, mainly alanine." [66].

              Kidneys seem to contribute 2/5 in fasting gluconeogenesis, while the liver does it in a ratio of 3/5. Ketogenesis is accelerated by the increased lipolysis which produces fatty acids and glycerol, "the latter being quantitatively incorporated into glucose by the liver" [66]. Serum ketones, as pointed by Cahill, can increase to approximate those seen in diabetic ketoacidosis (DKA) patients, but the scenario is never reached because the small insulin secretion prevents it from happening, unlike DKA where insulin secretion does not occur. And ketone bodies also stimulate insulin release, which is not possible in T1D where insulin production is lost.

              Elevated BOHB levels in the presence of minute insulin secretion prevent the release of free fatty acids from adipocytes [75, 76]. This means that increased ketone levels have a sparing effect not only on protein catabolism but also on how much lipolysis undergoes. Were it not for the small insulin secretion, the scenario would resemble what happens in T1D patients.

              There seems to be a thin line between TAG hydrolysis (=> fatty acids + glycerol) and serum ketone body predominance. For example, hibernating bears (as seen previously) do not consume food or drink anything for several months in a row. One would dangerously assume they are ketotic. However, they are not in ketosis. BOHB levels are below 0.5 mM (mmol) because glycerol from adipose tissue lipolysis is more than sufficient to support gluconeogenesis in the liver [90].

              In terms of caloric needs and to support the theory (proved by experiments) of non-obese prolonged fasting in humans, Cahill and Owen (1968) considered that fasting subjects would burn ~1,500-1,800 kcals/day in the beginning of the fast, and it would later settle at ~1,000-1,500 kcals/day thereafter, given that the subject does not have to increase thermogenesis from living in a colder environment [77].

              Obese subjects undergoing water-only fasting have been seen to reduce their adipose tissue efficiently. But, as previously mentioned, some of the very long fasting experiments done on obese subjects arose health issues and even death in a few cases. This may have had to do with the inappropriate initial health status of the subjects undergoing the experiment.

              In some other studies, total fasting was not quite total as it included small amounts and sometimes moderate amounts of protein so that proteolysis would be minimized [78, 79]. Even though there was substantial weight loss, the subjects may not have fully adapted to the efficient prolonged-fasting metabolism described and observed by George Cahill and other researchers. Hunger may have not been minimized, as it is in prolonged fasting experiments. I would personally say these studies are in-between starvation and much closer to the experiments of Ancel Keys, with regards to the gravity and emotional distress of food deprivation. 

              Johnson and Drenick (1977) published a study of 207 morbidly obese patients who lost weight through prolonged fasting (~60 days). All subjects lost weight and almost all of them gained back weight to reach the original set point or gain additional weight. In a 3 year follow-up, only seven subjects were able to maintain their weight. This study alone would make total fasting an inefficient strategy for weight loss. It takes me back to the success letters sent to Upton Sinclair in the beginning of the 1900s, where practitioners of total fasting were validating the success of their prolonged fasting only after gaining a lot of weight in the realimentation period.

              These facts strengthen my beliefs on weight loss strategies and maintenance of optimal weight in man. Even though there are tremendous benefits for people undergoing prolonged fasting, there are many more factors to optimal health than food restriction or food intake alone. For some changes in the body to be persistent over the long term (i.e. appropriate hormonal balance) fasting should be combined with other strategies. Secondly, realimentation is extremely important. If these 207 obese subjects got back to their pre-fast dietary habits and lifestyle, this explains their weight return to baseline and/or even go above it.

              Other studies done on obese subjects undergoing prolonged fasting show similar metabolic adaptations to those seen by George Cahill [81, 82]. During such advantageous stress, the body liberates its reserves of fat (other factors considered optimal) to support the metabolism. Since it does not have to focus on digesting food, it mostly focuses on repair and maintenance processes. In many cases, the benefits obtained from long-term fasting are kept over the long term, but in many more cases, realimentation and returning to older habits may eventually lead the individual to a recurring disordered health condition.

Physical Performance, Rejuvenation and Fasting

              While obesity, diabetes and other pathologic studies have been widely conducted during the second part of the 20th century, increasing interest was seen in physiologic adaptations to ketosis in terms of performance. In one study published in 1980 in the American Journal of Physiology, 5 obese subjects were observed for metabolic response to 45 minutes on a vertical cycle ergometer at 60% maximum effort in post-absorptive state (a couple of hours after a meal) and again after being fasted for 2 weeks [83].

              Blood glucose levels were constant in both states, but more glucose was produce and utilized in PA (post-absorption) compared to fasting. The Respiratory Quotient (R.Q.) increased in PA but did not change in the fasted state; "pyruvate and alanine increased less in PA than in fasting; lactate increased similarly in PA and fasting; FFA did not change in PA but increased in fasting; and 3-hydroxybutyrate did not change in PA but decreased in fasting. Insulin decreased in each subject with exercise in PA and fasting, whereas little change occurred in glucagon." [83].

              Phinney and colleagues (1980, 1983) have noted similar findings while studying exercising obese people [84] and elite athletes [85] before and after a couple of weeks on a strict ketogenic diet. R.Q. in elite athletes also decreased from ~0.83 at baseline to ~0.72 after 4 weeks on a ketogenic diet, marking a switch from carbohydrate and protein dominant metabolism to predominant ketone body and fatty acid metabolism [86].

              Imagine what may happen when one combines efficient fasting strategies with a well formulated ketogenic diet. We will see a lot more about this in my later n=1 prescription. It would become even more interesting if this is applied to a lifestyle where high intensity training and heavy lifting is preferred as exercising protocols.

              Other researchers have observed similar muscle metabolic adaptations during exercise before and after 21-26 days of fasting in 5 patients [87], while Veech and colleagues (1994, 1995) reported an increased output in the working perfused rat heart concomitantly with a decreased oxygen consumption when BOHB was added to the glucose in the medium [88, 89], marking an increased mitochondrial efficiency.

              To understand the immense importance of BOHB as metabolic substrate (both in fasting and in ketogenic nutrition protocols), Cahill explains it from an evolutionary perspective [66]:

"Most bacteria use poly-β-hydroxybutyrate as an energy store; coliforms are an exception. In some protozoans, up to 90% of dry weight is poly-βOHB. Even archaea use it for energy storage, which suggests it has been around for well over 2–3 billion years. It is possible that its selection was aided by the periods of low environmental oxygen that occurred during the Archaean, Proterozoic, and Palaeozoic eras."

              A little teaser for the fans of high-fat diets and for those of high-carb diets [66]:

"One then has to consider β-hydroxybutyrate as a unique nutritional compound. It has equally balanced hydrophilic and hydrophobic characteristics, and therefore is neither fat nor carbohydrate."

              As technology allowed for more insightful and highly complex anatomic experiments, increasing interest emerged in prolonged fasting and IF/IEF and their impact on cell rejuvenation, DNA repair, homeostasis, and delayed aging.

              Some of the research studies I've been following with tremendous interest are from Professor Valter Longo, currently serving as Director of USC Longevity Institute, from Mark Mattson, currently the Chief of the Laboratory of Neurosciences at the National Institute on Aging, as well as from Dr. Luigi Fontana, currently a Research Professor of Medicine. There are other bright minds' works who I follow closely and they will be mentioned throughout the book.

              Many of the studies have been conducted on model organisms, such as S. cerevisiae (yeast), C. elegans (small worms), Drosophila (fruit flies), rats, and monkeys. It is very convenient to study these creatures as some of the conclusions can be extrapolated and applied (to a certain extent) to human studies. We have a lot in common, genetically speaking, with each of these animal models. And studying them is even more convenient due to their shorter life span (except monkeys).

              Some of the early works of Prof. Valter Longo regarded observing antioxidative processes in yeasts in stationary phase. I have discussed some research on bacteria and increased lifespan in the stationary phase in Chapter 1. Longo and colleagues also studied longevity and stress resistance in organisms ranging from yeasts to humans.

              More recent studies involve sirtuins (proteins involved in cellular processes of inflammation, aging, apoptosis, stress resistance, and energy efficiency during low-calorie situations) and age-related disease, lifespan extension, using anti-aging genes to fight cancer, the link between sirtuins, IGF-1 and starvation, fasting and cancer treatments in humans, as well as many other related topics. Many of the studies were conducted together with the other two researchers mentioned above.

              Professor Luigi Fontana has been studying long-term calorie restriction and the extension of healthy life span, the molecular mechanisms of calorie restriction and cancer, aging, adiposity and calorie restriction, as well as other subjects of the same interest.

              Mark Mattson's research focuses on observing apoptosis in neurodegenerative disorders, the molecular pathways leading to/away from Alzheimer's disease, aging and neuronal vulnerability, aging and stem cells, brain aging, genes, diet and behavior, and many other similar topics.

              Linking the research conducted by these amazing individuals (as well as others) with intermittent fasting and prolonged fasting in the following chapters requires decent amount of work and study hours.

              But I will do my best to provide you with clear, digestible, and unbiased (as much as possible) information so that you can take the best decision for yourself if you consider using any of these protocols. Nonetheless, I will also get into more details on my personal 1 year and 2 months (and ongoing) daily IF protocol and insights into prolonged fasting (what I learned from my 5 day water-only fasting experiment).

              In the end of this chapter, I'd like to remind you of some n=1 medically supervised prolonged fasting experiments in healthy non-obese, that would provide helpful insight on the topic:

Dr. Tanner's Fast - 1880 - [45]

The 40 day-fast of Dr. Signor Succi - 1890 - [47]

Notes on a Thirty Day Fast - 1909 - [49]

A Study of Prolonged Fasting - 1915 - [48]

Chapter 4

Intermittent Fasting/IER and Prolonged Fasting: Practical Insights

There is no greater delusion than that a person needs strength to fast. The weaker you are from disease, the more certain it is that you need to fast, the more certain it is that your body has not strength enough to digest the food you are taking into it.

Upton Sinclair

              Have you ever considered why this type of protocol (fasting) may not get the buzz and popularity that conventional diets do? Who's got something to win from telling you not to eat? Supplement companies could go bankrupt if they stop selling you "hunger suppression pills" or "fat burners" or whatever "what not product" you can think of.

              Second of all, it may not have become popular because it involves sacrificing your satiety and the feeling of hungry for a couple of hours, in case you have to deplete your glycogen levels.

              Imagine that! One would die for not eating every 3-4 hours. The metabolism would crash. The thyroid will start to malfunction. Please excuse my sarcasm.

              To a certain extent, I can understand. I have been in that situation. Remember, I told about my early experiences of fasting on a background of high-carb nutrition. Hormone signaling (especially insulin secretion) may make one think that the hunger they feel is real hunger.

              When I tried doing 1 day water-only fast during Good Friday, by 3 P.M. the only thing I could think of was food. I felt so hungry that every minute passing felt like an eternity. But as dusk came and I pushed myself through those terrible hunger pangs, it gradually started decreasing. And when it was time to eat, I did not feel that hungry at all. My body had probably started efficiently burning fat.

              One reason I know it was false hunger is that I had enough bodyfat that I could do prolonged water-only fasting for more than 2 months (other factors considered optimal). In those situations I could understand why Ancel Keys' semi-starvation subjects felt so miserable on a daily 1,570 kcals diet.

              They were consuming low-calorie processed-high-carbohydrate diets. They never got adapted to burning fats and ketones for energy because their blood glucose levels and insulin secretion may not have allowed for that. Not using fat and ketones for energy primarily, they lost a lot of muscle and some fat. Their brains never tapped into burning ketones. It mostly ran on glucose (almost 100%), and given the low-calorie protocol, their brains were in a constant panic mode, screaming to: "Give me more sugar".

              So, for one to start efficiently doing prolonged fasting and intermittent fasting, I will briefly talk about their physiologic implications (in simple terms) as well as some strategies to reduce the first negative symptoms that may appear. This will serve as a basis to understand the upcoming chapters, where I will go deeper into the molecular mechanisms that occur as one stops consuming anything but water for at least 18 hours. Intermittent fasting can be so much fun, especially when you add different rewarding mechanisms to it (such as black coffee unsweetened or sweetened with some stevia, tea, and others).

Prolonged fasting - Some basic, very important, information

              The scientific literature has mostly focused, so far, on prolonged fasting. The possible benefits of this intervention can be:

- detoxification, as the body shifts to healing and repair instead of digestion, which is a great consumer of metabolic energy

- curing or alleviating acute illnesses

- curing or alleviating chronic illnesses

- rejuvenation and/or attempts to increase life span

- etc.

              From my personal perspective, the benefits of prolonged fasting can be experienced after a person stops consuming food for more than 72 hours, given they have to deplete glycogen stores (given they have a background of moderate or high-carbohydrate consumption), and more than 46-48 hours for people coming from a very-low-carb and/or ketogenic nutritional background.

              For people wanting to detoxify (to a certain extent), cleanse, and/or rejuvenate their body, 3-10 days water-only fast can be optimal. I would not find it necessary to go beyond this unless a serious medical condition implies such strategy; and if one attempts doing prolonged fasting for more than that, they should be under medical supervision. Even for the less experienced folks, a 3-10 days water-only fast should not occur without supervision.

              After all, complications may appear as I assume that the starting point for most wanna-be-fasters is not an optimal state of health. Plus, from a psychological perspective, I would rather shoot for 3-5 days fasts and once I reach the target I can decide if I want to go further and expand the fast to 7-10 days. Many success stories have used this technique because the mental burden ("OMG, I'm not gonna eat for 10 days") is reduced. And it may be more challenging for folks using a high-carb template; but it's far from unattainable.

              When I considered doing my first prolonged fasting, I initially proposed it to last 50+ hours. I knew it was very attainable, especially because I was far from feeling hungry with my many previous 24+ hours shorter fasts, and possibly because of my keto-adaptation status. At that time I was consuming a well-formulated-strict-ketogenic-diet (daily) for more than 6 months.

              However, 50 hours turned to 5 days. And I would have gone even longer, but I was quite lean and I did not want to lose more body fat. I suspect, from my research and from analyzing my physical appearance, that muscle catabolism was close to minimum because I did not have to go through glycogen depletion; and gluconeogenesis and muscle catabolism may have been significantly reduced (as described by Cahill [66]). I was already in efficient ketosis. Plus, I exercised with heavy weights 3 days out of the 5.

              Assuming that a person consuming a high-carbohydrate template attempts to do prolonged fasting for 3-10 days or more, I will describe the adaptation phases as pointed out by George Cahill and other researchers.

              In phase I (first couple of hours after the last meal), the body fuel is glucose, largely from exogenous sources. Glucose is burned at ~40g/h. From 4-16 hours (phase II), glucose is burned at ~7-8g/h and most of it comes from hepatic glycogen. At this point the body has already started to increase the production of glucose in the liver through the process of gluconeogenesis.

              Since no food is provided, gluconeogenesis substrates come from muscle catabolism, recycled pyruvate and lactate, glycerol (not so efficiently, yet), and to a certain extent from BOHB -> AcAc -> Acetone -> Propanediol -> Pyruvate -> Glucose [66].

              Gluconeogenesis (GNG) increases until the end of phase III, where glycogen stores are depleted. After phase III, GNG decreases significantly and glucose is used at a rate of 3.5-4 g/h. This is where the body starts efficiently burning fat and ketones, while holding tight of the muscle mass [66].

Redrawn and adapted from Cahill (2006) [66]

              During the first three phases is when the average person would find their most difficult time to cope with. As the body's sugar levels drop and as the metabolism switches to the fat burning mode, the panicking brain screams for the fuel it's been widely used to (especially in the first 0-16 hours).

              Since this is the most crucial time, I'd rather recommend one to start a prolonged fasting experiment consuming the last meal sometime in the evening, 3-4 hours before going to bed. Assuming an 8 hour sleep, the subject will be ~12 hours into fasting by wake-up time. There still remains a few more painful hours with respect to hunger.

              Serving some black coffee, tea, and a ton of water will definitely help. After 24-30 hours most of the (false) hunger symptoms are gone, glycogen is depleted, GNG is still undergoing but at a lower pace, insulin secretion is low and the body can tap into using fats and ketones efficiently. Occupying oneself with work around the house or other errands can serve as means of distraction from hunger.

              Some of the possible negative symptoms as these adaptations occur can be: increased hunger, light-headedness, fatigue (increased fatigue in many folks), higher irritability, headaches, higher acidity in the stomach (much reduced after a couple of hours), drowsiness, and others. If the faster has a fairly decent health condition, most of these symptoms will be reduced. However, they are uncomfortable and they are the reason why many people will not push through, to reach to the promised land :).

              Much of them may not be present if the faster comes from a very-low-carb or ketogenic nutritional background. I, for example, have not felt any hunger and/or the rest of the symptoms when I did my 5-day water-only fast. Though I had a headache by the end of the second day, it was gone when I woke up the third day.

              I would recommend increasing the consumption of water (purified) during the first day, and the consumption of decent amounts of water in the rest of the days. The kidneys may excrete minerals as the adaptation undergoes and this can be the reason for some of the negative symptoms.

              To mitigate this, as well as to fuel the reward mechanism in the brain, one can use a small vegetable bouillon cube (6-10g) dissolved in some hot water. It's ~10-15 kcals and cannot be considered to breaking the fast as it contains very little nutritional value.

              Coffee consumption is permitted (from my perspective), but it should be black and unsweetened or sweetened with a tiny stevia tablet, which contains 0-1 kcals. It may help as the blood pressure and pulse go down, as seen in many fasting experiments.

              In my case, I also used 1 multivitamin-multimineral pill/day because I was not supervised and I wanted to know I have an additional measure of precaution. But, nothing else; no diet soda and no workout supplements, no oil/butter enriched coffee, no nothing.

              In my future prolonged fasting experiments I will most likely use coffee and tea as companions and also as rewarding mechanisms, strategically. For example, in the second day of the fast I could have a cup of coffee in the morning and another one in late afternoon, and a nice big cup of tea in the evening. This will most likely help me.

              I would not recommend exercising if one feels the negative symptoms I mentioned above. And I would strongly discourage exercising for the first 2 days if one comes from a high-carb nutritional background. Thereafter, one could start exercising. I will provide more details on workouts and I will add more to the prolonged fasting strategy as we progress through the book.

              To help the detoxification and rejuvenation processes, one can adopt different strategies, as we have seen in prior examples. Prolonged fasters can use coffee enemas (may be a bit uncomfortable) to efficiently eliminate waste products from the bowels. The details of a good protocol are provided by Amanda Brocket [94].

              Daily cold showers and/or alternate hot/cold showers can also help tremendously. Cold showers could last for 5-10 minutes, depending on the level of cold adaptation of the experimenter, while hot/cold showers may last for up to 15 minutes. In hot/cold showers, one can alternate hot/cold water in a ratio of 2:1 (20 seconds cold, 10 seconds hot) or they can use hot water for the first 5 minutes and cold water for the remaining 5-10 minutes. Anyway you do it, please make sure your body can tolerate such stress. Consult your personal health care practitioner first.

              Luigi Cornaro, the fellow who subjected himself to life-long calorie restriction, Upton Sinclair and many others also made sure they got enough fresh air and sun exposure every day. Some of them slept with their windows wide-open at night, even in the winter time.

Do know that if your body has to increase thermogenesis (heat generation) to preserve its homeostatic core temperature, you may burn more energy in terms of kcals. In such situations it may be uncomfortable due to the mild or increased shivering thermogenesis, but once you get use to it, you know your internal engine can run smoother and cooler, with less inflammation, for a longer period of time.

              If you have to stay indoor for some reason, make sure you get some fresh air and direct exposure to sun light (predominantly in the morning) by opening the windows. It will not help if you stay by the window and the window is closed because beneficial UVB (Ultraviolet B) radiation does not seem to efficiently penetrate glass [95]. Sunlight is critical for many metabolic processes as it allows the production of vitamin D3 (which is considered a hormone); this does not mean it should be abused.

