Metabolic Autophagy

by Siim Land

  Figure 26 Fasting increases mitochondrial biogenesis through increased SIRT, AMPK, and PGC-1alpha activity

  The key to increased mitochondrial biogenesis and longevity is to prime the body towards a fat burning metabolism. This increases your cells’ ability to produce energy from its own internal resources (autophagy) and lowers insulin levels (less oxidative stress).

  Intermittent fasting benefits the mitochondria both ways – in protecting against free radical damage as well as enhancing energy production. But IF increases mitochondrial functioning in many other aspects as well.

  Fasting and Mitochondrial Density

  Mitochondrial density refers to the cells’ ability to produce more energy from fewer resources and become more efficient at it.

  Fasting increases NAD+ levels, which is an enzyme that helps with energy production and promotes longevity. NAD+ support mitochondrial functioning during youth and restore it in later life[144].

  NAD+ protects the cells against oxidative stress with the help of sirtuins[145]. NAD+ activates sirtuins which then help to grow blood vessels and muscle[146].

  NAD+ replenishment improves lifespan and healthspan through mitophagy and DNA repair[147]. NAD+ supplementation can promote DNA repair in mice[148].

  Burning fatty acids and ketones cause less damage to the mitochondria as well. Glycolysis, which is the process by which mitochondria burn glucose, causes more oxidative stress and the creation of free radicals, which in turn will speed up aging.

  Reactive oxygen species and oxidative stress activate FOXO pathway to adapt to the stress. Fasting causes mild stress that makes the body adapt to it through hormesis. Inactivity of FOXO factors accelerates atherosclerosis and compromises stem cell proliferation[149].

  As you age or when you experience high levels of stress, you become more prone to mitochondrial dysfunction and accelerated aging. Mechanisms mediated by fasting such as increased NAD+, sirtuins, and FOXO proteins make your cells more resilient against environmental stressors and energy depletion.

  In nature, animals would have to face high levels of stress only when going through some drastic seasonality or climatic change that would jeopardize their food resources. That inevitably imposes more bouts of fasting on them and thus make them react in a protective manner. If we were to replicate this response in the contemporary setting, then, as Herman Hesse pointed out: „the most intelligent thing to do would be to not eat.“ This can have a direct effect on one’s brain functioning and cognition as well.

  Fasting and the Brain

  Comprising about less than 2% of your total body weight, the brain uses roughly 20% of your daily calories[150]. It’s one hungry beast and for a reason.

  Keeping the brain energized and well is one of the main priorities of your body. Without enough higher executive functioning or learning, you would die in dangerous environments and you wouldn’t maintain consciousness.

  The growth of our brain has been one of the main drivers of our evolution as a species, skill acquisition, language, memory recall, social co-operation, tool crafting were all facilitated by improved cognition and getting smarter. That’s why you want to provide the brain with the essential nutrients and other foods it needs for thriving. However, there are also many benefits to not eating and depriving yourself of those things with intermittent fasting.

  Here are the benefits of fasting on the brain:

  Does fasting grow new brain cells? You bet. Fasting boosts brain power by increasing brain-derived neurotrophic factor (BDNF), which helps to grow new brain cells and synapses. It also promotes serotonin, which regulates synaptic plasticity with BDNF[151].

  Fasting can boost BDNF by 50-400%![152] Even 16:8 style intermittent fasting promotes neuroplasticity and stimulates the production of new brain cells[153]. BDNF also has anti-depressant benefits and it protects against stroke.

  Fasting protects the brain against neurodegeneration. During autophagy, fasting helps to clear out beta-amyloid plaques and lowers oxidative stress on neuronal tissues[154]. Fasting and the ketogenic diet are very commonly used to treat epilepsy.

  Fasting boosts growth hormone that provides neuroprotection and regeneration[155]. Growth hormone not only protects against muscle catabolism but also prevents brain cells from dying.

