Breaking Down The Science Of Autophagy – Beyond Popular Fasting Diets

Written by Andy Mobbs
featured image for article on autophagy

Intermittent fasting was the most popular diet of 2020. Whether they were doing 16:8, 5:2, or just fasting on workdays, 17 million people from the US jumped on this trend. Like all trendy diets, people and celebrities flooded Instagram with their success stories, and everyone got hooked.

But have you ever wondered what happens in your body when you’re doing intermittent fasting?

Do you know the science behind autophagy and fasting?

Today, I’m here to break down the science of autophagy and intermittent fasting, so you have 100% real insight into what’s going on in your body.

What Is Autophagy?

Autophagy comes from the words ‘auto’ and ‘phagy’. ‘Auto’ means self, ‘phagy’ means eat. Combined together, autophagy literally means ‘self-eating. It is a form of self-cannibalization but NOT in a bad way. It’s the body’s natural way of cleaning out dead, damaged, and cellular organelles and other components. By doing so, the body can regenerate healthy cells.

How is Autophagy pronounced?

It’s pronounced aa·taa·fuh·jee.

On How We Are Always Stuck in the Feast Mode

In the 2 million or so years of our evolution since humans diverged from the great apes, there were times when food was plentiful in our environment. There were also times when food was scarce. However today, for most in the developed world at least, there is an abundance of calories available all the time. So in normal life, we no longer go through the feast and famine cycle as we once would have. Instead, we are always stuck in ‘feast mode’.

The problem with this is that we evolved to go through feast and famine, so our bodies work best when they are exposed to both.

  • When we have enough food, the cells of the body can grow and reproduce. But when we don’t have enough food, the body can ‘flip a metabolic switch'(1), which instead focuses on strengthening our cells’ response to stress.
  • The cells do this by breaking down old and defective cellular components, renewing and regenerating them, and increasing the production of things like antioxidants.
  • The broken-down parts can then be used for the production of new cellular components or energy.

For a human to be healthy, ideally, we need a good balance between the two.

Intermittent Fasting Pros and Cons

PRO: Too much feasting and damaged proteins and other cell parts can build up, leading to cells not doing their jobs properly. Then because cells make up everything in our bodies, including our organs, eventually everything else starts to go wrong as well.

CON: However, too much famine can cause a problem too, because we spend too much time breaking down our cells in repair and not providing energy.

We really need a balance of the two functions. Intermittent fasting allows us to do this because we can mimic the periods of famine and easily mix this in with some feasting.

MTOR vs. Autophagy

The balance between feast and famine plays out in two opposing cellular processes that are both going on in our bodies at any one time; they are mTOR and Autophagy.

mTOR – An Enzyme, Easter Island, and What Bodybuilders Dream Of!

The first, mTOR, is the growth process. mTOR stands for ‘mechanistic target of rapamycin’.

It’s a funny name, but there is a good reason behind it. It was named after a soil bacteria that was first found on an expedition to Easter Island in the 1960s. Easter Island is an island in the Pacific about 2000 miles off the coast of Chile, famous for having a World Heritage Site with over 1000 ancient statues. Easter Island is also known by the island inhabitants as Rapa Nui, so the bacteria was called rapamycin after the island Rapa Nui.

mTOR isn’t the soil bacteria. It’s actually an enzyme produced in our bodies. But the soil bacteria rapamycin stimulates the activity of mTOR, so the enzyme became known as the ‘target’ of rapamycin. When this enzyme is stimulated, cells start growing and making proteins and reproducing more quickly. mTOR is well known to bodybuilders and other strength athletes who try to stimulate it as much as possible.

Autophagy – The Science Behind Fasting Diets

The opposite process of mTOR is called Autophagy, when the cells start breaking down old and damaged parts. Because the two processes are the opposite of each other, when mTOR is stimulated, Autophagy is correspondingly low. And when Autophagy is stimulated, mTOR is low.

How Does Autophagy Work Exactly?

• In autophagy, cells form special structures called phagophores.

• Phagophores are membranes that slowly grow to create a ball shape covered in a membrane.

• The membrane is made of something called a lipid bilayer.

• Lipids are fat-based molecules, and lipid bilayers surround all of the organelles in our cells and all of our cells as well, all 20 billion of them!

• Cell organelles perform different functions in our cells and can be pictured a little bit like the different organs in our body.

stages of autophagy

Phagophore formation

Whilst the ball or phagophore is fully forming, it moves around the cell. It gathers up proteins and other organelles that have been given a special marker that tells the phagophore they have been selected to be broken down. This special marker is called a ubiquitin. The phagophore then moves around the cell collecting all of the ubiquitinated proteins and organelles.

Phagophore formation completes

The membranes then fully form around the proteins and organelles. When this happens, the name of the structure changes from a phagophore to an autophagosome. This autophagosome then moves towards a lysosome and fuses with it. A lysosome is an organelle that can be thought of as the stomach of the cell, although it’s not exactly true, as a cell contains many lysosomes!