Refeeding after medium and long-term fasting

              From the wisdom of Upton Sinclair [42]:

"The one danger in the fasting treatment is that when you break the fast, hunger is apt to come back with a rush, while, on the other hand, the stomach is weak, and the utmost caution is needed."

              Before ending this part on longer-term fasting, I want to discuss some strategies of realimentation. First of all, it is of immense importance to always have in mind the way a long-term fast is gonna be broken. It is easier to break a 3-5 days fast and it can arose fewer complications (none - most of the time), but it requires thoughtful consideration to break a 10, 20, 30 day or even longer fast.

              From the experiences we have seen throughout this book, fasters have done realimentation with milk diets, orange juice, meats and meat broths, or even jumping back directly into their pre-fasting nutrition habits.

              From a practical and safer perspective, I would find juicing most appropriate. With juicing, the negative effects may be minimum or inexistent as it does not put burden over a fresh and rejuvenated digestive system which is about to restart its engines.

              In longer-term fasts, it would be safer to juice for the first two or three days and then gradually reintroduce solid foods in the routine: smaller and considerate amounts. And as we have seen, some folks still lose weight during realimentation.

              To give some personalization to the protocol, for those entering the fast with a ketogenic background, it would be nice to reenter alimentation in the same manner, and keep on with their ketogenic lifestyle.

As of such, I would recommend juicing on green vegetables and low-sugar foods instead of sugary fruits. Kale, brocolli, lemon, lime, avocado, and berries are only a few to mention. These are high-fiber low-starch-low-sugar foods which may feed the good bacteria from your gut.

              When one feels that their digestive tract is able to tolerate more solid, nutritious-rich-and-energy-rich foods, they could introduce olive oil to the green mix, coconut oil, coconut meat, nuts and seeds, and eventually the rest of the foods allowed on their dietary protocol.

              After 3-5 days of water-only fasting, it is easier, but still not without any risk, to break the fast more abruptly. Caution is necessary. It may be better to have the first 2-3 meals spread apart for at least 7-8 hours and use low-calorie keto-friendly foods like the ones mentioned above.

When I broke my 5-day fast I ate a small avocado mixed with some lemon juice from a freshly squeezed lemon. Then, after a couple of hours, I consumed some nuts (2-3 oz, 60-90g). That was it for the first day. The next day I resumed my keto-friendly nutrition protocol.

              I suggest (not only when breaking the fast, but as a general guideline) not consuming water at least 30 minutes prior, post, or during meals as this may burden the digestion process. This may be even more important as one starts refeeding after water-only fasting. You should consume water at your own disposal, but try not doing it around or during your meals.

              While I provided recommendations for breaking the fast the ketogenic way, this does not mean that I disregard other nutritional protocols, as long as they restrict the consumption of processed foods. If one follows a high-carb clean eating protocol (including fruits, whole-grains, sweet potatoes and others) they could break the fast with orange juice or other similar juices.

              Green vegetables would also come in hand into the mix. For longer fasts (7, 10, 20 days or even longer) one may juice for the first 2-3 days and then gradually and carefully add other foods (which do not require long digestion) to the strategy.

              Others consider appropriate that during re-feeding, good dietary practices should be no less than half the length of the fast [92]. In basic translation, if one fasts for 20 days, they should be very careful of the re-feeding process during the first 10 days after the fast is broken. That is a safe approach, but it does not have to be so rigid.

              One should observe how the body responds to food, and keep experimenting and adapting the tactic. Of course, it would not be wise to break a 10-day water-only fast with a copious meal of beef, sweet potatoes, bread and some red wine. While some folks could thrive doing that, many may experience negative consequences such as digestive system disturbances. And we have seen what can happen if a person suffers from a certain disease and are not careful in the realimentation phase (even death can occur - see the examples from the mid 1900s [44]).

              As a general guideline, I would suggest not going overboard with protein consumption (especially from meat, beans, soy and/or other complex foods) as it may prolong and harden the digestion process. Not going overboard does not mean one should avoid them; just be cautious.

              For the individual who wants to fast for rejuvenation, improved health, inflammation reduction, and overall a good health condition, 3-7 day fasts would be very appropriate. Some of them may not require medical supervision, but all of them should require some kind of supervision.

              If you decide to do this type of protocol, let someone close to you know about what you are about to do. You will have someone to talk to as the experiment goes along, aside that you'll be much safer compared to keeping everything for yourself.

              For longer-term fasts, I would strongly suggest being under medical supervision, most critically if you are in a diseased condition. Some folks may require strict supervision in a clinic that is specialized on therapeutic fasting. There are many throughout the world. One example is Buchinger-Wilhelmi in Europe, while two others are TrueNorth Health Center and Dr. Cinque's Health Retreat in the U.S. [91, 92, 93].

Intermittent Fasting - Some basic, very important, information

              Intermittent fasting and/or intermittent energy restriction (IF/IER) have only become popular, from what I know, in the last couple of years. Some of their recent popularity may be attributed to the books and programs written about the alternate-day diet, the every-other-day diet, the 5:2 diet, etc. Some of them are feasible, practical and extremely helpful, while some others may not be so.

              For example, while it may be healthy-wise to reduce caloric intake to ~500-600 kcals/day for 2 days a week, which is the basic idea behind the 5:2 dietary protocol, many folks may go overboard the other 5 days. Plus, it also depends on the quality of the food you are eating.

              Plus, molecular magic may only happen during water-only fasting for 3+ days and/or longer-term daily intermittent fasting of at least 16, 18 or 20 hours of fast, which over the long-run will naturally bring caloric restriction along, because it would be unnatural to force food down your throat in your 4, 6 or 8 hour refeeding window.

              In any case, most of the protocols that I mentioned above may invariably bring far more benefits to one's wellbeing compared to eating regularly and normally every day (which I consider we are not yet adapted for).

              Studies of IF/IER on animal models have shown to forestall and even reverse diseases like cardiovascular disease, various forms of cancers, neurodegenerative diseases, as well as diabetes. These diseases have been studied with a high interest mostly because of their prevalence in the population. However, fasting strategies may prove helpful for many other poor conditions of health, mostly because of their integrative effect on the whole body. As many more successful studies are conducted on animal models, many more may be adopted for human experiments [6].

              Mattson et al. (2014) [6] remind us how IF can increase antioxidant enzyme levels in mice muscle cells, observation which is augmented with exercise. Other studies show how IF elicits neuroprotective effects in animal models suffering from Alzheimer's and Parkinson Diseases [96].

              Moreover, recent studies (2014) show how IF/IER can boost brain health by increasing the production of BDNF (Brain Derived Neurotrophic Factor) leading to new neuron formation (neurogenesis), better survival of existing neurons, and strengthening of synapses [97].

              Even if I am not a huge fan of the 5:2 diet (5 days eating normally, 2 days restricting food to 500-600 kcals/day), its adopters experience better insulin sensitivity, lower insulin and leptin levels, better usage of fatty acids, higher ketone levels, as well as reduced IGF-1 levels. IGF-1 is the short for insulin-like growth factor which works together with insulin and often with mTOR (mammalian target of rapamycin) to regulate hypertrophy (cell/tissue proliferation) [98, 99, 100, 101].

              While some bodybuilders would want to increase the activity of insulin, IGF-1, and mTOR for increased muscle mass, the same pathways have been shown to be increased in cancer cell proliferation. In my opinion, there is not one single way to increase muscle mass.

              Recall the prior studies where I showed you how growth hormone levels can increase 10-20 fold (or even greater) in prolonged fasting, as well as in intermittent fasting (more than 18-20 hours). I will try to fine tune these mechanisms in further chapters, as well as in my n=1 prolonged intermittent fasting protocol.

              Intermittent fasting can be done in various ways. To generate a fasting window of 18 hours, I eat twice a day: 1 big breakfast around 8-10 A.M. and a small, but energy rich, snack around 2-3 P.M. If I stop consuming food from 3 P.M. until the next morning at 9 A.M., it means I fasted for 18 hours and I will re-feed (twice) in the remaining 6 hour window. There are many variations to this, depending on the approach that would be best for the individual.

              Less experienced fasters can do a 12/12 feeding/fasting cycle, having 2 meals a day: one early in the morning at 6 A.M. and another one in the early evening at 6 P.M. I would assume that any protocol of fasting for more than 12 hours is far better than a regular template of 3 meals/day with or without snacks.

              Some youngsters do daily intermittent fasting for 20-30 days, 2 months, 6-8 months or for even longer and they experience significant fat loss together with increasing their size and definition of muscle mass [102, 103, 104]. These folks also use strength training and/or calisthenics (body weight exercises), a possible reason for their maximized results.

              Hugh Jackman (a.k.a. The Wolverine) does intermittent fasting by eating in an 8 hour window and fasting for 16 hours (from 6 P.M. to 10 A.M. the next day). He claims to consume a lot of protein and he trains for ~3 hours everyday. He also eats a lot of food in his 8 hour feeding window [105].

              Many people use IF differently. Some people have 4 hour feeding windows, when they stuff calories and increase blood sugar and insulin secretion tremendously (for a short period of time). Depending on the purpose, I find that it is nothing wrong with that.

              For folks who want to increase muscle mass using insulin, IGF-1, mTOR and their related pathways, it is a good way to approach it. Others have 6, 8, 10 or even 12 hour feeding windows, allowing for more moderate insulin secretion, more convenience, compliance, and satiety. Of course, the benefits differ from one protocol to another.

              One who replenishes (partially or totally) their glycogen stores during refeeding may not acquire tremendous benefits from intermittent fasting, mostly because they cannot efficiently tap into their fat stores, as they will not lower their insulin levels significantly.

              I, for example, have been doing intermittent fasting for 1 year and 3 months (at the current date and time) almost everyday. I usually fast for 16-18 hours and eat ketogenic-friendly foods in my feeding windows of 6-8 hours.

              Often times, I fast for more than 24 hours, usually when I travel or when I combine intermittent fasting with religious fasting. I consume 1,500-1,700 kcals/day on average; sometimes more, sometimes less. So, I calorically restrict, eat ketogenic foods, and do intermittent fasting at the same time. And I've never been more satisfied or compliant with any other dietary protocol so far.

              My strategy will be described further in this book. First, I have to talk about the molecular mechanism of intermittent and prolonged fasting, as well as their implications in disease mitigation, health perpetuation, increased quality of life, and extended life span.

Chapter 5

The Molecular Mechanisms of Fasting:

When Magic Happens at Cell Level and Below

What happens when your body is adapted to irregular feeding cycles and you significantly do the opposite?

What happens when your body expects sleep to emerge as natural light (the sun) goes down and that never occurs?

What happens when you think and feel that 4-6 hours of sleep per night is enough for you, when in the long-term it will lead to an accelerated degradation of your health?

              These are few of the critical questions that we raise when we talk about the circadian clock and the deep mismatch (circadian desynchrony) most of us live in today. As Mattson et al. (2014) point out [6]:

"The modern lifestyle perturbed the human circadian system in three primary ways: shift work, exposure to prolonged hours of artificial light, and erratic eating patterns."

              Add to that agriculture and the food processing industry and you have a good recipe for disaster. Nobody denies the benefits of technology and modern day life. But I think we've taken things to the extreme.

              Even though we are able to cure many diseases that 100 years ago would have killed many, and even though we have tremendously increased our lifespan over the last two centuries, what would have happened if we mitigated most of the costs (health-related) associated with modern life from the very beginning?

At this point you may be a bit confused. Please bear with me. Things will eventually clear up.

Basic Concepts of Circa Rhythms

              The human body, nowadays, mostly never experiences seasonality in terms of temperature. People living in colder climates have close to minimum exposure to low temperatures during winter due to their constant warm environments (cozy homes), due to commuting from one place to another in a warm car, due to less commuting, and due to warm clothing as well. They do not have to go hunting for their food and be exposed to cold for various hours in a row everyday. Food availability and the convenience of getting it have never been greater than today.

              The human body mostly never experiences the dose of daily light exposure with which it was accustomed to for so many generations. Living in big cities where sun light may be partially blocked by buildings, staying indoors many hours during the day, and staying late at night being exposed to artificial light from TVs, light bulbs, tablets, smartphones and other devices prevents sound circadian rhythmicity.

              And when you desynchronize your internal clock, when you are exposed to too much artificial light, when you are not exposed to stress coming from the environment (living in constant conditions 365 days a year), and when you sleep poorly, no wonder you are so vulnerable to many ailments.

When you consume food regularly everyday and when you do not sleep enough, your body mostly never goes into repair and maintenance mode, mainly because it has to focus on food digestion; hence the higher exposure to diseases; hence accelerated aging. I strongly think that eating frequently every day is not an optimal strategy.

              The explosion of technology and the wide availability of information has lead to total chaos. But it's never too late to put the pieces together and try to benefit from the wonders of high-tech and the comforts of modern-day life, while at the same time mitigating the bad effects and the risks that come in the same package.

              As I get deeper into research, as I analyze more data from good and bad research studies, and as I experiment with different strategies myself, I come to realize that an optimal human condition has much more to do than the regular advice to focus on diet and exercise that most experts promote.

              Dangerously simplified strategies of eating a certain way and exercising everyday, without doing a background analysis of the subject wanting to improve his/her lifestyle is one of the reasons most folks fall of the wagon. A personalized well-considered strategy may include thorough blood work, sleep improvement, circadian synchronization, reduced exposure to EMF (electro-magnetic-field) radiation, fasting, reduced artificial light exposure, and even genome analysis.

In this context, I would safely assume it matters little what you eat as long as you eat naturally, irregularly, and use these strategies along the way (including fasting). Of course, optimizing nutrition would provide increased benefits.

              This is a holistic approach that I discussed in a previous book T-(Rx) - The Testosterone Protocol [106]. I was able to increase my testosterone levels naturally with a strategy including a multitude of interventions. That way I mitigated the risks of unnaturally using hormone replacement therapies and/or steroid injections. What I'm trying to point out here is that personalized medicine is on its way to becoming very popular.

              General guidelines are having less impact and I would encourage you to stay away from anyone (friends, family, media, government, etc) who tries to paint a simplistic picture of optimal health. I would also encourage you not to take any of my words for granted, but learn how to critically read studies, learn to discern from good and bad studies, and read as many of them so that you generate a more complex picture of optimal human condition. Many books may be biased.

              To better understand the molecular mechanisms of fasting, one may have to get a good grasp on circadian rhythms. As I mentioned earlier, the circadian cycle encompasses biologic processes that take place with a 24-hour periodicity. Evolution has fine-tuned the human body for daily exposure to light and nightly exposure to dark. Metabolic processes in the body are tightly correlated to circadian rhythmicity.

              Many hormones are secreted in a daily cyclical pattern. For example, in healthy people, cortisol levels are higher in the morning and gradually decreases throughout the day [107]. Testosterone levels usually peak between 8-10 A.M., while melatonin increases in the evening in the absence of light, preparing the body for sleep (repair and maintenance). Various biochemical processes in the human body are regulated in this fashion. But what happens when you're exposed to artificial light at night and, on top of that, you consume food right before going to sleep?

              One possible answer is that light exposure destroys melatonin production which disrupts the circadian cycle as it confuses the suprachiasmatic nucleus (SCN) inside your brain. SCN has been considered the master controller of circadian rhythms in mammals [108, 109]. Food consumption will make your body focus on digesting it instead of repairing damaged protein inside your body, building new cells, organizing memories, and doing maintenance work. This is a very simplified scenario as the picture and its implications are far more complex.

              The oscillation of the suprachiasmatic nucleus (SCN) is not exactly 24 hours, which is why it needs to be entrained to external light/dark cycles so that it remains synchronized. Factors that entrain the clock are called zeitgebers. One of the most potent is light, as it enters the retina and its signal is transmitted to the SCN. Other factors entraining the circadian clock are food and/or feeding cycles [119].

              Here's an insightful illustration of the circadian clock [110]:

              These findings are heavily backed-up by research studies from the past few decades. Currently, there is an ever growing attention on the mechanisms of the circadian clock and their health implications in humans and other life forms. Sadly, the public is mostly unaware of the importance of circadian rhythms. Hence, many of us live in mismatched conditions, as I explained above.

              Genetically modified animal models (mice) have exposed a certain correlation between metabolic disorders and the circadian clock [112]. Researchers have mutated and/or knocked-out clock genes (genes regulating the circadian clock) in mice and have observed how these animals become hyperphagic (eat a lot) and obese and develop signs of the metabolic syndrome, such as increased leptin levels, hyperlipidemia, increased glucose levels, as well as hepatic steatosis (fatty liver) [113].

              Calorie restriction has the potential to reset a disrupted circadian clock, resulting in improved overall biochemistry, which in turn may increase life-span and the quality of life [114]. On the other hand, mice put on an intermittent energy restriction (IER/IF - alternate day) protocol even though they consume more food in their feeding days compared to mice that are fed continuously, they show better blood sugar management, improved cardiac function, improved neuronal function, as well as increased resistance to developing cancer [112].

              Improved cardiovascular output was observed in humans who did intermittent fasting [115]. According to Froy (2011), calorie restriction may reset circadian rhythms in the periphery (cells and tissue specific circadian rhythms) and in the SCN (in the brain), while intermittent fasting resets circadian rhythms in the periphery and has the potential to extend life span [112].

              In plants and animals there are two genes coding for the cryptochrome proteins CRY1 and CRY2. These proteins are sensitive to blue light and are components of the vast repository of the circadian clock.

              In recent studies of CRY knock-out models (genetically engineered animal models with absent CRY proteins), researchers observed induced circadian arrhythmicity (disruption of the circadian clock), which lead to a constant expression of inflammatory cytokines. Such a scenario is also possible in people who disturb their circadian clock, like those traveling across multiple time zones at once, shift-workers, and also people who stay up late at night and are exposed to increased artificial light.

              A constant level of chronic inflammation may eventually progress into full blown chronic diseases such as obesity, diabetes, and cancer [116, 117]. Yet again, intermittent fasting and calorie restriction have been shown to mitigate these negative effects [114]. Of course this does not give one free permission to constantly disrupt the circadian cycle and think that if they calorically restrict or fast intermittently, it will not have a negative impact on them.

              But on the other hand, it may provide one with powerful tools of keeping the clock synchronized as much as possible when traveling, when working in shifts or in other disturbing circumstances. For example, when I traveled across continents, from Romania to Thailand (5 hours difference) or from Romania to America (7 hours difference), I suffered minimal jet-lag, possibly because I fasted mostly throughout these trips.

              Conventional wisdom says that full recovery from jet-lag takes 1 day per every hour of time-zone difference. So it would have actually taken 5 days, respectively 7 days for me to fully recover from my travels. Yet, I was able to mitigate this pitfall with fasting. And of course, it's much more convenient and cheaper because food is expensive in airports; and it would be impractical to carry packaged-food with me all the time.

              Restricted feeding (RF) is another strategy very similar to intermittent fasting and refers to limiting the duration and the time of food availability without restricting calories. Animal models (mice) doing restricted feeding for 4 months express more robust circadian rhythmicity as well as lower levels of inflammatory markers (TNF-α, NFκB, IL-6, and others), concomitantly with increased levels of the anti-inflammatory cytokine IL-10 [118].

              For some, it may be easier to follow a restricted feeding or intermittent fasting protocol daily over the long term, without having to tap into caloric restriction. However, I think that in time, if the food consumed is of higher quality and less/not processed, both RF and IF will progressively and naturally include calorie restriction.

              Some researchers have also investigated the metabolic implications of circadian rhythms and obesity. According to Froy (2011), hormones such as insulin, glucagon, corticosterone, ghrelin, leptin, and adiponectin express circadian oscillation [119].