  Fasting gives the brain ketones which lower inflammation and maintain stable energy levels[156]. The ketogenic diet has BDNF increasing properties.

  Fasting increases mitochondrial biogenesis, which helps to produce more energy. There’s a lot of mitochondria in the brain and other vital organs.

  Fasting helps to lose weight, which can improve brain function. Studies link a higher BMI with decreased blood flow to regions in the brain that are associated with attention span, reasoning, and higher executive functioning[157].

  But there’s a lot of people worrying about fasting causing starvation in the brain. Is it true?

  The brain can use about 120 grams of glucose a day and if glucose levels fall below 40mg/dl its functioning begins to suffer[158]. However, during fasting, the brain can get more than enough energy from other sources:

  Ketone bodies are derived from fatty acid metabolism and after keto-adaptation, they can cover 50-75% of the brain’s energy demands.

  Astrocytes in the brain and spinal cord can produce ketones that can be for neuronal metabolism and they have neuroprotective properties[159].

  Fatty acids from your body fat can also be converted into glucose through a process called gluconeogenesis which breaks fat molecules into 3 fatty acid chains and glycerol. Glycerol can contribute up to 21,6% of daily glucose production[160].

  Lactate can also give the brain energy during intense exercise. The brain prefers lactate over glucose when both are available[161]. Lactate gets produced during anaerobic metabolism.

  Recent research in vitro has shown that fuel alternatives to glucose improve neuronal efficiency and oxidative metabolism[162].

  There’s plenty of energy sources the brain can use while fasting and they all improve your cognitive functioning.

  If you look at what excess glucose does to the brain, then it’s obvious why there’s a lot of neurodegenerative diseases on the rise. Alzheimer’s disease is now being referred to as type-3 diabetes[163], as it’s caused by an energy crisis in the brain. Insulin resistance in the brain contributes to the development of cognitive decline[164] and people with type-2 diabetes have an increased risk of Alzheimer’s of 50-65% and higher.

  Fortunately, fasting may help your brain with cognitive decline as well.

  Autophagy clears out the beta-amyloid plaques that begin to accumulate with cognitive decline and Alzheimer’s progression[165]. Alzheimer’s is also linked to obesity and insulin resistance.

  One of the main ketone bodies, β-hydroxybutyrate, actually blocks part of the immune system that regulates inflammatory diseases like arthritis and Alzheimer’s[166].

  Ketone bodies also raise BDNF and lower oxidative stress. Ketones can also reduce too much excitement in the brain caused by excess glutamate and not enough GABA[167].

  Being in a fasted state with higher ketone production sharpens your mind and prevents it from getting dull because of the mild stress response.

  Fasting clears brain fog unlike anything else and it will boost your brain performance as well. A lot of people say they experience a heightened sense of awareness, mental clarity, focus, improved attention and motivation while fasting. This is caused by the rise in BDNF and other neurotrophic factors and hormones that increase your acuity, such as adrenaline, norepinephrine, cortisol, and other endorphins.

  In my opinion, fasting ketosis is the most potent and easiest nootropics at your disposal. You can literally shift your mind into a higher gear of functioning by simply not eating and going into deeper ketosis. One study found that a short 24-hour fast had no impairing effects on cognition, attention span, reaction time, or memory recall[168].

  I do all of my cognitively demanding tasks in a fasted state, inclu
ding writing this book, and it helps me to stay productive throughout the day. Constantly eating can cause laziness, sleepiness, brain fog, and distractions, which is why I prefer to eat only once a day. This makes perfect sense from evolution again – to get your next meal, your brain had to become extra sharp and alert so that you’d increase your chances of eating. If you were to be dull and tired despite not having eaten for days, then our ancestors wouldn’t have survived.

  The biggest problem that may arise is hypoglycemia while fasting. If your blood sugar levels drop below a safe margin, you’ll begin to experience shivers, fatigue, forgetfulness, and potentially pass out.