However, as in our stomach, lysosomes’ contents are acidic and contain digestive enzymes that break down the proteins and organelles. Once broken down into individual amino acids, they can be used again for building new proteins, organelles, and even new cells. Or they can also be used to produce energy by the liver in a process known as gluconeogenesis. The amino acids that are used for new cells and proteins do so by being stimulated by the mTOR enzyme, so the cycle completes itself as the body switches between autophagy and mTOR.

autophagosome fusing with the lysosome
The larger Autophagosome fusing with the orange Lysosome

There is also a specific type of autophagy that deals with mitochondria. This occurs by selective degradation of the mitochondria through a process called mitophagy. Mitochondria, also organelles, are the engines of our cells and produce our energy. We have large numbers of them in each of our cells, 2000 or more.

However, because we use oxygen to produce energy and oxygen creates oxidative stress, our mitochondria constantly deal with free radicals. This means they are very susceptible to damage, so breaking down and repairing damaged mitochondria is a critical process undertaken in mitophagy.

Autophagy and mitophagy

How Fasting Stimulates Autophagy and Mitophagy

When we fast, there is a reduction of energy coming into the body through food. This leads to a slight energy imbalance as more energy is used than produced. A special enzyme in the body constantly monitors this energy balance; this enzyme is called AMPK (adenosine monophosphate-activated protein kinase).

It does this by sensing something called the AMP-to-ATP ratio.

ATP releases energy as it releases a phosphate molecule and is broken down into ADP. When energy is low, 2 ADP’s are joined together to make an ATP, which leaves an AMP left over. (ATP is an adenosine molecule with 3 phosphates attached, ADP is an adenosine molecule with 2 phosphates attached, and AMP is an Adenosine molecule with 1 phosphate attached).

ATP = Adenosine Tri phosphate (3 Phosphates)

ADP = Adenosine Di phosphate (2 Phosphates)

AMP = Adenosine Mono phosphate (1 Phosphate)

When 2 ADP’s come together (2 phosphates plus 2 phosphates), it produces ATP (3 phosphates) with AMP (1 phosphate left over).

When the ratio of AMP increases relative to ATP, it signals that there is less energy available and so AMPK is stimulated. When AMPK is stimulated, it stimulates another protein called ULK1 which leads to the production of the membranes that become the phagophore.

Benefits of intermittent fasting

NAD+ and the Sirtuins

Fasting also increases the levels of NAD+, the oxidised form of NADH, which is an active form of Vitamin B3 (vital for energy production).

The Sirtuins are a family of proteins that directly stimulate autophagy

The production of energy in the mitochondria results in more NADH becoming NAD+. This increase in the NAD+ to NADH ratio stimulates the production of the Sirtuins.

The Sirtuins are a family of proteins that directly stimulate autophagy. Their production is also associated with an increased lifespan and an increase in DNA repair (2).

Both AMPK and the Sirtuins also activate other genes that are known to have many health benefits, most notably including the FoxO family, TFEB, PGC-1a and P53.

  • Activation of the FoxO family is associated with increased stress resistance, a longer lifespan, and less incidence of tumors (i.e. cancers). This is due to dysfunctional cells being made to commit cellular suicide (apoptosis) rather than continuing to grow and potentially becoming tumors (3).
  • TFEB is the master stimulator of the production of new lysosomes, so it is directly involved in autophagy.
  • P53 is known as the ‘guardian of the genome’ because it prevents DNA mutations (4) and suppresses tumor formation (5).
  • PGC-1a is the primary gene involved in stimulating the production of new mitochondria. The more mitochondria we have, the less stress there is on our existing mitochondria to produce the energy we need. This makes our energy production more efficient, and the more efficient it is, the fewer free radicals we have.

The Role of Ketosis in Autophagy

Intermittent fasting also leads to a breakdown of fat tissue, increasing the levels of free fatty acids arriving at the liver. This increases the amount of Ketones produced (1).

Ketones are fat-based molecules that can produce energy.

Ketones are fat-based molecules that can produce energy very efficiently. Burning ketones for energy produce fewer free radicals, and their use reduces inflammation. Ketones also stimulate the production of BDNF (brain-derived neurotrophic factor). BDNF is a growth hormone for the brain and stimulates the growth of new brain cells (neurons). It also promotes new synapses which are connections between the neurons (1). The more connections or synapses we have, the more we can learn and understand.

Why are Fasting Diets so Popular in 2021?

So how does this intermittent fasting science actually translate into health benefits?

Weight Loss

Many people decide to try fasting for its weight loss benefits. Studies have shown that, on average, subjects lose between 2.5% and 9.9% of their body weight during the 3-6 month period that fasting studies run for (7, 8). This weight loss has also been shown to be from fat mass as opposed to muscle mass.

Fasting Can Help Regulate Glucose and Insulin Levels

Intermittent fasting has also been shown to decrease fasting glucose and insulin levels in diabetics (10), obese people (7), and non-obese individuals (11). In addition, a study on young overweight women found decreases in total and LDL cholesterol, triglycerides, and blood pressure. They also found a reduction in the inflammatory marker C-reactive protein and the hormone leptin that will usually climb higher with obesity.