Leptin, for example, shows compelling circadian patterns in gene expression, with maximum levels during sleep [120]. Removing the adrenal glands or manipulating feeding times did not affect the rhythmic leptin secretion in rodents, but removal of the SCN did, marking a tight correlation between the SCN and circadian leptin secretion [121].

              In human studies, researchers observed lower leptin levels over 24 hours in obese subjects, possibly suggesting a role of disrupted circadian rhythms in leptin resistance and obesity [122].

              For folks not familiar with leptin and its action in the human body, you should know that leptin is a hormone secreted by your fat cells - affecting hunger and satiety. Its mechanism is similar to insulin and it is often mentioned in contexts regarding insulin resistance. Here's how it is supposed to work:

              Normal-weight subjects secrete leptin as a response to feeding. Leptin communicates with the hypothalamus telling your brain that it had enough food and that you should stop eating. In obese subjects, the adipose tissue releases more leptin and there is an inefficient communication between leptin and your brain, marking reduced leptin sensitivity (increased leptin resistance). Feeding cessation often occurs much later in obese subjects compared to lean subject, a mechanism that further promotes obesity.

              Animal models with destroyed leptin receptors and humans with genetic mutations affecting leptin activity have shown to exhibit early onset morbid obesity, hyperinsulinemia, hyperphagia, increased circulating glucose levels and other conditions associated with the metabolic syndrome [123, 124, 125, 126, 127]. Of course, these may be extreme cases, but my point is to show you the critical importance of normal circulating leptin levels and how they may be affected by disrupted circadian rhythms.

              Moreover, factors affecting the transport and the management of fatty acids (FATP1, ACS1, ADRP) are expressed diurnally (on a daily basis). Mice studies show that when they are activated (expressed) during nighttime (dark cycles), they lead to increased fatty acid uptake and higher adipogenesis [128]. Since mice are nice-feeder, it may be more challenging to extrapolate these findings to human studies.

              When the circadian rhythmicity of glucose metabolism is disrupted, it may lead to metabolic disorders, both in humans and rodents [129, 130, 131, 132, 133]. Some patients suffering from Type 2 Diabetes exhibit loss or non-functioning daily insulin secretion cycles and poor glucose tolerance [129]. I would suspect that constantly altering these cycles by consuming foods that increase glucose and insulin levels at inappropriate times of the day may contribute to the development of Type 2 Diabetes. After all, this condition is often induced by lifestyle.

              In one study, healthy subjects had to move their last meal from 19-20 P.M. to 23-24 P.M. (midnight). After a period of 3 weeks, the overall daily glucose levels and insulin secretion increased significantly, marking a correlation between feeding cycles, circadian rhythms, and glucose and insulin secretion [134]. Subsequently, sleeping less than 6 hours or more than 9 hours per night has been associated with increased risk of developing poor glucose tolerance and T2D [135].

              These studies suggest that we should not interfere with our circadian adapted metabolism, which has been polished and perfected over the thousands of generations of hominids on Earth. Constant exposure to artificial light, reduced sleep, and feeding at night may disrupt the processes involved in homeostasis and may actively participate in the development of diseased conditions.

              Conversely, overnight fasting, restricted feeding, irregular feeding cycles, calorie restriction and a combination between these strategies may promote better preservation of health, a greater focus on healing and maintenance processes, increased lifespan, and healthier aging. This is what I delve into in the next section.

When Food is not the Primary Focus

              As I previously explained, there is an increased ability of the human body to repair and rejuvenate itself when digestion is not its main preoccupation. For some people it could take a couple of hours for these mechanisms to kick-in, while for others it could take much more than that. Peristaltic movements, bowel discharge rapidity, glycogen depletion, and the current health status of the individual in discussion are only few of the contributory factors.

              One of the powerful players in the equation of rejuvenation that I'm going to focus on is AMPk (Adenosine Monophosphate-Activated Protein Kinase). From its name we find out that it is an enzyme activated by AMP (Adenosine Monophosphate), which is often the byproduct of ATP or ADP hydrolysis (these are involved in energy metabolism).

              AMPk is like an energy sensor inside the cells and one of its main purposes is to restore energy balance, whenever energy levels follow descending trends, such as in fasting regimens [136, 137]. AMPk partially works by modulating SIRT1 activity and NAD+ levels [114]. It is present in many tissues, including the brain, the liver, and the muscles.

              When AMPk is activated it stimulates the oxidation of fatty acids in the liver, it increases ketone production, it lowers cholesterol synthesis and TAG synthesis, it may inhibit both adipose tissue lipolysis and lipogenesis, it stimulates the oxidation of fatty acids inside the muscles, it may stimulate glucose uptake by the muscles and it can also modulate insulin secretion in the pancreas [138].

              Additionally to its intracellular and intercellular roles, AMPk is partially responsible to whole body energy metabolism as it regulates how the brain responds to feeding in the hypothalamus [136]. Insulin, leptin, and ghrelin seem to have a direct activity on AMPk activation/suppression in the hypothalamus. In healthy individuals, when insulin and leptin efficiently signal the hypothalamus to stop feeding, AMPk is suppressed as there is enough energy for a certain period of time to supply body demands. During fasting, AMPk activity is increased in the hypothalamus and it seems to be partially activated by ghrelin.

              AMPk is also thought to have implications with the circadian clock. As you've seen, the master clock in the brain (SCN) is entrained by light while peripheral (cell and tissue specific) clocks can be entrained by food availability. In mice fibroblasts, AMPk was seen to destabilize CRY1 (component of the circadian clock), altering their circadian rhythms [139]. While these results appear interesting, it would be challenging to see their resemblance in human studies who, unlike mice, are diurnal beings and it would also be interesting to observe the involvement of the SCN in this mechanism.

              According to Froy (2011), the modulation of three clock-related pathways (AMPk activation, mTOR inhibition, and SIRT1 activation) leads to increased longevity [112]. In his statement, Froy mentions AMPk activation by metformin in mice, mTOR inhibition by rapamycin in mice, and SIRT1 activation in metazoans (multi-cellular animals) [140, 141, 142]. Even though this may be trivial (to a certain extent) other studies (including humans) have lead to similar conclusions. I've mentioned the ones above to serve as a starting point of research on one hand, and because they have been widely cited, on the other hand.

To me, studying AMPk activation along with the activation/suppression of other pathways in the context of restricted feeding/fasting appears provocative. While AMPk can be activated by muscle contraction (ATP usage and AMP buildup, increasing AMP:ATP ratio), we have to be very careful in understanding every context in which it happens, so that the most beneficial conclusions can be withdrawn [143, 144, 145].

As brilliantly put by Adel Moussa (a.k.a. Prof. Dr. Andro from Suppversity.com), when mTOR (pathway partially responsible for growth processes) is constantly elevated and AMPk is constantly suppressed (i.e., usual feeding patterns of multiple meals/day everyday, and markedly elevated when consuming a lot of protein), repair and maintenance processes cannot occur for multiple reasons [146].

              On one hand, elevated mTOR leads to increased growth processes. When cells divide at an accelerated pace and AMPk cannot control this process efficiently, DNA mutations are likely to occur.

              Some DNA mutations will have no negative effect on the body, while other DNA mutations can lead to cells with defective apoptosis mechanisms. Apoptosis refers to triggered cell death (cell suicidal). When cells are mutated and they cannot undergo apoptosis, they may further replicate themselves, eventually leading to cancer growth. Inhibiting mTOR and activating AMPk can activate OGG1, which is an important enzyme in DNA repair mechanisms [147, 148].

              Similar results were recently (Feb. 2015) published in a reputable journal. Researchers targeted the inhibition of thyroid cancer cell growth using OSU-53 (dual AMPk activator/mTOR inhibitor) [149]. They concluded that:

"OSU-53, a novel dual AMPK activator/mTOR inhibitor, effectively inhibits growth in a variety of thyroid cancer cell lines, and is most potent in cells with activating mutations in RAS or BRAF." [149]

              Moreover, AMPk may make cancerous and defective cells to initiate apoptosis (programmed cell death), so further inappropriate growth does not occur [150]. In C. elegans (the small worm), reducing glucose intake promotes increased lifespan through the activation of a histone deacetylase and a homolog of AMPk [151].

Other studies have shown a powerful correlation between AMPk activation and carbohydrate intake, such as that higher carbohydrate intake leads to lower AMPk activity, regardless of the caloric intake [152, 153, 154]. Dr. Colin Champ, who works in radiation oncology, provided insights about this correlation in his presentation at UPMC in 2014 [155].

In this case, AMPk may not be perceived solely as an energy sensing molecule, and it should not be. It seems to be correlated with carbohydrate intake no matter the amount of calories consumed. In some studies observing patients on ketogenic diets (very low carbohydrate, high fat, moderate to low protein) AMPk was seen to be increased, regardless of the amount of calories consumed by the subjects [156, 157]. To support this correlation, Hawley and colleagues (2006) observed increasing AMPk levels as glycogen stores become depleted [158].

One of my assumptions is that carbohydrate intake may impact mTOR pathway, which is also affected by protein intake. However, the bigger picture may be far more complex than just activating or deactivating these pathways. As suggested by Moussa [146], AMPk activation may help:

- for fat to be used as major metabolic substrate,

- reduce the formation of new adipose tissue by preventing the differentiation of fat cells,

- increase the buildup of mitochondria,

- muscles take-up more glucose,

- suppress glucose synthesis in the liver,

              In terms of other possible benefits, Culmsee et al. (2001) observed highly expressed AMPk in the developing rat brain. They also mention how AMPk promotes neuronal survival after glucose deprivation [159], while other researchers point out how AMPk may control the aging process by stimulating FOXO/DAF-16, Nrf2/SKN-1, and SIRT1 signaling, which improve the stress resistance of cells and lower inflammatory responses [160].

              Being involved in similar processes to AMPk, Sirtuin 1 (SIRT1) is part of the 7 mammalian orthologs (1 – 7) of Sir2 in yeasts. In lower organisms such as yeasts, worms, and flies (animal models), Sir2 was suggested to participate in the molecular connections between energy restriction and longevity [161].

              As pointed out by Froy and Miskin (2010), SIRT1 may also link the metabolism with the circadian clock due to their observed transcriptional silencing potential and genome stability seen in yeast [114]. The authors consider that:

“Sir2 or its ortholog enzymes are involved in life span extension and the response to caloric restriction in yeast, Caenorhabditis elegans, Drosophila and mice.”

              As explained earlier, when AMPk is activated, it is thought to enhance SIRT1 activity because it may increase the levels of NAD+ inside the cell leading to the deacetylation of its targets [114]:

“Thus, the levels of NAD+ together with the cycling of SIRT1 can determine the activity and robustness of clock gene transcription at least in cultured cells."

To support the claim that Sir2 has anti-aging effects, some studies found that using resveratrol (which activates SIRT1) leads to increased SIRT1 activity and may extend lifespan in various species, same as caloric restriction does [162, 142].

Resveratrol is found in red wine. Think about increasing your lifespan using both strategies, consuming some red wine and doing caloric restriction through a high-fat diet (without ever feeling restricted). One may increase the activity of these potentially powerful factors AMPk, SIRT1, and others while reducing the number of mutations that may come from an increased mTOR activity.

Increasing Healthy Life Span – From Animal Models to Humans

              One of the papers that I want to delve into was published in 2010 and has been written by two of the contemporary researchers that I appreciate tremendously with regards to healthy aging and increasing life-span.

              We all know and hear in the media about the amazing pills and products made to magically increase your longevity. Sadly, it is not as easy as that. Any reasonable human being should be smart enough to know that there is not one single thing (i.e. drug, herb, etc) to have a holistic effect on the entire human metabolism. As we’ve seen so far, everything is amazingly complex; adopting multiple interventions would be a safer and sane approach.

              If caloric restriction was proven to increase longevity and promote healthy aging in many study models, even in humans, it would be of no use if it makes one feel miserable.

              I would personally not give a damn about caloric restriction if I’d feel deprived of food and hungry all the time. Luckily, I am able to efficiently combine a ketogenic diet with caloric restriction and mitigate many of the pitfalls often associated with energy restriction. Plus, I do intermittent fasting everyday and I sometimes use prolonged fasting as means to improve my health status and possibly increase my lifespan.

              It would pay nothing if I fast or restrict calorically and lose muscle mass. But I mostly mitigate these effects by lifting heavy weights. And I’m breaking personal records following this strategy, paradoxically.

But more details on my entire strategy will be revealed in a subsequent chapter. For now, we’ll stick to these molecular mechanisms of fasting by investigating some recent research on the topic.

              In the paper I mentioned above, Longo and colleagues (2010) analyze some of the metabolic changes observed in model organisms from yeast to humans when it comes to energy restriction and healthy life span expansion [163]. The paper was cited 883 times (as of March 2015).

              According to the researchers, many of the mutations observed to increase life span reduce the activity of insulin, IGF-1, and mTOR pathways. Nothing new so far. They also suggest that such scenario can induce a possible physiologic state much like the one resulting from periods of food shortage. To generate the same effects without having to mutate DNA, Longo et al. (2010) suggest reducing glucose consumption, as well as protein and fat consumption [163].

              This would be something similar to the strategy promoted by Thomas Seyfried [3, 111] in his view of cancer as metabolic disease, and not genetic disease. Seyfried advocates for a low calorie ketogenic diet. Why low calorie? You’ve seen the potential molecular and cellular advantages that arise when food is not provided abundantly and constantly. Why ketogenic? Because it may lead to increased compliance, it may drastically suppress hunger, and if it is well designed, it may provide the subject all the daily required nutrients (vitamins, minerals, micronutrients, etc).

              Getting back to the paper of Longo and his colleagues from 2010, let us see the life-span increase and the potential health benefits through dietary restriction and through mutations/drugs observed in model organisms [163].

              Dietary restriction increases the life-span of yeast 3 fold, while mutations/drugs in combination with dietary restriction or starvation increases it 10 fold. The beneficial health effects of dietary restriction in yeasts show how these organisms extend their reproductive period, while mutations/drugs extend their reproductive period, and decrease the rate of DNA damage [163]. By using drugs or inducing genetic mutations, researchers maximize the activity of genes that promote longevity.

              One of the explanations that I hear from many of my friends getting married and having children in their early twenties is that they don’t want to be old when their kids are in their teens. They want to be able to play with them and feel like they can be on the same page (like going out or some other activities that would imply a certain level of youthfulness in parents). Nothing wrong with that.

              I, for some reason, may have children in my 30s or 40s. I cannot know for sure now. But what I may be certain is that if I’m able to reach old age, I want to be involved in activities that imply the level of fitness mentioned above. I want to grow younger and not older when it comes to physical performance. Some of my cheapest and safest interventions so far are food restriction and fasting. Others that are yet to come may involve the use technology.

So, my philosophy is that I want to reach my 60s with a vibrant health status and I want to reach my 90s still being able to actively play with my grandchildren and grand-grand and so on. If Luigi Cornaro was vigorously healthy in his 90s about 600 years ago, it would be a pity that modern humans cannot do the same, if it takes so little investment. Moving on to the next model organisms, C. elegans.

Dietary restriction increases the life-span of worms 2-3 fold, while mutations/drugs can increase it 10 fold. The beneficial health effects of dietary restriction in worms include increased resistance to mis-expressed toxic proteins, while the beneficial health effects of using mutations/drugs include: extended motility, resistance to mis-expressed proteins and germ-line cancers [163].

In Drosophila, the fruit fly, dietary restriction leads to a 2 fold increase in life span, while mutations/drugs can increase their life span 60-70%. According to Longo and colleagues (2010), there have not been any reported benefits in terms of healthy aging when using dietary restriction in fruit flies. They just lived longer. On the other hand, when using mutations/drugs, fruit flies became more resistant to bacterial infections and they extended their ability to fly [163].

In mice, dietary restriction leads to 30-50% increase in life span, while mutations/drugs can increase their lifespan 100% (double their life span) when they are combined with dietary restriction. In terms of health benefits from dietary restriction, mice develop increased protection against cancer, autoimmune disease, diabetes, atherosclerosis, kidney disease, neurodegenerative diseases, and others.

When using mutations/drugs to increase mice life span, researchers noted a reduction in the incidence of tumors (one of the reasons could be the reduced activity of IGF-1, insulin, and mTOR pathways), increased protection against age-related cognitive decline, protection against developing fatty liver disease, renal lesions, cardiomyopathy, as well as higher insulin sensitivity.

As we get closer to more complex organisms, it becomes more difficult to conduct longevity studies mostly because they take much longer compared to studies done on organisms such as yeasts, flies, worms, and mice. That may be one of the reasons why it is not currently easy to derive strong conclusions on longevity studies done on monkeys or even humans. But there is data, and some trends can be noted.

Longo and colleagues (2010) are reserved when categorizing and listing some of these insights. They have seen similar trends in the increase of monkey life span to the ones seen in lower organisms when it comes to dietary restriction. They have not tested life span increase in monkeys with mutations/drugs.

When analyzing the beneficial health effects that come along with dietary restriction in monkeys, researchers observed increased prevention of obesity and protection against diabetes, cardiovascular disease and cancer [163].

In terms of increased life span in humans, researchers did not determine its correlation with dietary restriction. But they point out the beneficial health effects that may come along with dietary restriction, such as: increased prevention of obesity, decreased risk for developing diabetes, hypertension, cardiovascular disease and cancer. When it comes to mutations/drugs, some people deficient in human growth hormone receptor were seen to reach old age and possible reduce their prevalence of cancer and diabetes [163].

             Now let me get into the more specific molecular details of these adaptations/changes seen in model organisms and humans when it comes to increasing healthy life span through dietary restriction and/or mutations/drugs.

              Deletion of SCH9 and deletion or inhibition of TOR1 (both being amino-acid sensing pathways), increases the chronological and replicative life-span several fold in yeast [164, 165, 166, 167]. Longo and colleagues (2010) consider that altering protein synthesis is a powerful mechanism implicated in extending replicative life span (period of reproduction) as it reduces TOR/Sch9 activity, which may also pay an important contribution to life span extension.

              In humans, reproductive life is the period of years when it is most appropriate physiologically to reproduce. That period is usually around midlife, when hormone production and health status should be at their optimal levels (unfortunately, it is not the case for most people nowadays). Extending reproductive life would allow for people to successfully reproduce at older ages and it may most likely be correlated with a vibrant health status as well. It would be unreasonable to have offspring in your 70s and die in your 80s.

              In our yeast models, another important pathway refers to 3 proteins, Ras, AC, and PKA. Activating Msn2 and Msn4, which are transcription factors involved in cellular protection, leads to lower Ras-AC-PKA which may increase both chronologic and replicative lifespan. How these findings translate into other models and humans is still uncertain, but we have to start somewhere.

              In C. elegans, the small worm, reducing insulin activity and IGF1 signaling (often referred as the IIS pathway) leads to increased life span. This trend was also noted in other multi-cellular organisms. According to Longo et al. (2010) [164]:

"This life-span increase requires the Forkhead FoxO transcription factor daf-16, which regulates genes involved in a wide range of defensive activities including cellular stress response, antimicrobial activity, and detoxification of xenobiotics and free radicals. As in yeast, overexpression of the antioxidant SOD-1 causes only a minor extension in life span [168]".

              Reducing the activity of IIS also requires heat shock factor hsf-1, which was considered to increase lifespan on its own by regulating how heat shock proteins express [168]. Interestingly, heat shock protein activity is also increased in cold thermogenesis (CT). CT refers to the exposure to cold temperatures and environments which increases the uncoupled metabolism leading to heat generation and higher fatty acid utilization, among others.