  Hypoglycemia is a response to an energy crisis in the brain. Your entire body prioritizes fuel usage for the brain and whenever your blood glucose drops, you’ll become hypoglycemic as to motivate you to find sugar ASAP. Usually, it happens when a person’s blood sugar drops below 60 mg/dl or 3.5 mmol/L (See Figure 27).

  Figure 27 Optimal Blood Glucose Levels

  However, having low blood sugar while fasting shouldn’t be an issue as long as there are ketones present to provide fuel for your brain. During my own 5-7 day fasts, I tend to have blood sugar around 50 mg/dl, which is technically „hypoglycemic.“ Fortunately, my ketones soar up to 3-4 mmol-s, which prevents me from passing out and sustain a stable energy source for the cerebral tissue.

  Therefore, if a person experiences hypoglycemia and gets the symptoms of such, then their brain is simply unable to use the other fuel alternatives. Ergo, when the body is keto-adapted enough, it’s going to prevent any energy crises in the first place. The process of keto-adaptation will be covered in Chapter XIII where I’ll walk you through how to start using ketones for fuel without necessarily sacrificing all glucose in the brain. Let’s now carry on with the first line of defence against the environment – your immune system.

  Fasting and the Immune System

  Your immune system is the most important line of defence against the outside world as it helps to deal with foreign intruders, infections, and other environmental stressors. If you hate being sick, want to have more energy, be healthier, and live longer, then it’s vital to keep your immune system strong.

  Fasts that last for 48-120 hours reduce pro-growth signaling and enhance cellular resistance to toxins[169]. They also trigger stem cells, which help to reinvigorate old cells and promote their youthfulness.

  One study in particular done by one of the leading researchers of fasting Valter Longo et al showed that you can reset your immune system by fasting[170]. Mice and chemotherapy patients who didn’t eat for several days saw a significant reduction in white blood cell count. This then turned on signaling pathways for hematopoietic stem cells (HSC), which are responsible for the generation of blood cells and the immune system. Longo said:

  When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged.

  This study shows that extended fasting has a profound impact on the way your body can self-heal itself and strengthen its accord. There are also a lot of potential applications for this, starting with bolstering your immune system against the cold and ending with providing a healthier option for chemotherapy. But what causes these beneficial reactions? How does fasting reset the immune system? Valter Longo was thinking the same thing:

  We noticed in both our human work and animal work that the white blood cell count goes down with prolonged fasting. Then when you re-feed, the blood cells come back.

  While fasting, your body starts mobilizing a lot of its internal fuel sources, such as body fat stores, stem cells, glycogen, and old cellular debris. Some white blood cells also get broken down as a means of throwing away unnecessary material.

  Longo found that in order for the stem cells to be turned on, an enzyme called cAMP-dependent protein kinase A (PKA) needs to be shut down (See Figure 28). PKA inhibition signals the stem cells to become activated and start regenerating the immune system.

  Prolonged fasting has also been shown to lower blood sugar, insulin levels, and other hormones such as mTOR and IGF-1, which are all growth factors that prevent the body from healing itself using its internal resources.

  Figure 28 Fasting shuts down IGF-1 and PKA, which triggers stem cell regeneration

  Fasting can weaken your immune system only if it becomes an overbearing stressor on your body. It’s like any other physiological stressor your immune system has to deal with. If you’re fasting for five days, having mad CrossFit workouts, not sleeping enough, controlling three screaming kids in the mini-van, and being stressed out, then, of course, you’re more prone to getting sick. For the beneficial effects of hormesis to sink in, the stressors have to be taken at the right dose. Too much of the good stuff will still be bad and you can’t expect to be a champ from day one.

  It’s important to expose yourself to different stressors to make yourself more resilient against them as well. However, you have to start from where your current ability is at. As you start practicing more intermittent fasting, your immune system gets stronger and you become less affected by the ebbs and flows of stress.

  It’s important to note that fasting boosting your immune system works both as disease treatment as well as prevention. If you want to keep your immune system strong, then you should practice some form of intermittent fasting continuously and adopt other hormetic lifestyle habits.

