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Fasting and autophagy

Published : Sunday, 3 June, 2018 at 12:00 AM Count : 1416
HU Shekhar, PhD

HU Shekhar, PhD

HU Shekhar, PhD

The word autophagy is derived from the Greek auto (self) and phagein (to eat). So the word literally means to eat oneself. Autophagy was first described in 1962 when researchers noted an increase in the number of Lysosomes (the part of the cell that destroys stuff) in rat liver cells after infusing glucagon (hormone). The Nobel prize-winning scientist Christian de Duve coined the term autophagy. In 2016, Nobel Prize in medicine was awarded to Japanese scientist Yoshinori Ohsumi for his discoveries of mechanisms for autophagy.

Yoshinori Ohsumi used baker's yeast to identify genes essential for autophagy. He then went on to elucidate the underlying mechanisms for autophagy in yeast and showed that similar sophisticated machinery is used in our cells. Essentially, this is the body's mechanism of getting rid of all the broken down, old cell machinery (organelles, proteins and cell membranes) when there's no longer enough energy to sustain it. It is a regulated, orderly process to degrade and recycle cellular components. There is a similar, better known process called apoptosis also known as programmed cell death. Cells, after a certain number of division, are programmed to die. It sounds really cruel, but that's life. That's the process of apoptosis, where cells are predestined to die after a certain amount of time. It's like leasing a car.

After a certain amount of time, you get rid of the car, whether it's still working or not. Then you get a new car. The same process also happens at a sub-cellular level. You don't necessarily need to replace the entire car. Sometimes, you just need to replace the battery, throw out the old one and get a new one. This also happens in the cells. Instead of killing off the entire cell (apoptosis), you only want to replace some cell parts. That is the process of autophagy, where sub-cellular organelles are destroyed and new ones are rebuilt to replace it. Old cell membranes, organelles and other cellular debris can be removed. This is done by sending it to the lysosome which is a specialized organelle containing enzymes to degrade proteins.

Autophagy requires the right kind of conditions for it to occur. Nutrient deprivation is the key activator of autophagy. When the body is fasting, it signals the brain that there is not enough food available and the body then seeks out stored foods. Autophagy is activated and the cells break down old and damaged proteins in the body. When insulin levels in the body are low, glucagon begins to work in the body, cleansing the body of dead and damaged cells and cell parts.

Activation of autophagy counteracts the age-associated accumulation of damaged cellular components and enhances the metabolic efficiency of cells. Autophagy-related genes (ATG) are responsible for creating the structures that carry out autophagy. The VPS34 complex initiates the autophagosome, ATG9 contributes to its expansion, and the ATG12-ATG5-ATG16L1 complex recruits ATG8 proteins which complete formation and are involved in the targeted capture.

Autophagy is a response to stress that helps cells to become more resilient and conservative with their energy. In particular, autophagy can be activated to remove dysfunctional mitochondria (mitophagy) which produce a lot of harmful reactive oxygen species (ROS) that degrade the cell. These processes are reported to extend the lifespan of several species.

Nutrient deprivation is the key activator of autophagy. Remember that glucagon is kind of the opposite hormone to insulin. If insulin goes up, glucagon goes down. If insulin goes down, glucagon goes up. As we eat insulin goes up and glucagon goes down. When we don't eat (fast) insulin goes down and glucagon goes up. This increase in glucagon stimulates the process of autophagy. In fact, fasting (raises glucagon) provides the greatest known boost to autophagy.

Fasting is actually far more beneficial than just stimulating autophagy. It does two good things. By stimulating autophagy, we are clearing out all our old, junky proteins and cellular parts. At the same time, fasting also stimulates growth hormone, which tells our body to start producing some new snazzy parts for the body. So fasting may actually reverse the entire aging process by getting rid of old cellular junk and replacing it with new parts.
Going through the process of depriving ourselves of food for 12 hours or longer, as Muslims are obliged to do during Ramadan and recommended to do twice a week, is a potent motivator of our internal autophagy processes. Not only does fasting help induce autophagy in the body's cells in general, it has been found to be specifically potent in helping the brain's cells engage in this process.

This potentially makes fasting one of the ways in which we can stave off neurodegenerative disorders such as Alzheimer's and Parkinson's. People pay thousands, or hundreds of thousands, of dollars for stem cell therapy. But prolonged fasting not only kills your senescent cells, it results in the creation of new stem cells, for free. Whenthe fast is over if we then eat enough highly nutritious foods the body will replace the cannibalized senescent cells with new, healthy stem cells.

This is truly remarkable and was only recently verified in laboratory studies. It was thought for a long time that only very young humans (babies) could produce new stem cells; adult bodies could not. But it turns out that they can, and will do so when we fast. Doing a prolonged or extended fast followed by a re-feed is the only known way for an adult to create new stem cells. Being true stem cells, the ones created in the hours and days after a fast can become heart cells, liver cells, pancreas cells, or even brain cells, increasing our intelligence and our "processing power."

Autophagy is a highly regulated process. If it runs amok, out of control, this would be detrimental, so it must be carefully controlled.  Remember, autophagy is turned on when your body is in stress response mode. Stressing your cells is the natural way to turn on autophagy. You can do this through intermittent fasting and protein cycling to create nutrient deprivation in your cells. You can also create cellular stress in the body through exercise. By taking polyphenol-rich supplements and using unique nutritional ingredients, you can control your autophagy.

And that means you can influence the way you age. In mammalian cells, total depletion of amino acids is a strong signal for autophagy, but the role of individual amino acids is more variable. However, the plasma amino acid levels vary only a little. So, during autophagy, old junky cell components are broken down into the component amino acids (the building block of proteins). In the early stages of starvation, amino acid levels start to increase. It is thought that these amino acids derived from autophagy are delivered to the liver for Gluconeogenesis. They can also be broken down into glucose through the Tricarboxylic acid (TCA) cycle. The third potential fate of amino acids is to be incorporated into new proteins.

What turns off autophagy? Eating. Even the slightest amount of food is easy to stop the autophagy process. It requires complete abstinence from food for at least 12 hours, which is the typical duration of the Muslim's fast. It was a regular practice of Prophet Muhammad (peace be upon him) to fast every Monday and Thursday. Prophet Muhammad (peace be upon him) also recommended fasting the same way that Prophet Dawud used to fast, which was fasting on alternate days.

It is praiseworthy to fast three days each month; some scholars say any three days and others say specifically the 13th, 14th, and 15th days of the lunar month. So this process of autophagy is unique to fasting. There is a balance here, of course. You get sick from too much autophagy as well as too little; however, it gets us back to the natural cycle of life -- feast and fast. Not constant dieting. This allows for cell growth during eating, and cellular cleansing during fasting -- a balance. Life is all about balance.

The writer is Professor, Dept of Biochemistry and Molecular Biology, Dhaka University

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