              Researchers have pointed out a connection between TOR and IIS pathways, suggesting that a reduction of TOR may lead to increased life span in C. elegans, same as in yeasts [164]. For those who do not know, TOR (target of rapamycin) and mTOR (mammalian target of rapamycin) are ortholog pathways (with similar or identical functions across species). Increased survival requires autophagy (digestion of cell components) and autophagy is inhibited by TOR and mTOR, which often promotes hypertrophy in combination with other factors. Unregulated or poorly regulated growth may lead to increased DNA mutation rate, increased DNA damage, and often proliferation of cancerous cells.

              When inhibiting mTOR in mice by administering rapamycin or by deleting S6K1 (a ribosomal protein kinase), researchers observed increased life span along with a reduction of age-related disease, such as motor, immune, and bone dysfunction and insulin resistance. Treating mice with resveratrol also lead to similar effects as those seen in dietary restriction, most of them resulting in lower morbidity rates and protection against morbidity [169].

              In their extensive review, Longo and colleagues (2010) remind us of a study that shows how fasting may protect mice against high-doses of chemotherapy by reducing the IGF1 pathway, but it does not protect cancer cells "in which the constitutive activity of pro-aging pathways (oncogenes) blocks the activation of stress resistance in response to nutrient deprivation" [164, 170].

              Optimizing nutrition when reducing energy intake by caloric restriction, intermittent fasting and/or prolonged fasting is crucial because a poorly formulated low-calorie protocol may lead, as pointed out by researchers, to impaired wound healing, increased susceptibility to bacterial and viral infections, as well as reduced immunity, along with other multiple downsides [171, 172].  

              Moving up the chain of life, "many metabolic, hormonal, and structural adaptations in dietary-restricted rodents, including a major reduction in body fat mass, higher insulin sensitivity, and reduced inflammation and oxidative damage, were also observed in dietary-restricted monkeys" [164, 173].

              In human studies, dietary restriction was seen to provide markedly increased and sustained health benefits against conditions such as diabetes, inflammation, insulin resistance, oxidative stress, and others. These findings align with the functional and metabolic changes seen in dietary-restricted rodents, possibly suggesting that manipulation of other pathways (done in mice, not yet in humans) may lead to similar advantages [164].

              In the last part of their review, Longo et al. (2010) specify that [164]:

"...dietary restriction in humans induces some of the hormonal adaptations observed in dietary-restricted rodents (e.g., increased adiponectin and reduction in triiodothyronine, testosterone, and insulin) and reduced cholesterol, C-reactive protein, blood pressure, and intima-media thickness of the carotid arteries, all risk factors for cardiovascular disease." [174, 175].

              Even though there are many metabolic similarities across species, it would be dangerous to assume that what works for mice may automatically work for humans.

              As pointed out by researchers, dietary restriction was seen to decrease IGF1 activity in rodents (by 30-40%), "but does not reduce total and free IGF-1 levels in healthy humans, unless protein intake is also reduced. These results indicate that a high protein diet is responsible for the different effect of DR in mice and humans and raise the possibility that protein restriction alone may provide some benefits." [164, 176].

              To see a different side of the spectrum, other researchers consider that low protein, high carbohydrate diets may be associated with increased lifespan, may delay age-related disorders, and may elicit an impact on aging biology [177].

              However, I am not too convinced of these findings mostly because they never considered using, or at least they do not show, what would happen if their interventions are observed on a well formulated very-low-carb-ketogenic-low-protein diet.

              Plus, the researcher acknowledges that his animal models were more corpulent (overweight) when following the high-carbohydrate protocol and from my research, I find compelling evidence correlating adiposity with inflammation (the starting point for many chronic and age related disease).

              A strong point of the research is that Simpson (2014) analyzes dozens of dietary protocol; yet it does not present findings in context of ketogenic low protein diets. What is interesting in his research is that animal models that were fed low protein high carb diets (ad libitum - whenever they wanted and how much they wanted) they consumed more food compared to animal fed higher protein diets [177].

              I suspect that lower protein intake (protein is very satiating) and higher insulin levels may have promoted increased hunger and increased energy intake. Going into the other extreme, consuming high-carb-high-protein diets would mostly lead to similar metabolic implications.

              In another study by Mattson et al. (2014), when autophagy undergoes, lysosomes degrade dysfunctional and damaged protein, organelles, and membranes. For this process to occur, energy intake and amino-acids (especially) have to be low. When organisms consume meals in regularly manner, cells remain in an anabolic mode, which suppresses autophagy [6]:

"The nutrient-responsive mTOR pathway negatively regulates autophagy. Accordingly, fasting inhibits the mTOR pathway and stimulates autophagy in cells of many tissues, including liver, kidney, and skeletal muscle. In this way, fasting “cleanses” cells of damaged molecules and organelles."

              Ignoring the many drawbacks from the research study of high-carb diets [177], especially the fact that AMPk would mostly not be activated, while mTOR, IGF1, and insulin would be activated, I believe several good insights can be taken because there's a lot of data that was processed and charted quite accurately [177].

              In light of these findings, from now on, I would pay a cautionary eye when extrapolating findings from studies across species. To generate a better understanding of the processes dictated at molecular levels in fasting, energy restriction and similar situations, I would like to observe how AMPk and SIRT1 work together in metabolic tissues.

Interplay between SIRT1 and AMPk

              Lower ATP levels increase AMPk activation for the immediate purpose to restore energy balance. In a similar way, SIRT1 is activated when the energy status of the cell changes (from high to low) leading to the transcription of genes involved in the metabolic response to calorie restriction, fasting, starvation, stress and/or in similar situations [161].

              If ATP levels remain consistently low, AMPk may lead to the phosphorylation of transcription factors regulating gene expression [178], including, FoxO3 [179], PGC1-α [180], p300 [181], and HNF4 [182], many of which are also regulated by SIRT1 [161]. In calorie restricted rodents, SIRT1 was considered to be responsible for increased physical activity and also for the modulation of gene expression in the liver, muscles and white adipose tissue [183].

              As pointed out by Fulco and Sartorelli (2008), the overexpression of SIRT1 in transgenic mice leads to similar characteristics as in mice undergoing caloric restriction: "they are both leaner and metabolically more active, exhibit reduced blood cholesterol, insulin and fasted glucose levels." [161, 184].

              Both of these molecules (AMPk and SIRT1) can be activated by caloric restriction, fasting, starvation, resveratrol, exercise and even drugs like metformin and thiazolidinediones. Increased SIRT1 activity leads to higher mitochondrial biogenesis as well as oxidation of fatty acids by deacetylating and activating PGC1-α. To a certain extent it's logical that increased oxidation of fatty acids needs more mitochondrial support, which is why the observations. Through similar mechanisms, AMPk also increases the oxidation of fatty acids by phosphorylating ACC, MCAD, and PGC1-α [161].

              These mechanisms are so complex that it would be overly dangerous to try to simplify conclusion derived from them. As pointed out by Fulco and Sartorelli (2008), SIRT1 concentration in the liver is different in fasting compared to a calorically restricted context [161]. Remember, fasting implies lack of nutrients, while calorie restriction refers to reducing nutrient intake.

              Besides being activated by similar metabolic contexts (low glucose levels, exercise, caloric restriction, fasting, oxidative stress, and others), both SIRT1 and AMPk have common effects on longevity and the aging process. One of the primary important conclusions is that SIRT1 and AMPk are known to decrease their activity as organisms age. When C. elegans are being given additional copies of the AMPk gene, the small worms increase their life span [161].

              You may wonder how gene manipulation experiments are relevant. Such studies involve comparing genetically mutated models with models exhibiting the reference genome. In the case of C. elegans with extra AMPk copies, researchers only added these additional AMPk genes to the reference genome of these model organisms, and then they compared the results. Since most of these studies involve controlling for a single variable, they may be relevant to deriving strong insights from them. Yet, it is still questionable how such conclusions can be extrapolated or applied in higher order organisms, but it isa good starting point.

              Same as SIRT1, activated AMPk leads to increased PGC1-α and PPARα (perixosome proliferator activated receptor) expression, which promotes the transcription of genes for CPT1, FABP3 and ACO (carnitine palmitoyltransferase I, fatty acid binding protein 3, acyl-COA oxidase) all involved in mitochondrial fatty acid oxidation [161]. Increased AMPk activation, same as SIRT1, may lead to increased muscle mitochondrial biogenesis and increased endurance capabilities in mice, processes which involve PGC1-α and NRF1 (nuclear respiratory factor) [185, 186, 187, 188].

"Thus, it appears conceivable that SIRT1 and AMPK converge on PGC1-α mediated signaling to regulate lipid oxidation and mitochondrial biogenesis." [161].

              Even though there are similar factors activating both AMPk and SIRT1 and even though they display convergent regulatory functions, they also exhibit divergent regulatory processes. In the muscles, both of them seem to upregulate fatty acid oxidation, glucose uptake and mitochondrial biogenesis.

              However, divergent effects are seen when "considering hepatic glucose production in response to energy deprivation and in the insulin release from pancreatic β cells" [161]. This is why careful steps should be taken when considering administering activators (drugs) of both AMPk and SIRT1 pathways in people suffering from T2D. Fulco and Sartorelli (2008) also advise for the need of further studies to examine what happens when SIRT1 is chronically activated, "as recent reports have unveiled a pro-aging role of SIRT1 in the brain" [189].

              One possible solution would be to examine the activation of different factors downstream the AMPk and SIRT1 (and the rest of the sirtuins) activation cascades, such as manipulating NAD+ levels.

              In terms of drugs and/or dietary supplements, David Sinclair, well known researcher of the aging process and avid advocate of resveratrol as activator of SIRT1, says [190]:

"Resveratrol is not the cure all. In mice it had some good results and some bad results. It works better if the body is out of whack so if you try to treat disease such as heart attack...or obesity in mice it works very well but I think we can do better than that..."

              Sinclair (2014) acknowledges the many possible liabilities of resveratrol as an intervention factor, one of which being that it's very insoluble and barely absorbable. Further on [190]:

"You know, I'm taking it not because I think it's gonna make me live to 200 but maybe because I know what's gonna happen if I don't take it. I don't want to make the impression of anybody to think it's the best thing we have (resveratrol). In fact that's 10-year old technology. We have better things now...I think that the NAD+ approach that I mentioned is going to be superior..."

              Sinclair mentions the ability of some drugs targeting NAD+ to turn on the sirtuins family and to recover NAD+ levels in aged tissues and organisms back to younger levels [190]:

"The way we do it is that we have a molecule called NMN, which is a precursor of NAD+"

NMN -> NAD+ -> cellular reset

NMN = nicotinamide mononucleotide

              Injecting NMN into old mice leads to restoration of NAD levels. NAD (nicotinamide adenine dinucleotide) is involved in cellular metabolism and, most importantly, in redox (reduction-oxidation) reactions. It basically carries electrons from one reaction to another and it is found in two main forms: NADH (as a reducing agent - donator of electrons) and NAD+ (as an oxidizing agent - acceptor of electrons) [191].

              As pointed out by Sinclair (2014), when humans get older, NAD levels go down, same as the ability to protect our cells. When mice were given NMN, aspects of their aging were reversed in just one week. I suspect, it may take more than that in humans, if NMN elicits similar effects (which we may not know yet).

              Same as with telomere extension interventions, many have questioned whether NMN and/or NAD will promote cancer. Sinclair [191] reveals an experiment where they've given mice: drinking water vs. drinking water + NMN and wanted to see the effects on liver cancer:

"And if you just put NMN in the drinking water of these mice for a few months, you barely can see any tumor. So this is not a tumor promoting molecule at least in liver cancer."

              What I think it is amazing is that many of these brilliant researchers have developed a critical eye even for their own experiments. Quite a few of them do not stubbornly hold onto their beliefs as they understand the complexity of the nature of optimal health.

              Singularity University is one of the institutions that gathers such researchers to work together into solving the greater problems of humanity, among some of which are: space exploration, aging research, development of biotechnologies, eliminating world hunger and increasing water supply, and many others. It is a great place to investigate research on aging. And they have a ton of videos and recorded conferences available on their website and on their Youtube channel [192].

              What would be one of the simplest ways to leverage upon the benefits of AMPk and SIRT1 activation? I would safely say that through 16+ hours of intermittent fasting and/or a well formulated prolonged fasting protocol. In both cases, exercising may increase the activation cascade. Add a small glass of red dry wine if you break your intermittent fasting at night, and you may enhance the activity of SIRT1.

              Before getting into my n=1 of fasting, I want to investigate some more research studies conducted recently on fasting, IF, calorie and protein restriction from Longo, Mattson, Fontana, and other bright minds of the field.

Chapter 6

Recent Research in Fasting and Related Fields

Prolonged Juice Fasting (not the kind of protocol I'd follow)

              A good starting point would be to observe substrate oxidation in a 28 day prolonged fasting (juice fasting) experiment. In 2009, Steiniger and colleagues wanted to determine how the parameters of energy, carbohydrate, protein, and fat metabolism change over the course of 28 days in obese patients with or without training [194].

              The sample size of the study goes well beyond 100 subjects (obese adult men and women). Researchers tabulated their age, height, initial weight and initial BMI:

Adapted from Steiniger et al. (2009) [194]

              If I were to opinionate on this, I would say that endurance training may not be the best intervention in obese patients who fast, mainly, for weight loss. And the results of the study are not far from that. As noted by the supervisors of this experiment, endurance training lead to a certainly significant increase in body mass loss (12.2±3.2kg vs. 10.4±2.2 kg) and fat loss (8.1±1.6kg vs. 5.9±1.3kg) [194].

              Male subjects who did not do endurance training lost about 1kg of protein mass (~2.2 pounds) while female subjects not doing endurance training lost about 650g  (~1.43 pounds) of protein mass. Male subjects engaged in endurance training lost an additional ~130g of protein mass over the course of the entire period of 28 days [194].

              In a lunch lecture (you can hear the noise of forks and spoons on the dishes in the background) on Type 2 Diabetes and Insulin Toxicity presented in 2013, Dr. Jason Fung [197] talks about how alternate-day fasting may preserve lean mass by pointing out to a paper from 2010 [198]. From my perspective, the lecture is excellently presented, but the context is somewhat weird due to the ironic nature of talking about fasting to people who are currently gorging their meals.

              The subjects on this study were obese, and the protein loss would not matter for them as much as it does for leaner subjects, especially considering the great amount of fat they lost over the entire experiment.

              However, doing endurance training may not be the best intervention to go along with prolonged fasting, as it seem to slightly increase protein mass loss compared to not engaging in any type of exercising.

              I would speculate that doing resistance weight training may have reduced protein mass loss in both male and female subjects. In a similar study done on subjects doing 21-day juice fasting combined with endurance training, subjects had marked increase in power despite the reduction in body mass [195].

              In the subjects who fasted for 28 days, researchers selected two groups: n=95 included male and female subjects doing endurance training, and n=85 included male and female subjects not doing any type of training.

              They determined substrate oxidation in day 1 and day 28 of the juice fasting experiment [194]. Results were as follows (values are the average and are approximated):

Substrate utilization in day 1 and day 28 of a 28-day juice fasting Experiment. Adapted from Steiniger et al. (2009) [194]

              Substrate utilization was calculated in the lab in day 1 and day 28 when the subjects who did endurance training during the whole period of fasting had to be subjected to a 4-h ergometer at 30-40% of VO2max). Far from the optimal protocol that I would personally do in a prolonged fasting, this study did show some interesting results, especially the marked reduction in protein and carbohydrate utilization and the marked increase in fat utilization in fasting with or without endurance training.

              Another possible pitfall of this experiment is the fact that subjects consumed ~80g (~2.5 oz) of fruit juices, multivitamin products, vegetable broth and about 3L (~100 oz) of water every day, according to the Buchinger Clinics' fasting protocol. I see this as a pitfall because it may not induce total metabolic adaptation to ketosis as well as all the molecular changes and expression of repair mechanism discussed previously. While I see this as drawback, researchers consider it a well formulated approach (translated from German) [194]:

"The relatively high fluid intake per day corresponded not only to the general recommendations for the stabilization of the metabolic and cardiovascular systems during fasting, but from today's perspective it is also favorable and supportive for weight loss by inducing thermogenesis."

Moreover:

"Endurance training is an important, safe and necessary component of a 28-day Buchinger fasting therapy."

              I was not able to observe markers of compliance and the general state of wellbeing of these patients undergoing the therapy, but even though I see some downsides to their approach, Buchinger-Wilhelmi fasting clinics have housed more than 5,000 patients over the course of several decades until 1999 and who knows how many more ever since [195].

              In a similar Buchinger fasting (daily 200-500 kcals from fruits/fruit juices) experiment conducted in 2013, researchers recruited 30 female subjects and divided them in two groups, with or without metabolic syndrome (MetS) [196]. They were followed on a 7-day fast according to the Buchinger protocol which included a nutritional energy intake of about 300 kcals/day (not the best approach, from my perspective). They were also followed on a stepwise reintroduction of solid food over a 3 day period after the 7 day fast has ended. Subjects did not consume caffeine or alcohol during the fast and the realimentation period.

              The mean age was 49±8.1 years old, BMI was 30.4±6.7. The metabolic syndrome group included 12 patients, while the non-metabolic syndrome group included 18 patients. Markers of the metabolic syndrome that had to be satisfied were:

- abdominal adiposity ≥88 cm (that's probably waist circumference)

- low-HDL-C (≤50 mg/dl)

- high serum triglycerides (≥150mg/dl)

- high blood pressure (≥130/85 mm Hg)

- high fasting plasma glucose (≥110 mg/dl).

              As a result of the 7-day juice fasting experiment, researchers observed [196]:

- reduction in weight from 85.4±18.8 kg to 79.7±18.2 kg

- marked reduction in blood pressure (almost unanimously seen in fasting experiments)

- lower LDL-c levels

- lower leptin and insulin activity

- increase levels of resistin, adiponectin, and leptin receptors.

              They also noted [196]:

"Fasting-induced mood enhancement was reflected by decreased anxiety, depression, fatigue, and improved vigor. Patients with MetS showed some greater changes in BP, LDL-cholesterol, triglycerides, adiponectin, leptin, and sleep quality. Fasting was well-tolerated."

              The full results of this study are finely categorized and explained and they can be accessed by following the link at [197] in the references section. What I'm intrigued of is that even though the study does not meet my personal standards of a well formulated prolonged fasting experiment, it is an overall well conducted and highly-detailed study which has been cited only 3 times in the literature.

              One of the possible reasons for the unpopularity may be that it does not benefit from the exposure of studies published in highly trafficked journals, while another possible reason is that most subjects do not want to put themselves on a long-term fasting experiment because of their fear of hunger (which is a very understandable fear, but which can be reduced to minimum or eliminated completely).

Reducing Protein Consumption

              In a recent article published in 2014, Levine and colleagues marked the complexity of protein restriction in both humans and mice studies in the context of growth hormone receptor/IGF-1 deficiencies. They wanted to observe its impact on age related diseases. In the subjects who reported high protein intake (aged 50-65), there was a 75% (quite significant) increase in overall mortality and a 4-fold increase in death from cancer in the following 18 years [199].

              Respondents who were 65 years or older and reported consuming high-protein diets had a lower cancer and overall mortality. As pointed out by Levine and colleagues (2014) [199]:

"Mouse studies confirmed the effect of high protein intake and GHR-IGF-1 signaling on the incidence and progression of breast and melanoma tumors, but also the detrimental effects of a low protein diet in the very old."

              Their conclusion is that low protein intake during middle age and moderate-to-high protein intake in older age may lead to increased longevity and healthy aging. In a similar finding by Fontana and colleagues (2013), researchers conclude that reducing dietary protein is highly effective in the inhibition of tumor growth. The study was done on human xenografts (grafts of tissue) of prostate and breast cancer models and the researchers think that the possible mechanism by which reduced protein intake inhibits tumor growth is by lowering the activity of IGF/AKT/mTOR pathways [205].