  In Longo’s study, it took about three days of fasting to reset the immune system. This was so because of shutting down PKA, lowering IGF-1, and elevating ketosis. For a complete reboot and strengthening of the immune system, you should have extended fasts of 3-5 days at least 2-3 times per year. I aim for about 4 and I also have 24-48 hour fasts sporadically every month as well. I’m also doing intermittent fasting daily and I usually fast about 20-22 hours every day so I don’t have to have these very long 7-10 day fasts as my body isn’t that damaged. Arguably, you can get a much stronger effect faster by fasting on the ketogenic diet that’s already characterized by lower levels of liver glycogen and insulin.

  PKA is a collection of enzymes who regulate glycogen, sugar, and fat metabolism through a molecular messenger called cAMP (cyclic adenosine monophosphate). PKA and cAMP get activated by several things but they’re caused by the body mobilizing its energy stores. During the fast, once glycogen runs out, you’ll start converting body fat into energy and ketones. That’s why it takes such a long time to inhibit PKA and activate the stem cells – the body has to burn through the glycogen first before it goes for the fat. Having lower levels of liver glycogen and IGF-1 signals the body that it’s okay to release stem cells and turn on cAMP.

  You won’t be able to have a complete reboot on your immune system or activate autophagy with eating the ketogenic diet throughout the day because high amounts of fat and calories still signal the presence of excess energy in the body. However, you can definitely get into the immune system reset zone much faster with an already depleted glycogen reserve when eating low carb. Combine that with eating one meal a day and you’ll be in mild autophagy even on one-day fasts.

  Fasting Mimicking Diet and the Immune System

  Valter Longo has also come up with his own way of replicating these benefits with what he calls the Fasting Mimicking Diet (FMD). Here’s how it works:

  You eat about 500-1000 calories every day

  Your daily macros are low protein, moderate carb, moderate fat

  You eat things like a nutbar, a bowl of soup, and some crackers with a few olives or something

  Day One you eat about 1000 calories – 10% protein, 55% fat, and 35% carbs

  Day 2-5 you eat about 500-700 calories – 10% protein, 45% fat, 45% carbs

  Day 6 you transition back to a normal caloric intake with complex carbs, vegetables, and minimal meat, fish, and cheese

  Studies on the fasting mimicking diet have shown that it lowers cholesterol, C-reactive protein, blood glucos
e, IGF-1, and blood pressure[171]. However, it’s possible these effects simply came from the caloric restriction. FMD is often prescribed to elderly people or someone who can’t handle fasting.

  To get the full benefits of autophagy and stem cell growth, I’d say you still have to avoid all calories and fast for a longer time. The macronutrient ratios of the FMD aren’t optimal either as you’d want to lower the carbs and total calories to inhibit PKA. Eating very low protein with high carb also causes less satiety, which makes it more difficult to stick to the FMD schedule. You’re much better off by having a longer fast.

  Whatever the case may be, you should adopt a fasting focused lifestyle as to promote longevity, youthfulness, and create an antifragile immune system. The next most important thing for that is to take care of your gut because that’s where most of the immune system is located in.

  Fasting and Gut Health

  Diet and lifestyle play a huge role in modulating the gut microbiota, which has an enormous impact on health and lifespan. Microbial dysbiosis or imbalances are associated with increased risk of cardiovascular disease, obesity, metabolic syndrome, cancer, and autoimmune disorders[172].

  Different macronutrients and foods reshape the composition of the microbiome and both short term and long term dietary changes can influence microbial profiles[173]. However, not eating and fasting have a profound impact on the gut as well.

  Gut homeostasis plays an important role in longevity. Dietary restriction has been shown to prevent gut pathologies and extend lifespan in fruit flies[174].

  Short-term intermittent fasting improves gut health and extends lifespan in fruit flies independent of the TOR pathway[175].