Fasting Helps with Testosterone Regulation

They also found an increase in SHBG (sex hormone-binding globulin), which helps to reduce the effects of testosterone. However, when testosterone climbs too high in women, it can have unwanted side effects (12).

Intermittent Fasting Can Even Have Anti-Aging Effects

Most of the studies on intermittent fasting and ageing are conducted on animals. The reason is simple – it’s very difficult to conduct these studies on humans as you can’t follow people for a lifetime, at least not whilst ensuring they stay on an intermittent fasting protocol.

However, stimulation of AMPK and the Sirtuins during intermittent fasting are strongly associated with increased lifespan in animals.

Studies have found that intermittent fasting increases lifespan in mice and monkeys and makes it less likely for them to develop diseases associated with aging (13). One study in mice also found that the mice who fasted also avoided the decrease in muscle mass that happens during normal aging (9).

Conclusion: Is Stimulating Autophagy with Intermittent Fasting Actually Worth It?

Intermittent fasting can have some very positive health benefits:

  • It can stimulate autophagy.
  • It’s associated with an increased lifespan.
  • It can stimulate the production of new mitochondria.
  • It can reduce inflammation as well as improve cardiovascular health.
  • It helps people lose weight.
  • And it can help with reducing high testosterone levels in women.

However, whilst there are some excellent benefits, I haven’t mentioned one potential problem with fasting. And that is, we must be making sure we are definitely fasting and not just starving ourselves.

When fasting is done correctly, it shouldn’t be something that produces bad side effects like dizziness, weakness, irritability, or anything else that’s very negative.

It’s OK to feel a bit hungry. However, when you feel bad or think you can’t wait until your eating slot, you’ve initiated a starvation response.

The starvation response happens when we aren’t producing enough ketones to fuel our brains. Instead, because it doesn’t have enough energy coming in as we eat, our brains perceive a dangerous food shortage. It then does everything it can to make us stop doing things and save energy by making us feel lousy.

I have written a detailed guide on how to avoid the starvation response, so please read it before deciding if this is for you.

With the right information and understanding of how intermittent fasting works, most should give it a try and feel all the potential benefits in their health!

References

(1) Stephen D. Anton, Keelin Moehl, William T. Donahoo, Krisztina Marosi, Stephanie Lee, Arch G. Mainous, III, Christiaan Leeuwenburgh, and Mark P. Mattson, Flipping the Metabolic Switch: Understanding and Applying Health Benefits of Fasting, Obesity (Silver Spring). 2018 Feb; 26(2): 254–268.

(2) Uribarri J, Woodruff S, Goodman S, Cai W, Chen X, Pyzik R, et al. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc. 2010;110: 911–916

(3) Eric L Greer & Anne Brunet, FOXO transcription factors at the interface between longevity and tumor suppression, Oncogene volume 24, pages7410–7425(2005)

(4) Read AP, Strachan T (1999). “Chapter 18: Cancer Genetics”. Human molecular genetics 2. New York: Wiley.

(5) Surget S, Khoury MP, Bourdon JC (December 2013). “Uncovering the role of p53 splice variants in human malignancy: a clinical perspective”. OncoTargets and Therapy. 7: 57–68.

(6) Sanchis-Gomar F, García-Giménez JL, Gómez-Cabrera MC, Pallardó FV (2014). “Mitochondrial biogenesis in health and disease. Molecular and therapeutic approaches”. Curr. Pharm. Des. 20 (35): 5619–5633.

(7) Heilbronn LK, Smith SR, Martin CK, Anton SD, Ravussin E. Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. Am J Clin Nutr [Internet] 2005;81:69–73.

(8) Byrne NMM, Sainsbury A, King NAA, Hills APP, Wood REE. Intermittent energy restriction improves weight loss efficiency in obese men: the MATADOR study. Int J Obes [Internet] 2017:1–10.

(9) Van Norren K, Rusli F, Van Dijk M, Lute C, Nagel J, Dijk FJ, Dwarkasing J, Boekschoten MV, Luiking Y, Witkamp RF, Müller M, Steegenga WT, Behavioural changes are a major contributing factor in the reduction of sarcopenia in caloric-restricted ageing mice. J Cachexia Sarcopenia Muscle. 2015 Sep; 6(3):253-68.

(10) Deng X, Cheng J, Zhang Y, Li N, Chen L. Effects of caloric restriction on SIRT1 expression and apoptosis of islet beta cells in type 2 diabetic rats. Acta Diabetol. 2010;47(suppl 1):177–85.

(11) M’guil M, Ragala MA, El Guessabi L, Fellat S, Chraibi A, Chabraoui L, et al. Is Ramadan fasting safe in type 2 diabetic patients in view of the lack of significant effect of fasting on clinical and biochemical parameters, blood pressure, and glycemic control ? Clin Exp Hypertens. 2008;30:339–57.

(12) Harvie MN, Pegington M, Mattson MP, Frystyk J, Dillon B, Evans G, et al. The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: A randomized trial in young overweight women. Int J Obes. 2011;35:714–27.

(13) Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems. Mattson MP, Wan RJ, Nutr Biochem. 2005 Mar; 16(3):129-37.