              I would suspect that staying away from a high-protein diet in middle age (among other interventions) may mitigate the negative effects that appear in older adults (many of which may come from damaged protein and DNA, increased cellular waste, poor detoxification, and others) would increase healthy aging without necessarily needing to up the intake of protein in older adults. Though this mechanism may be much more complex than that.

              In a similar study from 2014, Cheng et al. studied various cultured cells and noted that prolonged fasting leads to lower IGF-1/PKA activity which in turn leads to increased stress resistance and regeneration. Further more [200]:

"Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients."

              In mice and in human studies, it was shown that fasting for 48 to 120 hours increases cellular resistance to toxins, as in the case of heavy dose chemotherapy. I'll get back to this concept farther in the book, but the basic idea of fasting for more than 24 hours leads to enhanced results is because of "the requirement to fully switch to a fat and ketone bodies based catabolism after glycogen reserves are depleted during prolonged fasting" [200].

              My suspicion, as previously illustrated, is that these molecular adaptations for cell repair and rejuvenation only happen some time post glycogen depletion. This is also why I believe the high-carb-high-protein theory presented by Simpson (2014) [177] falls short.

              Hu and colleagues (2014) also observed that alteration or deletion of TOR-Sch9 (protein sensing complex) in yeasts increases lifespan by their ability to rapidly deplete accumulated acetic acid, unlike wild-type cells [201]:

"These results indicate that Tor-Sch9 deficiency extends longevity by switching cells to an alternative metabolic mode, in which acetic acid can be utilized for the storage of stress resistance carbon sources. These effects are reminiscent of those described for ketone bodies in fasting mammals and raise the possibility that the lifespan extension caused by Tor-S6K inhibition may also involve analogous metabolic changes in higher eukaryotes."

              In support of these findings, Valter Longo, Professor at and Director of University of Southern California, has patented various inventions that would alleviate or treat conditions such as various cancers, Type 1 Diabetes, Type 2 Diabetes, and other conditions of the metabolic syndrome. Some of the interventions described in these inventions involve using fasting, fasting mimicking diets, refeeding protocols, calorie restriction, and others. Two of the inventions worth throwing an eye at are:

Induction of Differential Stress Resistance and Uses Thereof (2014) [202]

Fasting Condition as Dietary Treatment of Diabetes (2015) [203]

              An implication of the fasting mimicking diet can be seen in a recently published article on cancer therapy which, not to my surprise, is yet to be cited by any other piece of literature. Researchers created a fasting mimicking diet (FMD) and observed how it impacts carcinogenesis [204]:

"In a cohort of female C57Bl6 mice, bi-monthly 4 day FMD feeding cycles followed by normal food intake, significantly improved survival in mice without causing excessive weight loss. Mice in the FMD cohort had a significantly reduced lifelong cancer incidence rate."

              When comparing subjects from the FMD group with subjects fed ad libitum (how much they wanted and whenever they wanted), they noted that lymphoma (cancer of the immune system) affected ~67% of the subjects in the ad libitum (control) and ~40% of the subjects in the FMD group [204]. These are significant findings, especially because the fasting mimicking diet is supposed to elicit similar metabolic adaptations as prolonged water-only fasting does.

              Brandhorst et al. (2014) also found that the FMD intervention lead to a switch from higher metastasis (tumors in ≥3 organs) to tumors being present in 2 or less organs or not being present at all [204]:

"In summary, the periodic FMD cycles had a significant impact on the development of cancer while allowing the preservation of lean body mass and animal weight until old age and extending longevity."

The Molecular Mechanisms of Hormesis

              Setting aside (until later) studies involving cancer treatment and prevention in the context of healthy increased life-span, I would like to briefly introduce and devote a few words to the concept of hormesis.

              As defined by Mattson and Calabrese (2009), hormesis refers to exposing to lower doses of damaging factor for beneficial effects, which at higher doses would be damaging or even lethal. Others understand hormesis as the use of "beneficial stressors" [206].

              Some examples could be:

- using cold showers or cold therapy to boost the immune system (among others), while prolonged exposure to extreme cold may induce hypothermia and be lethal.

- ingesting small doses of toxic chemicals, from food or water.

- reducing energy availability (food scarcity)

- increasing short-term energy expenditure (fighting, sprinting)

- increasing cognitive challenges.

- etc [206].

              If used appropriately, all these stressors may lead to positive adaptive changes in the organism, some of which may include increased stress resistance and prolonged healthy lifespan.

              Life likes to be challenged even though it allures us with the comforts of stability and habitual existence. Life is perpetuated in disordered environments in which randomness is accentuated, while patterns are less prevalent. Such context increases alertness and boosts antifragility, a concept wonderfully explain in Taleb's 2012 Antifragile: Things that Gain from Disorder [207].

              It is one of the reasons for which I do not rigidly stick to everything that I do in my life. Even though I adopted a nutrient protocol that promotes long-term ketosis, I always experiment with different foods (that keep me in ketosis). To boost randomness into my life and to increase antifragility, I sometimes alter my 2 meals/day protocol to 3-6 meals/day, 1 meal/day, or no meal at all. I, most of the times, fast intermittently, but I do have days in which I do not restrict calories and do not do IF.

              There are days when I consume 4,000-5,000 kcals (still ketogenic). Even though I love cold thermogenesis, there are times when I take hot baths/showers. These are some of the very few interventions I use to keep myself away from a pattern-driven, ever boring, life. I may discuss about it in more detail in my n=1 part of the book, though I do not promise you that (it may be the subject of another book).

              Hormesis fits surprisingly well inside the concepts of antifragility and randomness [207]. Moreover, recent studies implicate hormesis in the epigenetic regulation of ROS (reactive oxygen species production) and the aging process [208]:

"Together with drugs such as the mTOR inhibitor rapamycin or inhibitors of the growth hormone-IGF-I axis, external stimuli that mimic those caused by mtROS have the potential to promote long-lasting protective states that delay aging and prevent diseases."

              The plethora of ill conditions associated with modern life may also point to the importance of using hormesis as a strategy of intervention. When one never challenges their body and their brain, complacency may be established, paving a neat, straight-forward, route to increased risks of injury and disease. Mattson and Calabrese (2009) affirm [206]:

"Lack of physical and mental exercise, in combination with excessive food intake, results in a condition called insulin resistance that is a harbinger of diabetes and cardiovascular disease."

              Challenging one's system by fasting, consuming fewer calories, and/or by other interventions will lead to mild metabolic stress and will allow the body to adapt, with the ultimate purpose of survival and reproduction (when viewed from an evolutionary perspective).

              Talking about mitigating the couch potato lifestyle, Mattson and Calabrese (2009) assert that restricting nutrition in combination with exercising may trigger a hormetic mechanism that can result in lower heart rate and blood pressure (which would logically increase lifespan, other factors considered optimal), increased gut motility (reducing risk of colon cancer), better insulin sensitivity, and other beneficial effects [206].

              Brilliantly highlighted by these authors is the underappreciated contribution of mental challenges to increased brain health [206]:

"Studies have shown that neurons respond to mental and physical activity by increasing their production of “neurotrophic factors” that may help them to resist disorders such as Alzheimer’s disease and Parkinson’s disease."

              A good example, though there may be many confounding variables, is the case of Irving Khan, investor, who was still going to work at age 104, keeping his mind sharp and busy everyday [209]. Irving's company handled ~$700 million in assets in 2010, so he's not your average very old grandpa. One of the motivations for his longevity, in his own words:

"To wake up in the morning and have something to look forward to."

              I know you may say that such statement is already overused, and you may be right. Given that it's widely overused, we tend to have forgotten its importance. To test that, try to recollect how many times you woke up recently with big enthusiasm and fired up for the day. Extra-credit goes for Monday mornings.

              Even though Irving recently passed away (Feb. 24, 2015) [210]:

"...he, his sisters, and his brother were, collectively, the world's oldest living quartet of siblings. Kahn himself lived to 109. His sister, Helen Reichert (1901–2011), nicknamed "Happy", died seven weeks before her 110th birthday. The youngest sibling, Peter Keane (1910–2014), died at the age of 103. Kahn's other sister, Lee (1903–2005), died at the age of 101."

              This may give you some clue about the genetic factors of longevity in this family of centenarians. Kahn himself smoked a lot during his lifetime, while his sister smoked for !!! 80 years. They also did notconsume a specificdietover the long term. These remarks would point out to the important factors regulating cellular detoxification and increased expression of repair and rejuvenation pathways. If you follow the links in the references section, you may find many other examples related to Khan's. Don't forget to always maintain a critical perspective!

              In another paper from 2014, Mattson [211] discusses how intermittent fasting improves one's health and wellbeing through various mechanisms. One is to induce the expression of chaperones (glucose-regulated protein and heat-shock protein) and increase autophagy inside the cells. Through autophagy, cells are able to dispose damage organelles and proteins, and, I suspect, they become better equipped to use smaller amounts of protein provided through food.

              As indicated by Mattson (2014), Masiero et al. (2009), Harvie et al. (2013) and other researchers as well, autophagy is required to preserve muscle mass when intermittent fasting protocols are implemented [211, 212, 213]. Moreover, IF lowers leptin levels and is able to increase adiponectin levels. And as Mattson (2014) suggests [211]:

"IF can also increase neurotrophic factor signaling in brain cells, which may contribute to its abilities to enhance hippocampal neurogenesis (Lee et al., 2002) and protect neurons against oxidative and metabolic stress in animal models of Parkinson’s disease (Duan and Mattson, 1999), Huntington’s disease (Duan et al., 2003), Alzheimer’s disease (Halagappa et al., 2007) and stroke."

              To trigger the beneficial hormetic mechanisms, Mattson proposes the use of energy restriction/fasting, running, and ingesting hormetic phytochemicals that may initiate mild cellular stress, further leading to the activation of chaperones, UCPs (uncoupling proteins), Mn-SOD (Manganese Superoxide Dismutase - antioxidant enzyme, trophic factors, APE1, PGC-1α, and other factors [211]. Increasing the activity of these factors inside the brain may lead to: more efficient cellular energy metabolism, lower oxidative stress, lower inflammation, and reduce DNA damage [211]. This translates to increased resistance to diseases and, I would also assume, it translates to healthier lifespan.

              The hormetic phytochemicals referenced by Mattson (2014) are: sulforaphanes (found in cruciferous vegetables), curcumin, resveratrol, and epicatechins (from dark chocolate and green tea). As we've previously seen, flavanoids such as resveratrol and epicatechins can act by increasing the activity of AMPk, AKT, and SIRT1 and by expressing increased neuroprotective effects against metabolic and oxidative stress [211]. No wonder my increased appetite for very dark chocolate and strong red dry wine.

              In a 2014 textbook on hormesis in health and disease, Rattan and Le Bourg agree that hormesis may be seen as "the mounting of a physiological defense at the cellular and tissue/organ level against a mild stress". They also agree that the longer any fasting protocol is implemented, as opposed to the average overnight fasting most of us do (and not do), the greater decrease in ROS (reactive oxygen species production) during energy substrate use [215].

              One of the mechanisms by which beta-oxidation (oxidation of fatty acids - primary energy production pathway promoted by fasting protocols where glycogen is depleted) lowers ROS production is that electron transfer bypasses complex I inside the mitochondria, as discussed by Guarente (2008) [216]. Rattan and Le Bourg (2014) also remind about fasting as a tool in cancer therapy (as we'll see later in the book) [215]:

"Fasting prior to cancer treatment has been recently trialed and there is evidence for a single episode of fasting (48–140 hours) to reduce side effects of chemotherapy."

              Even though they seem to have gotten their homework done appropriately, these authors empathize with hypocaloric low-fat diets. Given the importance of carefully selected healthy dietary fats in cellular health, mitigation of inflammation, gut health, brain health and in the many other positive effects in the organism, I'm a bit cautious when reading from their book. But overall, their title is a good reference to use when learning more about beneficial stressors.

              In a hormesis context, as pointed out by Rattan and Le Bourg (2014), periodic fasting is an intermittent energy substrate flux that alternates catabolism and anabolism. This may lead to higher SIRT1 activity that can (for the sake of repeating myself):

- increase antioxidant levels

- increase insulin sensitivity

- increase mitochondrial biogenesis

- increase HSP (heat shock proteins) activity.

Such mechanisms may lead to:

- lower oxidative damage

- increased cognitive function

- increase metabolic, functional and physical health

All of these can contribute to increased lifespan and healthspan [215].

              In a review article from March 2015, Mattson discusses the same three (earlier seen) major interventions for increase lifelong brain health, such as: fasting, exercise, and intellectual challenges [214]. Building on top of that and on my recently written ideas, our brains and our bodies live in predictable and boring environments, mostly never seen throughout the evolution of life on Earth.

              Intermittent fasting, interactive and interesting intellectual brain challenges, and strenuous/severe/demanding short-term workouts may be the injection of hormetic triggers required for the body to increase its resistance to stress (the hormetic cure).

Revisiting Obesity, Diabetes, and Inflammation

              Building on top of studies of intermittent fasting and improved brain health, Vasconcelos and colleagues (2014) observed rats that were put on an intermittent fasting protocol for 30 days and then administered 1 mg/kg of LPS (lipopolysaccharide - an endotoxin) or saline solution intravenously. They were randomly assigned to 4 groups: normal feeding with saline administration (Control), normal feeding with LPS administration (LPS), IF with saline (IF), and IF with LPS administration (IF+LPS) [217]. This was a well formulated distribution, if you ask me.

              Researchers reported that intermittent fasting alleviates cognitive deficits in a rat model of sepsis (infection-triggered inflammation) by activating NF-κB (regulator of the immune response to infection), lowers the expression of pro-inflammatory cytokines, simultaneously increasing neurotrophic support [217]. In their own words:

"IF also resulted in reduced levels of mRNAs encoding the LPS receptor TLR4 and inducible nitric oxide synthase (iNOS) in the hippocampus. Moreover, IF prevented LPS-induced elevation of IL-1α, IL-1β and TNF-α levels, and prevented the LPS-induced reduction of BDNF levels in the hippocampus. IF also significantly attenuated LPS-induced elevations of serum IL-1β, IFN-γ, RANTES, TNF-α and IL-6 level."

              From what I see, this means that IF lead to fewer genes being expressed to result in the creation of LPS receptors, needed for LPS to appropriately trigger damaging effects at cellular levels. Through an associated mechanism, IF prevented the increase of pro-inflammatory cytokines as well as the reduction of BDNF (factor responsible for neuronal growth). While this may not translate exactly in humans, it hints to a possible protective, anti-inflammatory effect that IF invariably has inside organisms.

              Harvie and colleagues (2013) conducted a type of randomized study that I was always curious to read about - intermittent fasting vs. daily calorie restriction. They followed 115 overweight women, aged 20 - 69 years. These women had a family history of breast cancer. Before analyzing the findings, I would like to assert that a possible drawback of the study is that it may not apply accordingly to lean individuals, but overall it provides very good findings [218].

              They randomised these women into 3 groups, all of which had to restrict 25% of their daily energy intake compared to the calculated baseline. The groups were:

- IECR (intermittent energy restriction + carbohydrate restriction - <40g carbs/day)

- IECR + PF (intermittent energy restriction, carbohydrate restriction, protein and fat ad libitum)

- DER (25% daily energy restriction) - high-carb-high-protein Mediterranean type diet

              This study has to be read carefully so that the reader may clearly understand how the diets were formulated and how the subjects were able to achieve the overall 25% daily energy restriction.

              First of all, both groups doing intermittent energy restriction (IECR or IECR + PF) had to consume 70% less calories (compared to baseline) and consume no more than 40g of carbohydrates for 2 consecutive days a week. On a weekly basis, this would translate to 140% fewer calories compared to baseline. Spread over a daily basis, that would be 20% energy restriction (not exactly the 25% they talk about).

              IECR group consumed a Mediterranean type diet that would meet the carbohydrate restriction initially established, while IECR + PF consumed the same type of diet but would be allowed to consume protein and fat as much as they wanted (ad libitum). The other group (DER) did daily 25% calorie restriction and consumed a Mediterranean type diet of 45% carbohydrates, 30% fat, and 25% protein [218].

              A greater reduction in insulin resistance was seen in both IECR and IECR + PF groups, compared to DER group. Both IECR groups had greater reduction in % bodyfat compared with the DER group. Markers such as HBA1C, glucose, IGF-1, IL-6, TNF-α, leptin, adiponectin, total cholesterol, TAG, HDL, LDL and others have all been measured and can be studied as this article is available for free [218]. It goes beyond the scope of the book to treat each of them in details.

              This study could have been optimized in terms of the results if the researchers had randomised subjects into a couple of more groups: such as one that would do daily intermittent fasting, another that would do daily IF + calorie restriction, another one that would do daily IF + carb restriction, and many others. However, that may not be easily attainable as they would have had to measure for significantly more variables and pay closer attention to a much wider pool of results. Sadly, I have to be realistic and digest from the studies we have available :).

              In another study from 2014, Barnosky et al. wanted to compare calorie restriction with intermittent fasting and alternative day fasting. The purpose of their in-depth review was to assess the possibility of replacing calorie restriction with IF/ADF as they seem to result in improved compliance [219].

              The IF protocols they refer to require energy restriction 1-3 days/week and eating freely on non-restricted days. The ADF protocols that they investigate involve alternation between days of 75% energy restriction and days of ad libitum food consumption [219]:

"Results reveal superior decreases in body weight by CR vs IF/ADF regimens, yet comparable reductions in visceral fat mass, fasting insulin, and insulin resistance. None of the interventions produced clinically meaningful reductions in glucose concentrations. Taken together, these preliminary findings show promise for the use of IF and ADF as alternatives to CR for weight loss and type 2 diabetes risk reduction in overweight and obese populations, but more research is required before solid conclusions can be reached."

              For some reason, I do not find their modest results as being surprising. And I think the key is hidden inside the ad libitum feeding days. In most of the studies the feeding days are not carefully considered, while in many of them, subjects consume all kinds of crappy foods. A superior approach to ADF would be to improve the diet during the feeding days. I would not mind for ad-libitum consumption of food as long as it includes whole foods which are carefully selected. And I also think that such an intervention would provide far more benefits and greater adherence compared to the average calorie restriction protocols.

              I have to, once again, remind you that I empathize with calorie restriction especially when it comes in the same package with daily intermittent fasting and a well formulated ketogenic nutritional protocol. In this context, calorie restriction would reveal a much different meaning to what's out there, especially because of the powerful anti-hunger effect elicited by the long-term well formulated ketogenic protocol.

              In an in-depth review, Lee and Mattson (2014) investigate the neuropathology of obesity, primarily referring to brain diseases which are influenced or caused by obesity. They get into details about leptin deficiency, Bardet-Biedl syndrome, MC4R deficiency, epilepsy, Alzheimer's Disease, Multiple Sclerosis and several other conditions. What they find is an association of obesity to altered metabolism, abnormal signaling of hormones, as well as increased levels of inflammation. Some of the interventions they propose to alleviate these disturbing conditions include: fasting and other interventions derived from or related to energy restriction. Their review is a great starting point to better understand the connection between these conditions [220].

              When examining obesity and diabetes, Dr. Jason Fung (2014) has some interesting, well formulated, and logic theories (which in practice have lead to amazing results of disease reversal) [221]. He takes into consideration the two large myths that have widely been accepted and promoted by the medical communities all over the world, and (sadly) have been further promoted by most health care practitioners:

1. Diabetes is a chronic progressive disease.

2. Lowering blood sugar levels is the primary goal of the therapy.

              In Fung's (2014) perception, the truth is that diabetes (especially Type 2) is a disease of high insulin resistance, is a curable dietary disease, and the treatment should be directed to lowering insulin resistance.

              His approach is fairly rational from my point of view. If diabetes associations unanimously recommend patients to consume their normal diets (carbohydrate rich) and inject insulin (in case of T2D) to lower their blood sugars, this is clearly a chronic progressive disease as the only focus is on treating the effects of the disease (high blood sugar because of altered carbohydrate metabolism). This will further desensitize the body to insulin's action (making the condition chronic), instead of shooting for the opposite effect.

              Sadly, people do not seem to catch onto the messages promoted by Fung and other well intentioned professionals, one of the reasons being the louder media voice and the heavily promoted, irrationally formulated initial intervention.

              Folks put too much trust into their healthcare practitioners, who unfortunately do not stay current with research and who still promote the same old dogma that was derived from manipulated research studies. The dogma was pushed mainstream by Ancel Keys (a very influent person) and lead to the adoption of the widely cited dietary guidelines, which frightened nations of fat consumption. Dr. Peter Attia (2015) beautifully explains the history of this message in a recent lecture [222].

              While, as pointed out by Fung (2014), T2D may be a disease of high insulin resistance (and not high blood sugar) it is only logic that it may be a curable (mostly through diet) disease by targeting the reduction of insulin levels. I consider this a safe approach as the human body has been well crafted by evolution for surviving and thriving in the context of low insulin levels, provided that the metabolism can be fueled by ketone bodies and fatty acids primarily. This is a mechanism that most of us can shift into, except for some rare cases of genetic mutations that would prevent it from working properly.

              In such a scenario (ketosis), blood sugar levels are mostly low and insulin secretion follows the same pattern, given that the diet is well formulated and that nutrition consists of whole foods (avoiding the use of low-carb bars, breads, and all the related packaged products). If the strategy of keeping low insulin levels is persistent over a certain period of time and if it is efficiently combined with fasting and/or energy restriction, it can restore the ability of the body to process higher amounts of carbohydrates, should that come into discussion. From this perspective, diabetes is a treatable and reversible condition and it does not imply the burdens that come with the current medical treatment protocol.

              From Fung's (2014) point of view, the current treatment protocol leads to no cure of diabetes. And this protocol includes: insulin administration, drugs, and low-fat diets.

              Fung proposes three reasonable and logic interventions to reverse and cure T2D: very-low-carbohydrate diets, fasting, and/or bariatric surgery (proven extremely successful in dozens of clinical cases) [221].

              Current bariatric surgery procedures include gastric bypass surgery (golden standard of weight loss surgery - very efficient in diabetes too), the use adjustable gastric bands (reducing the amount of food the stomach can hold), sleeve gastrectomy, and others [223]. While this strategy may be a bit extreme, a combination of fasting and very-low-carbohydrate diets could serve as beneficial and very powerful first approaches for diabetes care and cure.

              To support this theory, Dr. Jason Fung (2014) mentions the diabetes-cure approach of Dr. Taylor and colleagues (2011) who consider that T2D is partially a dysfunction of beta cells in the pancreas [221, 224]. They showed that beta cell function and insulin sensitivity can be restored by acute energy restriction [224].

              Taylor et al. (2011) followed 11 obese adults with T2D (9 males, 2 females) for 8 weeks on a very low calorie diet. They consumed approximately 600 kcals/day [224]. They also had a control group of non-T2D, matched for age, sex, and weight. According to the researchers, after the first week of energy restriction, fasting plasma glucose levels of the T2D patients normalized (from 9.2±0.4 mmol/l to 5.9±0.4 mmol/l), while liver TAGs fell from 12.8±2.4% to 2.9±0.2% in the T2D group after 8 weeks on the protocol. In their own words [224]:

"Normalisation of both beta cell function and hepatic insulin sensitivity in type 2 diabetes was achieved by dietary energy restriction alone. This was associated with decreased pancreatic and liver triacylglycerol stores. The abnormalities underlying type 2 diabetes are reversible by reducing dietary energy intake."

              The most rapid improvements are seen in hepatic insulin sensitivity, while slower and later changes are seen in beta cell function. As Dr. Jason Fung (2014) explains, liver fat comes down very quickly and this would explain the rapid increase in hepatic insulin sensitivity. People with diabetes often have very fatty livers and fatty pancreases, and as fat in the pancreas comes down, beta cell function starts to recover [221]:

"It's not that the beta cells were 'dead', but their function was impaired."

              While the dietary intervention of Taylor and colleagues (2011) was proven to be extremely efficient (and, to a certain extent, similar with Valter Longo's patents [202, 203]), it may also be poorly adopted and implemented by the general public [224].

              Let's be honest. Who is going to be happily living on a 600 kcals/day diet (in this case it was not a very-low-carb diet)? This is even more extreme than Keys' semi-starvation experiments from late 1940s [55].

              I would opt for: a well formulated low-calorie-ketogenic-diet, daily IF or prolonged fasting (water-only fasting), or a combination of these as more feasible approaches.

              Out of the three I mentioned above, daily intermittent fasting and/or a well formulated-low-calorie-ketogenic diet may provide very beneficial results as they may not only mimic the effects of Taylor and colleagues (2011) intervention, but it may also speed up the molecular mechanisms to support cell repair and rejuvenation (explained previously).

              Let us now observe some recent studies on intermittent fasting. Obviously, the literature is much vaster than what I will discuss. In the hope that what's below is relevant and to the subject, it can serve as starting point for the reader in case either of the concepts are to be further analyzed.

Recent Literature of Intermittent Fasting

              A type of study that I always wanted to see, since it's similar to my personal approach, was conducted by Hartman and colleagues in 2013. They implemented an intermittent fasting protocol in 6 children (between 2-7 years old) who had a partial response to the ketogenic diet [225]. The specifics of their IF protocol was that subjects had to skip two consecutive meals on two non-consecutive days (i.e., skipping breakfast and lunch on Mondays and Thursdays). This is something similar to the 5:2 diet. As per the researchers:

"Seizure improvement (universally in the range of a 50—99% reduction) was noted by four families. One patient’s seizures improved only on fast days (patient 4). One patient’s family modified the intermittent fasting schedule to occur for 24 h once per month, which led to a further decrease in seizure frequency (patient 3) (Table 1). After an initial improvement, three patients had a recurrence of seizures during the intermittent fasting/ketogenic diet regimen. In terms of tolerability, the two patients who did best in terms of seizure control reported no adverse effects. However, the other patients reported varying levels of difficulty in implementing the intermittent fasting regimen, especially due to hunger. One patient lost 1 kg during the combined regimen."

              Given that patient 4's improvements were only seen during fasting days, this could suggest a combined effect of the two protocols (IF+KD). This may be supported by patient 3's improvement in seizure control, as a possible result of the modified 24 h once a month fast. While this may not be the most appropriate design for an IF protocol, I would have to be realistic and understand that it may not be easy to adhere children to IF protocols easily. But since these kids have shown improvement through the combination of these protocols, it would be reasonable to keep using them until other interventions/drugs are developed for improved results.

              In another review article, Rothschild et al. (2014) investigate time restricted feeding, as a component of IF in animals and in humans. TRF allows for unrestricted feeding during restricted time frames (i.e., ad libitum feeding in a 3-12 hour window every day). What they highlight is that animal studies suggest an association between TRF and reduced body weight, reduced total cholesterol, reduce concentrations of TAG, insulin, glucose, IL-6, TNF-α, and better insulin sensitivity. Accordingly [226]:

"Human data support the findings of animal studies and demonstrate decreased body weight (though not consistently), lower concentrations of triglycerides, glucose, and low-density lipoprotein cholesterol, and increased concentrations of high-density lipoprotein cholesterol. These preliminary findings show promise for the use of TRF in modulating a variety of metabolic disease risk factors."

              Sadly, this article has also failed to catch the public's eye because as of March 2015, it has only been cited 5 times in the literature. Even though the concept of intermittent fasting has been receiving a lot of popularity recently, it needs to be crafted in such a way in which it's not perceived as a burden but as something extremely enjoyable, something to which I attribute my long-term strict adherence.

              Slightly shifting from pathologic conditions to enhancing human performance, Hayward et al. (2014) wanted to determine the effects of IF and resistance training on body composition, resting energy expenditure and mood state [227]. They recruited 24 participants (8 males and 16 females). They assigned them into 3 groups:

- resistance training only (RT)

- intermittent fasting only (IMF)

- intermittent fasting + resistance training (IMFRT)

              While the researchers are shy to give us the very details of the results (or they will be published sometime in the future), they conclude that [227]:

"An 8-hour eating and 16-hour fasting day resulted in a decrease in fat mass as well as weight for the Intermittent Fasting plus Resistance Training group when compared to the Resistance Training only group.

On the other hand no differences were found between the Resistance Training only group and Intermittent Fasting group, hinting to that intermittent fasting alone may not be affective in decreasing body fat percent. However, when paired with resistance training, lean mass can be retained and/or enhanced while decreasing body fat, thus enhancing body composition."

              I agree that IMFRT may retain or enhance lean mass while lowering % body fat at the same time, and, contrary to what the researchers suggest, I also think that IF alone can be effective in decreasing body fat percentage. It would be rational to say that restricting feeding to an 8 hour window would allow for a greater mobilization of fatty acids from the adipose tissue, regardless of the dietary pattern. However, since I do not know the specifics of their protocol, as well as the exact results, it would be unsafe to further derive conclusions about this. 

              In another study, de Lucia et al. (2014) explored the effects of long-term intermittent fasting on cardiac function. While the study was conducted on rats and it may not be so easy to translate it to humans, researchers found that one year of IF on these animals lead to decreased body weight, improved cardiac systolic function and lower left-ventricle diastolic diameter. In their own words [228]:

"We have demonstrated for the first time that IF, started when HF is already established, ameliorates cardiac function and inotropic reserve in an experimental model of HF. At the molecular level, IF diet significantly improves βAR signaling in HF."

              To me, these findings would also be loaded into the repository of molecular mechanisms of repair and rejuvenation that result from long-term IF or similar protocols. I have to remind you that what I would like to see under clinical investigation is: a study of long-term intermittent fasting combined with a well formulated low-calorie ketogenic diet, which is similar to the protocol I have been following for more than a year now. You will learn more about my n=1 later in this book.

Fasting, Ketone Bodies and HDAC

              In a review article published in 2014, Newman and Verdin consider the possibility of ketone bodies to serve as signaling metabolites, an additional feature to their already widely established status of energy providers. In their own words [229]:

"Here, we review the regulation and functions of ketone bodies, the relationship between ketone bodies and calorie restriction, and the implications of HDAC inhibition by the ketone body βOHB in the modulation of metabolism, and diseases of aging."

              HDAC (histone deacetylase) is a class of enzymes that removes acetyl groups from certain histones (proteins that package and order DNA), often leading to transcriptional repression (not allowing DNA to be transcribed). HDAC inhibitors are currently under high research as possible treatments for inflammatory diseases and cancers.

              According to Newman and Verdin (2014), HDACs are responsible for various pathways of longevity, some of which involve IGF signaling and autophagy; modulating the activity of HDAC has been shown to regulate lifespan in model organisms [229].

              When double stranded DNA breaks occur in neurons, HDAC1 is important in the repair process. When this happens, HDAC1's activity is increased by SIRT1, which I have already discussed previously [229].

              Ketogenic diets have, in part, similar effects to calorie restriction through their impact on IGF-1, insulin activity, Foxo3, AMPk, mTOR, fatty acid metabolism and not only. As outlined by researchers [229]:

"The finding that βOHB is an inhibitor of HDACs, together with the coincidence of biological effects of ketone bodies and HDAC inhibition, suggests the fascinating possibility that βOHB could be an endogenous avenue to attain some of the benefits of lifespan extension seen with HDAC inhibition in model organisms."

              When mice were treated with βOHB, researchers noted histone hyperacetylation which is often associated with changes in gene expression, some of which include Foxo3a ad DAF16 activity. Along the same lines, they also hint toward increased protection to oxidative stress [229]:

"This resistance to oxidative stress may be due to induction of antioxidant genes, including Foxo3, metallothionein 2 (Mt2), superoxide dismutase 1 (Sod1) and catalase. Mt2 and Foxo3 in particular are both up-regulated by βOHB via its effect on HDAC inhibition and promoter hyperacetylation [5]. The full suite of genes regulated by βOHB via HDAC inhibition is not yet known, but

HDAC inhibition provides a possible mechanism by which multiple stress-response pathways could be activated by βOHB."

              Given the complexity of the subjects, I want to provide a simple graphic overview adapted from Newman and Verdin (2014) insightful review:

Mechanisms of HDAC Inhibition. Adapted from Newman and Verdin (2014) [229]

              There are many more studies out there left to be analyzed. Dozens of experiments can be found for each small molecule in different given contexts. Even if I try to keep things simple, I may have already went into too much detail on some topics. This may bother the non-technical reader who only wants to know what to eat, when to eat, or when not to eat to increase his/her health status.

              But it was a necessary evil to specifically explore some of the molecular complexities that occur when organisms move away from nutrients; I had to add more science to the topic of fasting which until not long ago was often only discussed in religious practices. Before getting to my n=1, there's another topic that I want to address in light of recent research.

Chapter 7

Fasting and the Emperor of All Maladies

The shift to ketogenesis may play an important role in suppression of tumor growth by IER/fasting because many tumor cells are largely unable to use ketones as an energy source; accordingly, ketogenic diets may potentiate the antitumor effects of IER.

Professor Valter Longo

              If the title is not explicit enough, in the next few pages my focus is going to be on cancer and some of the fasting strategies that can help with this major (mostly) metabolic disorder, as Thomas Seyfried sees it [3]. I will build upon lectures made by two brilliant researchers: Professor Valter Longo from University of Southern California and Dr. Colin Champ, who works in radiation oncology [193, 155].

              As I get deeper into my studies of genetics, the human genome, and the related fields, I start to accumulate a wider, multi-perspective view of this issue. While not until long ago, we've seen tumors only as abnormal growth of cells, recent technology allows us to understand that every form of cancer can include a multitude of different cancer cells. This fact alone would render ineffective any kind of single approach to obliterate it. We need to attack it from several fronts at the same time. And since some of its aspects can display Darwinian effects (survival of the fittest - in this case, the strongest), we need to eradicate it completely because each remaining cell can further mutate and proliferate into undruggable tumors.

              I've briefly discussed the differences between normal cells and cancer cells in my first book Ketone Power and I've given my 2 cents for which I think that ketogenic diets may help [230]. Unlike normal cells, cancer cells do not know when to die, possibly as a result of genetic mutations and also possibly as a result of long-term accumulated metabolic damage. There's a good reason to validate Thomas Seyfried's approach of viewing cancer as a metabolic disease, due to its increased prevalence in aged people (but this is not a generalization).

              Ketogenic diets have worked efficiently in many cases of cancer treatment because they are able to exploit the ineffectiveness of cancer cells to use the Krebs Cycle (TCA Cycle, Citric Acid Cycle) for energy. They are stuck in anaerobic glycolysis, turning most of the glucose that comes inside the cells to lactate, regardless of the availability of oxygen. This is often called the Warburg Effect.

              Consuming a high-fat-very-low-carbohydrate ketogenic diet will provide plenty of energy for normal cells, allowing them to survive and thrive, while cancers cells may die partially due to the lack of energy (very few carbs coming in -> low blood sugar) and also because of the multitude of other effects that ketones have on human metabolism. The issue is extremely complex and it may be dangerous to over-simplify and to focus only on energy metabolism.

              There are growth factors (insulin, IGF-1, mTOR, etc) to be accounted for, there is angiogenesis (building blood vessels to supply for the increase in the energy needed by the tumor), there are genes involved in maintenance and repair (p53), increased oxidative stress, and many others to be considered when approaching efficient cancer treatment. Let me start by reminding about some of the effects of reduced energy intake on healthy aging and lifespan.

Fasting, Longevity and Cancer

              As pointed out by Longo (2013), calorie restriction may reduce mortality from major disease in monkeys but it does not increase their lifespan [193]. While long-term studies done on model animals only account for the amount of energy intake and not macronutrient partitioning, I think that future well conducted studies may result in different outcomes.

              Reducing calories over the long term may protect from conditions such as cancer, high inflammation, diabetes, cardiovascular disease and others, but if the nutrition protocol is not well formulated it can also lead to reduced immunity, decreased libido, poor mood, irritability, increased hunger, and many other conditions that may make life miserable.

              In a simplified view (which most of us would like to see), increased glucose and protein intake was shown to activate genes that promote aging and disease, partially by enhancing the activity of IGF-1 and Tor-S6K (by protein) and RAS-AC-PKA (by glucose) [193]. The question is:

How do we apply what we know, right now, without using drugs?

              And one of the answers is, as you may have guessed, through fasting. Thomas Seyfried (2010) argued that if each one of us were able to do water-only fasting once a year for 7-10 days we would basically reduce our risk to develop cancers by 99%. Now, this may have sounded extreme if you would not have the knowledge you acquired throughout this book.

              What happens when your body focuses away from food? It shifts its attention to repair and maintenance. It rebuilds broken DNA, it gets rid of cellular waste products, it finally is able to remove most of the stuff inside your bowels (which never get depleted if you're eating food regularly), it uses fatty acids and ketone bodies for energy (a second way to kill cancerous tumors), it enhances neuroprotection, it lowers oxidative stress, and many other highly complex mechanisms, all very interconnected to each other.

              As explained by Longo, fasting and starvation cycles were seen to increase lifespan several fold in organisms such as bacteria, yeast, and worms. The major drawback is that it is not as easy to apply the same strategies in mammals. But we can derive various conclusions that can apply on most aspects of life on Earth, regardless of the species [193].

              Two of the hypothesis that Longo (2013) started from are [193]:

1. Short-term starvation (STS) may promote resistance to chemotherapy in normal cells by reducing proto-oncogene product activity and causing entry into a non-dividing 'protected mode'

2. Short-term starvation (STS) does not protect cancer cells because of the constitutive activity of oncoproteins

              These two hypotheses were tested by Raffaghello and colleagues (2008) in an experiment where they observed how starvation dependent differential stress resistance protects normal but not cancer cells against high doses of chemotherapy [170]. As I previously mentioned, many of these researchers use starvation and fasting interchangeably, but I think it is not the same thing. But, for the sake of closely reproducing their findings I will use their taxonomy.

              These researchers found that short-term starvation (48 hours of fasting prior to chemo) [170]:

"provided complete protection to mice but not to injected neuroblastoma cells against a high dose of the chemotherapy drug/pro-oxidant etoposide. These studies describe a starvation-based DSR (differential stress resistance) strategy to enhance the efficacy of chemotherapy and suggest that specific agents among those that promote oxidative stress and DNA damage have the potential to maximize the differential toxicity to normal and cancer cells."

              Similarly, Longo (2013) mentions targeting IGFBP-1 (IGF-1 binding protein) as an extremely powerful approach to fight cancerous tumors. The full name of IGFBP-1 is Insulin-like-Growth-Factor-Binding-Protein-1 and it is responsible for binding IGFs. When IGFs (I and II) are bound to IGFBP1, their interactions with cell surface receptors is altered. In my basic translation, IGF-1 (responsible for proliferation) cannot do its job if it's bound to IGFBP-1 [193].

              Since both IGF-1 and glucose decrease (more than 50%) following 72 hours fasts and since IGFBP-1 was seen to increase 11 fold in fasting versus normal fed control subjects, fasting would exploit the synergistic mechanism between these factors. Less glucose and IGF-1 may be secreted and, at the same time, more IGF-1 will be bound to IGFBP1, rendering it less activated [193].

              Based on the points mentioned above, a combination of fasting and chemotherapy may be better at fighting cancers, much better than fasting alone or chemotherapy alone.

              Moreover, Safdie and colleagues (2009) show how fasting patients before chemotherapy help mitigate many of the negative side effects often associated with this intervention. The data below is the average of 6 patients who received either chemotherapy-alone or chemo-fasting treatments [231] (search for this study on Google Scholar and you will find all the details about it because it has open access):

Adapted from Safdie et al. (2009) [231]

              In another interesting trial, Longo (2013) shows how 72 hours of fasting leads to reduced DNA damage and reversal of lymphocytopenia in patients receiving chemotherapy [193]. He also points out that 24 and even 48 hours of fasting prior to treatment may not be enough to see the beneficial effects that are seen when 72 hours of fasting are implemented. And that is understandable. As I have mentioned a couple of times in this book, it takes some time until glycogen stores are depleted and until the body shifts to fatty acid and ketone body metabolisms predominantly.

              The sad part is, as Longo (2013) observes, that many patients suffering from different forms of cancers do not want to undergo fasting. Think about it, the fear of not eating for a couple of days is much greater than fear of a possible increase in the chances for survival.

              Almost nobody copes well with the idea of water-only fasting, mostly because of their fear of hunger (most often, false hunger). As we have seen, real hunger may only surge when the body is depleted of fat stores at the end of a long-term water only fasting protocol, the same time when the body is into, what I personally perceive as, starvation mode.

              And this is tricky because this false hunger drastically fades away once the body efficiently starts using ketones and fatty acids for fuel. But many people do not go beyond the 48 - 72 hours that are most often a good limiting step between somewhat glucose based metabolism to fatty acid and ketone metabolism.

              A possible solution for this problem, from what I see, would be to cope with a long-term very well formulated ketogenic diet at first, until a certain level of keto-adaptation is achieved (this most often reduces the false hunger and the panic associated with not eating for more than a couple of hours); then to start using intermittent fasting and gradually increase the duration of the fasting window, while reducing the duration of the feeding window.

              Of course, this may be an ideal scenario as not many patients suffering from cancers have the luxury of spending time experimenting with protocols. Plus, what I'm saying here is rarely being pushed as intervention strategies by doctors, mostly because of the poorly considered nutrition involvement in cancer progression.

              Professor Thomas Seyfried (2015) advocates a low-calorie-ketogenic-diet (an intervention that I find very logic) [111]. Professor Valter Longo (2013) proposes a fasting mimicking diet, ChemoLieve, which may lead to better compliance and less resistance of folks to strategies like fasting. ChemoLieve, if modified to be ketogenic, may also serve as the bridge between Seyfried's approach and water-only fasting, prior to or during chemotherapy [193, 204].

Augmenting Cancer Therapy through Diet

              When Dr. Colin Champ, radiation oncologist, wanted to publish an article about dietary treatment in cancer therapy, several journals gave him responses such as [155]:

"We don't have any data showing an effect of diet on cancer treatment or outcomes."

and

"Diet is unlikely to play any part in cancer care, therefore this article is irrelevant for this journal."

This makes me think of:

American Medical Association, 1949:

"There is no scientific evidence that food or other nutritional essentials are of any specific value in the control of cancer."

American Medical Association, 2002:

"It appears prudent for all adults to take vitamin supplements."

              While there may not be an exactly direct contradiction between AMA's statements when it comes to cancer, I'm implying their radical change in approach for nutrition essentials (vitamins, minerals, micronutrients).

              Dr. Champ's paper (2013) eventually got accepted in the Journal of Nutrition and Cancer [232]. Even with the advent of modern technologies, there still seems to be a persistent gap between the conventional medical approach and other interventions. As Champ (2014) points out: radiation therapists are very reluctant to cast an eye on something that's somewhat different from their usual strategies [155].

              While I empathize with fasting as an intervention for disease management and cure, I want to reiterate what I said in the previous section:

Combining multiple therapies (fasting, chemotherapy, radiotherapy, ketogenic diets, herbs, drugs, and others) may be much more effective rather than rigidly sticking to one, as we are just beginning to understand the highly complex nature of cancer!

              Champ (2014) begins his presentation by reminding the reader about the history of cancer diagnostics, treatment and their connection to nutrition. He mentions a group of studies from 1909, 1910, 1947, and 2002 where calorie restricted or fasted animal models exhibited markedly reduced tumor growth [233, 234, 235, 236].

              As pointed out by Champ (2014) there are a few dogmas that still persist in cancer treatment, one of which goes along the lines that weight should not be lost during therapy but that it should be gained so that patients are able to tolerate toxic exposure better. I'm not sure if one can view things from my perspective, but if you focus on gaining weight and keep fueling the body with a lot of nutrients, it may not build its protection against chemo and radiotoxicity, as its primary focus would be to process nutrients.

              While calorie restriction may result in weight-loss (nothing wrong with that if an appropriate protocol is undertaken), fasting prior or during cancer treatment may reduce weight loss, while building protection against toxicity. Another possible argument that may be brought to support fasting is that it may increase compliance compared to calorie restriction, especially if the protocol is designed in such a way that it maximizes nutrient richness and it decreases hunger.

              Following these concepts, it may be least rational to say that nutrition, macronutrient partitioning, and feeding cycles do not have a prominent place in the literature on treating cancer. As pointed out by Champ (2014), evidence to support nutrient importance in cancer therapy was there all along. It is just that it was and it still is widely ignored [155]. Crabtree (1929) made interesting observations on carbohydrate metabolism, while Crabtree and Cramer (1933) have done some studies showing the interaction between radiation therapy and diet [237, 238].

              The wide disregard of nutrients as important factors in cancer therapy was investigated by Champ et al. (2013). They assessed survivorship and treatment recommendations for cancer patients by analyzing dietary recommendations on 21 websites of NCCN institutions (National Comprehensive Cancer Network). Out of the 21, only 4 websites provided nutritional guidelines [232].

              Half of these promoted low-fat-high-carbohydrate diets and half of them supported weight maintenance during treatment. As described by the researchers [232]:

"One third of all NCCN sites (n=7/21) had links to nine external websites. Four external websites provided nutrition guidelines, and half favored a low fat, high carbohydrate diet, while half favored high-caloric intake to maintain weight."

              Following this scenario, it is no wonder that nutritional intake, feeding cycles, and macronutrient partitioning are disregarded. From my perspective, adhering to such dietary recommendations during cancer treatment would provide minimal advantage or no advantage at all.

              In most of the studies mentioned earlier, mice were restricted in the consumption of calories and/or carbohydrates, some of the studies applying a cancerous tumor, others applying a cancer promoting agent [233 - 238]. A good question posed by Dr. Colin Champ (2014) is whether or not we can harness the effects of nutrient restriction in the modern treatment of cancer [155].

              One of the possible answers comes from Saleh and colleagues (2013) who showed how caloric restriction enhances the efficacy of radiotherapy in breast cancer. They injected tumors into the mammary fat pads of mice and as soon as the tumors were palpable, they treated the mice with radiation alone (IR), with a dietary intervention of alternative day feeding (ADF) or calorie restriction (CR) or with a combination of the two. There was a control group given no radiation which was fed ad libitum. As explained by the researchers [239]:

"In two murine models of TNBC (triple-negative breast cancer), significant tumor regression is noted with IR or diet modification, and a greater regression is observed combining diet modification with IR. Two methods of diet modification were compared, and it was found that a daily 30% reduction in total calories provided more significant tumor regression than alternate day feeding. At the molecular level, tumors treated with CR and IR showed less proliferation and more apoptosis. cDNA array analysis demonstrated the IGF-1R pathway plays a key role in achieving this physiologic response, and multiple  members of the IGF-1R pathway including IGF-1R, IRS, pIK3ca and mTOR were found to be downregulated."

              In this case, alternative day feeding (ADF) does not seem to be as good as caloric restriction. From the details of the study, we find out that mice in the ADF group had significantly increased caloric intake during their feeding days which lead to an overall 9% decrease in caloric intake, if averaged to a daily basis [239]:

"Measurement of food intake over the course of the experiment showed an average intake of 3.71 g per day per mouse for ad libitum fed animals, whereas ADF mice consumed an average of 6.78 g per fed day or 3.39 g per day per mouse, about a 9% decrease in caloric intake."

              This may not be sufficient to expose the possible benefits that may come along with a combination of fasting and caloric restriction. Perhaps if these mice were given limited chow during their feeding days, we would have seen different results. It may also have lead to decreased bodyweight (depending of the diet type), but this does not necessarily make reduced bodyweight a bad thing. When trying to derive conclusions that could be applied to humans, we also have to consider that mice have a distinctly different metabolism from ours and that they are night-feeders.

              Hence, as remarked by Dr. Champ (2014), to achieve similar effects to those seen in caloric restricted mice, humans would have to fast for multiple days prior or during cancer therapy. Although possibly an exaggeration, Seyfried (2010) supports fasting for 7-10 days at least once a year to dramatically reduce the risk of developing cancerous tumors by 99% [155, 3].

              At the end of his presentation, Dr. Champ (2014) reminds us of the possible significant importance of AMPk in treating cancerous tumors. Increased AMPk activity, as widely mentioned in this book may [155]:

- increase glycolysis and glucose uptake while decreasing gluconeogenesis (increasing insulin sensitivity)

- increase mitochondrial biogenesis

- decrease lipogenesis and cholesterol synthesis

- increase fat oxidation

- reduce the activity of mTOR.

              In light of these remarks, Champ (2014) discusses the different effects of dietary macronutrient composition of AMPk and SIRT1 expression and activity in human skeletal muscle [155, 240]:

Adapted from Champ (2014) [155, 240]

              I have previously mentioned that AMPk activity is different if different dietary protocols are undertaken. While AMPk was usually observed to increase in activity as calories were restricted, changing the macronutrient partitioning may result in increased AMPk activity even in the face of 40% caloric surplus, as seen above.

              Even if the dietary protocol of lean individuals (utmost left) may not be the most appropriate, as it is high in fat and only moderate in carbohydrates, it still shows expression of increased AMPk levels compared to the high-carb dietary protocol of lean individuals. In such circumstances, I suspect that we could benefit from increased AMPk activity and reduced weight loss during cancer treatment (if that's the purpose) as long as a well-formulated ketogenic diet is followed.

              As pointed out by Lee and colleagues (2012), fasting can elicit remarkable changes in the levels of IGF-1, glucose, IGFBP-1 and in other proteins [4]. Similarly shown by Champ et al. (2013), caloric restriction can induce unique activation of certain metabolic pathways [241]. Individually or implemented together, these strategies have:

"...the potential to improve the efficacy of chemotherapy against tumors by protecting normal cells and tissues and possibly by diminishing multidrug resistance in malignant cells."

              It still remains to be explored how to fine tune personalized approaches for cancer treatment and cure by implementing a multitude of strategies such as fasting/IF, calorie restriction, ketogenic diets, radiation therapy, chemotherapy, natural therapies and not only. A combination of these approaches based on individual assessment may be appropriate, rather than just trying to generalize and implement a rigid one-type approach for all types of tumors, which still is the most used strategy today.

              In the next chapter you find out about my n=1 intermittent fasting protocol that started at the beginning of 2014 and is still going on (March 2015). As an early warning signal, I have to remind you that what seems to be working for me may not work for you. Even though there may be some similarities across the population, we are all genetically and epigenetically different. Hence, I will not provide general recommendations as I do not believe in such, and I would suggest you to implement your own interventions, observe, adjust and find out what works for you.

              I find it necessary and cautious to remind you not to forget to consult with your primary healthcare practitioner before/during/post any of the interventions you may make.

Chapter 8

My Personal Long-Term Fasting Experiment

Testing the Waters

              I started eating a keto diet at the end of September 2013 and I started coping with intermittent fasting in November 2013 when the Christmas Orthodox religious fast began. I've almost never been out of ketosis since September 2013, and I'm not likely to be anytime soon. I have never felt better, been more productive, more energetic, better mentally equipped and significantly much more satisfied from the type of food I eat. And the beauty of it is that I never feel deprived.

              While I focus on consuming real foods from carefully selected sources, such as eggs from chicken raised by my grandparents, locally produced cheeses and meats, locally produced vegetables and fermented foods, I know that whenever I want, I can mimic most of the foods that I gorged on when I was on a more processed food type of diet. I know that I can cook a keto-friendly pizza, keto-friendly cheese, as well as keto-friendly French fries. But, since September 2013 I have only consumed these types of foods 2 or 3 times.

              This book is supposed to focus on not eating, more than on eating. I knew that following a ketogenic type of protocol over the long term makes fasting far easier. From my perspective, since one does not have to deplete glycogen levels (which happens in ketosis) and since the brain is more adapted to using ketones, shifting from eating to not eating is painless on a ketogenic diet.

              When I started experimenting with IF in Nov. 2013, I usually did it on Wednesdays and Fridays, as part of my religious fasting protocol. I could easily compare my experience with the type of fasting that I did when I was younger and when I was consuming a higher-carbohydrate (mainly processed foods) protocol.

              During those Wednesdays and Fridays I was fasting until 5 - 6 P.M., from 10 - 11 P.M. the previous day. So if I did not consume food from Tuesday 10 P.M. until Wednesday 5 P.M., it means my fasting window was of 19 hours. Looking back now, I remember that I was startled because I was challenging one of my personal dogmas: How could one thrive for 'so long' without eating, when I was used to eating every 3-4 hours. My dogma was that if I didn't eat at least twice or three times a day consistent meals I would faint or feel sick.

              That was not the case. Waking up on Wednesday morning and not having to cook food, allowed me to focus on writing and optimizing stuff for my blog. I was so caught up into what I was doing that hours were passing by quickly. Hunger was my least concern. I usually had a cup of coffee and sometimes I sweetened it with a small stevia pill. That was mostly what I consumed. At ~ 5 P.M. I ate some nuts, some avocado with squeezed lemon juice, and some dark chocolate (85% cocoa), according to my keto-friendly and my religious fasting protocol.

              Obviously, with only one meal I never met my caloric intake on Wednesdays and Fridays and I mostly did not overeat during the following days. That helped with my fat loss, a story that I describe in Ketone Power [230]. And Wednesdays and Fridays happened to be two days of the week that I did my kickboxing practice. I usually did kickboxing from 8-10 P.M.

              To be honest, it was not easy at first. Implementing so many changes in my routine was a big challenge. Having to go through the demanding kickboxing sessions in an energy restricted state was not at all a piece of cake. It took a few months for me to start adapting and recovering my past (carb fueled) performances of high intensity training.

              During those same weeks of Nov. - Dec. 2013 I decided to try and complete a fast that would go beyond 24 hours, since I was beginning to get familiar to fasting for 19 hours twice a week. From what I can recall, I stopped consuming food at 5-6 P.M. on a Tuesday until Thursday morning. That translates to 36+ hours of fasting, during which I had a kickboxing sessions on Wed. evening and a heavy lifting workout on Thursday morning, after which I consumed food.

              Surprise after surprise, I learned how the human body (my body) can easily go without food and thrive for longer periods of time as long as it becomes adapted to using fats and ketones for the bulk of energy demand. And I never actually felt fearful of losing muscle mass because I know that the likelihood for that to happen is minimal, if existent, when the body gets keto-adapted, especially if heavy lifting is part of the strategy. Increased muscle catabolism is more likely to occur for folks on warrior diets who fast for 16-20 hours or more and force themselves to meet their caloric demands in the remaining 4-8 hour windows. And on top of that, they gorge on higher-carbohydrate foods, never actually adapting to efficiently burning fats and ketones.

              During the winter holidays of 2013 my family and my friends had to get used to me not eating what they ate. It's not like my mother had to cook something different for me. It's just that I ate whatever was friendly with my protocol. And I had to say 'no' to a lot of people, which is something that most folks cannot resist when they are on any type of diet.

              For me, there was not 'just one piece of cake' or 'just this once' or 'see how it tastes'. I was so keen to stick to strict ketosis because of the multitude of benefits it provides to me. Had I been more permissive with my self, I may have possibly disrupted the adaptation process. And it took a while for those around me to get used to my protocol, more than just a couple of months. I never felt the need that I had to explain myself, I just said 'no, thank you'. This may not be as easy for females.

The Thai Experience

              Then, during January 2014, I had a 2 week trip to Thailand. I took things to the next level. To get there, I selected a cheaper flight through a Russian airline. It took more than 2 days to get from Romania to Thailand. I had to go to Budapest airport in Hungary by minibus, then fly to Moscow, stay in the airport for ~24 hours, and then fly to Phuket in Thailand for another 10 hours. It was not an easy to go through experience and I suspect that if I hadn't been on a ketogenic protocol and had not been fasting mostly throughout the trip, my experience would have been miserable.

              I only consumed some nuts (once), drank plenty of water and drank some black coffee. Since my focus was not on getting fed, I was able to concentrate and finish some work for my blog during the long stay in the Russian airport. I barely got some sleep during the flight from Moscow to Phuket and as I got to Phuket (it was late afternoon), I took a shower and I went out to the clubs with some friends until 4 A.M. the next day. To get an idea of duration of the trip, it lasted from Tuesday afternoon until Thursday afternoon.

              And I almost completely forgot about food. I remember when I woke up on Friday at noon, I had a walk along the beach of Patong in Phuket and I found a nice restaurant where I had this meal:

Patong Beach (Jan. 2014)

              I believe you can image that I did not consume the wheaty-stuff from the top-left side of the image, but only the butter. This barely made for a couple of hundred of calories.

              No jet-lag, no huger, no cravings...was this for real? Did I just discover something new? Could I live my life in a hyper mental state, always full of energy, always focusing on being more productive, always enjoying the moment, and whenever I felt the time was right, I ate...making every meal one of the most enjoyable and tasteful experiences ever?

              Yes it was for real, and it still is. But this is not something new. Humans have been doing it for eons. The sad part is that such lifestyle is currently hidden behind the fear of hunger (false, by the way), behind 24/7 food advertisements, behind unlimited availability of food, and behind the ingrained habits of regular daily feeding regimens.

              While some of you may have already read my first book Ketone Power, there may be quite a few who didn't. Which is why, I will re-emphasize some of the experiences that I may have mentioned in that book. Since I was not feeding regularly, I had the chance to experiment with all kinds of local (and not so local) foods:

Not so Tempting - Phuket - Jan. 2014

              No, I did not eat that, though that thought crossed through my mind a couple of times. Yet, I only took pictures, like most folks did. You were only allowed to take one picture. On the other hand, I did ate these:

Another breakfast in Phuket - Jan. 2014

Evening snack in Phuket - Jan. 2014

Getting Deeper into the Rabbit Whole

              As I got home and become conscious of my recently encountered 'superpowers', I decided upon designing an intermittent fasting protocol that I would stick to for an indefinite period of time. I made it that I would consume food twice a day, a nutritious breakfast and a small high-caloric snack early in the afternoon. That was my feeding window. Then I would fast from 3-4 P.M. everyday, until 8-9 A.M. the next day, clocking at 17-18 hours of no-feeding.

              Of course, I did this most days, but I had exceptions. There were and still are times when I feed at night, times when I over-consume food (still ketogenic), though most days I combine a well formulated low-calorie-ketogenic-diet with intermittent fasting. I deviate from my standard just to inject randomness into my routine. I do not plan my days of over-consuming foods. But when they happen, I'm very excited about them and it seems that it makes me adhere even more strictly to my current protocol.

              As you may recall from the beginning of the book, at the end of March 2014, I decided to do a longer term fasting experiment. Being already fairly keto-adapted and having some experience with fasting, I initially shot for 50+ hours, but that turned into 5 days of water-only fasting. I was a lean individual doing prolonged fasting. Nothing new about that.

              As you've seen earlier, 30-40 days prolonged fasting experiments were conducted by lean individuals 100 years ago. And these are only those which we can find in medical journals. Who knows how many others may have done similar experiments? Mine pales in comparison when put in this context.

              But I was fairly satisfied by my endeavor. I came out of fasting on Friday evening (started on Monday) with some avocado mixed with lemon juice, then I had some nuts and then, the next day, I started eating according to my protocol. Upon entering, during, and in the re-alimentation phase, I was in ketosis, which made the entire experiment less of a burdening.

              This is not the same with most people doing prolonged fasting experiments. They usually have to deplete glycogen stores, bringing 24-48 hours of possible irritating hunger pangs and cravings for food, light-headedness, fatigue and other symptoms associated with sugar withdrawal. Then it becomes easier as they enter ketosis. Then they start realimentation with orange juices and other sugary drinks. I don't tag that as an inappropriate protocol. I just want to do it my way.

              One thing that should be persistent across all types of prolonged fasting protocols would be the gradual realimentation: starting with easily digestible foods for the first couple of hours (1-2 days) and then progressing into your normal feeding regimen. This also depends on the duration of the water-only fast. Longer experiments may require longer periods of realimentation, while shorter ones (like mine) may require less.

              I personally plan on doing more of these types of prolonged experiments, especially now that I became more aware of the science behind them and especially because of the potential rejuvenation and anti-cancerous effects they may provide, as we've seen throughout this book.

Always adapting, never becoming rigid. Increasing Anti-Fragility

              I do not like to stick to fixed patterns. That's why I always try to change something. Even though I usually fast for 18-20 hours and feed in the remaining 4-6 hours, I often fast for 24-36 hours. There are also times when I consume 3-4 (or even more) meals per day. I suspect this increases anti-fragility, a concept widely described by Nassim Taleb [207]. My anti-fragility approach seem to make me even more adherent to what I usually do.

              During 2014 I traveled a lot. I went to Thailand, I went to Greece twice, I went to several places in my home country, I went to Austria for a couple of days, and I also went to the United States for more than 3 weeks in Sept. 2014. These were all opportunities for me to adapt, expand, and finely tune my approach to fasting and feeding.

              While in Greece I experimented with local foods (tahini, olives, olive-based vinegar, and others), in Austria I consumed several brands of very dark chocolate, while in Brooklyn I ate from a Turkish fast food almost every day.

              During my stay in Greece I was using a 14 - 10 hours fasting/feeding protocol, eating a small breakfast (some nuts and cheese) and a nutrient rich afternoon meal (eggs, greens, bacon, and others). During my stay in the United States, I was consuming a similar 14 - 10 hours fasting/feeding regimen, consuming some mixed nuts, cheese, and, surprisingly (even to myself) dark chocolate in the morning and some Turkish fast-food (keto-friendly) in the early after-noon. To that, I added some strong red dry wine in the evenings.  Here are a couple of pictures:

What I brought home from Vienna - Aug. 2014

Handpicked in Romania - Aug. 2014

Turkish Keto-Friendly 'Fast Food' - Brooklyn - Sept. 2014

Keto-Friendly Cheesecake - Home - Dec. 2014

Keto-Friendly Pizza - Home - Dec. 2014

              While I experiment with different meals, I usually eat eggs, bacon and greens for breakfast, and some nuts, dark-chocolate, and cheese for my afternoon high-caloric snack.

As a reminder, my current strategy includes:

- a well-formulated low-calorie ketogenic-diet and IF (18-6 hour fasting/feeding) everyday (1,400-1,700 kcals)

- some randomly injected days of prolonged fasting (24-36+ hours of fasting)

- some randomly injected days of over-consuming foods, eating 4-6 (or even more) meals a day, but still remaining ketogenic (3,000-4,000 kcals).

- other interventions.

              I will not give you recipes for foods or exact times of the day when I eat because I do not believe in fixed and rigid strategies. You can find tons of cookbooks over the internet. The purpose is to give you an idea of what I do, and sometimes get into the nitty-gritty details.

What about Muscle Loss? - On my Current Workout Regimen

              The mainstream media and bro-science may drive you into the panic of losing muscle if you don't consume increased amounts of protein every couple of hours. Similarly, other folks promoting IF protocols may also suggest forcing consumption of food (especially protein) during feeding windows, otherwise you will lose muscle.

              While that may hold true for many, especially those not adapted to burning fats and ketones, I personally do not follow such. And besides the plenty of studies and experiments you have seen throughout this book, muscle loss is reduced to minimum, if existent, when fasting undergoes. Please remember that fasting is not starvation. Fasting occurs when your body uses your own fat to derive the majority of its energy demands and its main focus encompasses repair, rejuvenation, detoxification and maintenance.

              Starvation occurs when your body fat stores are depleted and energy is derived from increased muscle catabolism. Starvation is the extreme end of fasting, and even most lean people have enough body fat to go into prolonged fasting for weeks before starvation undergoes, maintaining muscle catabolism at minimum.

              While my main focus is not to become Mr. Olympia (yet), I rarely consume more than 1g of protein per kg of body weight. I am currently weighting 66kg and I'm 174 cm tall. I consume much less than that when I combine IF with religious fasting. In those cases, I consume 35-50g of protein per day. Paradoxically, I do weight lifting in those days, and I feel like my energy levels go through the roof. Yes, I allow you not to believe me because it's totally against mainstream. The days that I overeat, I go little above 100g of protein per day.

              I usually go to the gym 2-3 times a week. My current protocol is adapted from Doug McGuff's Big 5 Protocol (you can find it on the internets). Doug's regimen suggests training once a week: very high intensity, heavy weight training. I found that my recuperation time due to my fairly keto-adapted status is much accelerated, which is why I did not rigidly got stuck to the 'once a week' recommendation. The duration of 1 workout session is ~20 minutes.

I do something along the lines of (as of March 2015):

- 3 sets to failure - barbell curs - 35kg/repetition

- 3 sets to failure - leg press - 280kg/rep

- 1 set to failure - squat - 110kg/rep

- 2 sets to failure - overhead dumbells - 16kg/dumbell/rep

- 1 set to failure - wide laterall pulldown - 56kg/rep

- 20 chinups

- 20 dips

This is highly adaptable and it is altered almost every session.

              I also keep my kickboxing practice, though not every week. And I also do calisthenics (body weight) workouts at home. During my calisthenics workout I focus on my chest, abs, and legs.

              Many times I skip gym workouts and often times I do fewer sets with heavier weights. Some other times I do more sets with lighter weights. There have been times when I did not go to the gym for more than 10 days (when I was in Thailand or in The United States). Did I panic of losing muscle? Of course not. It's not like I was totally inactive. I exercised, but differently. I focused on calisthenics and I carried a resistance band that I used for working-out my arms. I describe this in more detail in my second book called T-(Rx) - The Testosterone Protocol [106].

              I'm not sure if you get the picture here. I'm trying to focus not on rigid routines, but on implementing randomness while maintaining a certainly flexible protocol. You may understand my protocol much better if you read Nassim Taleb' Anti-Fragile [207].

              I'm sorry if this is not your average: do 6 sets of this and 7 sets of that and train for 3-5 times every week and eat 3 times a day, using pre/during/post workout supplements, etc.

              I personally believe that for many folks those strategies will lead to decreased compliance over the long-term. If you read Arnold Schwarzenegger's autobiography Total Recall you will see that even though while training for Mr. Olympia and other body-building championships he mostly followed strict routines, he also used the anti-fragility concepts that I mentioned earlier [242].

Some Tools, Some Supplements

              Whether you are doing IF fasting everyday or every once in while, whether you are entering prolonged fasting from a high-carb background, or whether you just want to know if you are in ketosis, the three most used measurements that I know of are: Ketostix, Ketonix, and blood ketone meters. You can find them online.

              Ketostix measure urine ketones and may become a less relevant measure for people who become keto-adapted; it still works fine for me. Ketonix measure breath ketones (acetone), while blood ketone meters (often measuring blood glucose levels in parallel) are considered the most accurate (so far). They measure blood levels of BOHB (beta-hydroxybutyrate).

              I also use tools on my smartphone and laptop to help me keep track of my daily food intake, weight fluctuations, exercise logs, supplements, etc. Cronometer.com (free) provides nice diagrams that can be extremely insightful if they include data taken over a long period of time (3, 6, 9 or even more months). There are many more smart tools and accessories out there, but I did not use them yet.

              In terms of supplements, I currently use: cod liver oil, organic magnesium, alpha lipoic acid, and 1 multivitamin-multimineral pill/day. I also use, but recurrently, iodine (from carefully considered sources), garlic extract, green tea extract, and vitamin D3 (though I rather get my intake from the Sun). I have used other supplements in the past but right now I'm trying to stick to my minimum considered requirements. I do think that supplements can augment one's diet, especially if the diet is well formulated. But the supplement industry has over-exploded during the past few years, and it's not easy to find good products when there's a lot of crap in the market.

              When I do a 24 hour fast, I often consume a lot of lemon juice. I peel the lemons, throw them in the blender, blend, then I store the concentrated paste in the fridge for later use. When considered necessary, I take 1-2 tbsp and put them in a glass, then pour water over it and, sometimes, add a few drops of liquid stevia. I also use unsweetened tomato sauce in a similar fashion (without the stevia, of course). A good sauce should contain: tomatoes, salt, and a bit of water. If the ingredient list is longer than that, please disconsider it.

              I do not use oil enriched coffee (the bullet-proof type) and I do not think it provides benefits when fasting (either IF or prolonged). I considered oil enriched coffee as energy-rich-nutritious-poor, but I may be wrong. When I consume coffee during my fast, I mostly use black coffee, and sometimes I sweeten it with a stevia pill; that's all. When I do not fast and want to consume coffee, I add a bit of heavy whipped cream on top of it.

              As mentioned previously, I also consume red-dry wine every once in while, sometimes every couple of evenings, sometimes twice a week, and sometimes never. You gotta love randomness. :)

              Even though it contains minute amounts of resveratrol which may potentiate the activity of SIRT1, to me it's a great drink to have at night (1-2 small glasses) while being accompanied by a nice person or even alone while pondering upon the immortality of the soul, and in a couple of years the immortality of the physical body as well.  :)

              As for my weight lifting protocol, I sometimes use C4 (contains nitric oxide, creatine nitrate, beta alanine, caffeine, and others) as pre-workout. I'm also starting to cope with creatine monohydrate as part of my supplement stack due its potential benefits not only on muscle synthesis and maintenance, but also due to its interactions inside the gut microbiota and inside the brain.

              Another important tool in my repertoire includes cold-thermogenesis. As seen in Upton Sinclair and his followers' protocol, I do take cold shower post heavy-lifting and I do not advise you to do that. I also take ice bath and do criosauna sessions (exposing myself to temperatures of as low as -193 degrees Celsius).

              Cold-thermogenesis engages your brown adipose tissue into burning energy as heat through an uncoupling metabolism, leading to reduced oxidative stress, increased metabolic rate, and increased activity of the immune system (through hormesis to a certain extent). I wrote about my first criosauna experiment on my blog and in my second book [246, 106].

              Conversely, I also take very hot baths and started to cope with the idea of using infrared saunas. It may serve as part of a very efficient detox mechanism, possibly the subject of an upcoming book. As one may see, I test the extreme ends of a certain spectrum, not trying to rigidly stick to cold-thermogenesis alone or hot baths/saunas alone.

              This is only a part of my current protocol, probably the most important one. If I would go into details about each and every aspect of what I do, I could possibly fill another 500 pages, rendering the book as unreadable, more than it, possibly, is now :).

              Hopefully you can extract many useful concepts from the studies presented in the book, from the long-life experiences of the folks I mentioned, as well as from my personal interventions. I have to, once again, remind you not to take my words for granted, but to conduct further research upon the subjects of your interest, adapt and implement them into your own protocol and see what works for you. In the next and last section (for the sake of re-emphasizing), I will try to answer some of the questions you folks sent me, though many of them have already been answered throughout the book.

My Opinion for Some of Your Questions/Concerns

Katherine is quite interested about the subject:

What are the best foods to eat to break a prolonged fast and still stay in ketosis?

              While I do not empathize with using words such as best, top, excellent and other absolute words, I would consider that there are many foods and food combinations you can use to break a prolonged fast and still stay in ketosis. My personal approach, so far, includes: avocadoes, squeezed lemon juice, and all sorts of nuts. Of course, this could also be extended to vegetable broths, tomato sauce, coconut oil and coconut derived products, as well as other foods that would be easy on the rejuvenated digestive system that is about to start its engines.

Are there certain condition which people may have that would make fasting dangerous?

              Yes there are, and many of which I am not very familiar with. Some of them can include genetic mutations making impossible for fats to be used as primary metabolic substrates. I would strongly advise for folks to consult with their health care practitioners before undergoing any type of fasting protocol.

Should any supplements be taken during prolonged fasts?

              Yes and no. If you think it increases your safety, besides consuming copious amounts of water, you may take a multi-vitamin-multi-mineral pill every day of the fast, as well as consuming a bouillon cube in a hot glass of water. You may also strategically use coffee and/or tea enemas to boost your antioxidant activity. However, letting your body figure out it own way through a fast may be more efficient.

Could any foods be eaten during a prolonged fast that are very low in nutritional value (such as coffee with 1 tbsp cream, bone broth, jello, etc.) to help a person stay on their fast?

              My answer is no. Prolonged fasting should be about not eating. That's why it is called fasting. You may drink black coffee and lemon juice from squeezed lemons. But no BPC, jello, bone broth and other nutriments. Bone broth is an excellent tool and you may use it in your feeding windows or when you eat normally.

JP gives us some details of his experiences:

Today is day 12 of my water fast. As it relates to your upcoming book, I have a few questions/observations:

1. Most if not all of the current extended water fasting literature assumes that one is burning glucose prior to beginning their fast. I have been fasting with several other men who were burning glucose prior to beginning their fast, they had a more difficult time than I did during the first few days (the beginning of the fast) most likely because the transition from burning glucose to ketosis was so rough. For me it wasn't too bad because I was already in ketosis. These gentlemen were given the advice to begin a very low fat, low calorie diet several days prior to beginning the fast.

What specific foods or protocol do you recommend prior to beginning a water fast if you're already in ketosis? Do I have to change my diet at all?

              If you plan on being in ketosis before, during, and after your fast, it does not really matter what you eat before your fast, as long as it follows a well formulated ketogenic diet. Such diet would be nutritious-rich-energy-rich and may include lots of vegetables (rich in vitamins, minerals, fibre and trace nutrients), marine foods (rich in iodine and essential fatty acids), coconut oil and coconut derived products, olive oil (use for salad dressings, don't heat it), eggs, organ meats and some fatty meats.

              In terms of meat consumption, I would skip the highly promoted steak and focus on organ meats due to the extreme concentration of nutrients that such foods contain. However, you have to be extremely careful when sourcing for your organ meats because, besides concentrating nutrients, organ meats also concentrate toxic chemicals to be either stored in the fat tissue of the animal or eliminated through various pathways.

              I would say that if your diet is well formulated, you may not have to change it when you enter prolonged water fasting. But be careful during realimentation. Please consider the recommendations I make through this book.

2. Regarding breaking an extended water fast; again, most of the literature assumes that you'll want to dive right back into burning glucose, which is not the case for me. I would like to stay in ketosis for as long as possible. As such, almost all the articles and books recommended you break it with fruit or juice or a combination of fruit and vegetables blended.

My preference is to break up with bone broth or even egg yolks with a little bit of grass fed butter, is this recommended? What foods do you recommend for breaking a fast for the person who would like to remain in ketosis?

              While this may not bring any possible negative effects to your digestive system, I would personally not break a prolonged fasting with egg yolks or butter, especially if it is very long (more than 7-10 days) and especially in the first day of realimentation. I gave my recommendations above (avocadoes, lemon juice, vegetable broths, coconut derived foods, various nuts, tomato sauce, etc). You do not have to follow them, but you may use similar foods to the ones I use.

Some topics that Lawrence thinks would be awesome to see covered are:

The effects on muscle mass for prolonged fasts more than 24 hours

              As you have seen in the book, it widely depends. Muscle loss is minimal post glycogen depletion.

So, straightforward: if you are in ketosis, if you do IF, and if in your feeding window you do not spike your insulin levels and replete the stores, your muscle mass may be well protected. It may even be enhanced if you do resistance training, as considered in a study done on caloric restricted subjects [247]. A potential argument to promoting muscle mass during fasting/IF may be the massive spike in growth hormone levels, the sparing effect of ketones on muscle mass, as well as the increased efficiency of using protein when energy intake is restricted.

              You may not see these protective benefits if you are force-feeding protein and carbs in your IF experiments, but you may see (in some cases) growth effects from the infrequent (meal dependent) spikes of insulin (+IGF-1+mTOR). Though, I would personally not go that route.

Is it really fasting if you do a sort of fat fast where one only eats fat and little to no protein?

No. Fasting is not eating.

Fasting for weight loss I assume would be covered, but how effective is long term fasts on weight loss compared to short term fasts.

              The results are widely distributed as you have seen in this book. If you fast for short-term and never go past glycogen-depletion, that may not be efficient. I would personally suggest IF protocols that include at lest 16 hours of fasting, if not 18 or 20 (this is when growth hormone starts spiking significantly).

And Christina has some questions as well:

Why do people feel light headed fasting and what can you do about it?

              This is a symptom often associated with sugar withdrawal. It may also happen because your body is switching its primary metabolic substrate from sugar to fat. That's not easy and it may take some time to adapt. As suggested by many folks, consuming a bouillon cube in some hot water, making sure your mineral intake is appropriate (especially magnesium and potassium) and consuming decent amounts of water would often mitigate most of these negative effects.

What if you are hungry all of the time while fasting?

              I think that if you start doing intermittent fasting on a daily basis, and if you eat naturally and normally in your feeding windows (not force feeding to meet your caloric intake), that may go away in a couple of weeks, especially if along the way you're consuming a nutrient protocol that depletes your glycogen stores and allows your body to efficiently burn fats and ketones.

              In almost all prolonged fasting experiments of people coming from a high-carb background (especially mine when I was younger), hunger is only experienced during the first 1-2 days. Then it goes away. Hunger is the least concern in prolonged fasting experiments. If someone would feel hungry post glycogen-depletion, I suspect that person may have some genetic defects leading to such circumstances.

Acknowledgements

              Finishing this book would have never been possible were it not for the support of my family, who spared me from many familial obligations and duties.

              I would not have been able to gather data for Periodic Fasting were it not for the brilliant work of the hundreds of researchers and experimenters cited throughout. Thank you Luigi Cornaro. Than you Upton Sinclair. Thank you George Cahill. Thank you Mark Mattson. Thank you Luigi Fontana. Thank you Valter Longo. Thank you Thomas Seyfried. Thank you Froy Oren. Thank you David Sinclair. Thank you Jason Fung.

              Thank you Professor Richard David Feinman for reviewing the book and also for increasing my awareness about statistical fallacies and poorly conducted research studies. You are a great mentor.

About the Author

              I, Cristian Vlad Zot, conduct research and experimentation in nutrition science (especially nutrigenetics and nutrigenomics), neuroscience, genetics, exercise physiology, and entrepreneurship (you would not have guessed).

              I hold a Master’s Degree in Civil Engineering since 2013, but I did not get a chance to use it yet because at the time of my graduation I was already deep into the rabbit hole (the fields mentioned above).

              I try to gather as much input as possible from my daily activities, analyze it, and come up with solutions that can help me and other folks as well.

Other books:

1. Ketone Power - Superfuel for Optimal Mental Health and Ultimate Physical Performance

Available on Amazon. More info about it:

http://cristivlad.com/ketone-power-the-book/

2. T-(Rx) - The Testosterone Protocol - On Achieving True Male Status

Available on Amazon. More info about it:

http://cristivlad.com/testosterone-protocol/

More at: http://cristivlad.com

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