How to renew your body: Fasting and autophagy

Yoshinori Ohsumi – awarded the Nobel Prize for his discoveries of mechanisms for autophagy

Yoshinori Ohsumi

On October 3rd, the Nobel Assembly at Karolinska Institutet awarded the Nobel Prize in Physiology or Medicine to Yoshinori Ohsumi for his discoveries of mechanisms for autophagy.

But what is autophagy? The word derives from the Greek auto (self) and phagein (to eat). So the word literally means to eat oneself. 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.

junker_sot_up-300x200There 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. While this may sound kind of macabre at first, realize that this process is essential in maintaining good health. For example, suppose you own a car. You love this car. You have great memories in it. You love to ride it.

But after a few years, it starts to look kind of beat up. After a few more, it’s not looking so great. The car is costing you thousands of dollars every year to maintain. It’s breaking down all the time. Is it better to keep it around when it’s nothing but a hunk of junk? Obviously not. So you get rid of it and buy a snazzy new car.

The same thing happens in the body. Cells become old and junky. It is better that they be programmed to die when their useful life is done. It sounds really cruel, but that’s life. That’s the process of apoptosis, where cells are pre-destined 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. You don’t have to worry about it breaking down at the worst possible time.

Autophagy – replacing old parts of the cell

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.

zh10080957560005-1Autophagy 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. The Nobel prize winning scientist Christian de Duve coined the term autophagy. Damaged sub cellular parts and unused proteins become marked for destruction and then sent to the lysosomes to finish the job.

One of the key regulators of autophagy is the kinase called mammalian target of rapamycin (mTOR). When mTOR is activated, it suppresses autophagy, and when dormant, it promotes it.

What activates autophagy?

Nutrient deprivation is the key activator of autophagy. Remember that glucagon is kind of the opposite hormone to insulin. It’s like the game we played as kids – ‘opposite day’. 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.

This is in essence a form of cellular cleansing. The body identifies old and substandard cellular equipment and marks it for destruction. It is the accumulation of all this junk that may be responsible for many of the effects of aging.

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. We are really giving our bodies the complete renovation.

You need to get rid of the old stuff before you can put in new stuff. Think about renovating your kitchen. If you have old, crappy 1970s style lime green cabinets sitting around, you need to junk them before putting in some new ones. So the process of destruction (removal) is just as important as the process of creation. If you simply tried to put in new cabinets without taking out the old ones, it would be pretty fugly. So fasting may in some ways reverse the aging process, by getting rid of old cellular junk and replacing it with new parts.

A highly controlled process

Autophagy is a highly regulated process. If it runs amok, out of control, this would be detrimental, so it must be carefully controlled. 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. Amino acid signals and growth factor / insulin signals are thought to converge on the mTOR pathway – sometimes called the master regulator of nutrient signalling.

So, during autophagy, old junky cell components are broken down into the component amino acids (the building block of proteins). What happens to these amino acids? 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.

The consequences of accumulating old junky proteins all over the place can be seen in two main conditions – Alzheimer’s Disease (AD) and cancer. Alzheimer’s Disease involves the accumulation of abnormal protein – either amyloid beta or Tau protein which gums up the brain system. It would make sense that a process like autophagy that has the ability to clear out old protein could prevent the development of AD.

What turns off autophagy? Eating. Glucose, insulin (or decreased glucagon) and proteins all turn off this self-cleaning process. And it doesn’t take much. Even a small amount of amino acid (leucine) could stop autophagy cold. So this process of autophagy is unique to fasting – something not found in simple caloric restriction or dieting.

There is a balance here, of course. You get sick from too much autophagy as well as too little. Which 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 – balance. Life is all about balance.


Jason Fung

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48 Comments

  1. Robbin Hayman
    Great metaphors Doc! Another good argument for fasting. Thanks for making the science so accessible.
  2. amy
    Great article! I wonder how all this plays a part in cancer and tumors, too much growing without enough cleansing?
  3. Nicholas
    Does this mean that after 12hrs of fasting (and when regularly in nutritional ketosis) would eating some fat only and not not carbs/protein - keep glucagons up and also autophagy - until carbs/protein were eaten of course?
  4. Peggy
    This is so interesting! Thanks!
  5. Deborah
    Great article Dr. Fung. As a supplement, this is an insightful interview (including a deep dive into mTOR, IGF1,etc.) with Dr. Valter Longo, a professor of gerontology and biological sciences and director of the longevity institute at the University of Southern California. Dr. Longo is a researcher in the field of aging, including the role of fasting and diet in longevity and healthspan in humans as well as metabolic fasting therapies for the treatment of human diseases.
    https://www.youtube.com/watch?v=d6PyyatqJSE
    Reply: #15
  6. Alan
    Thanks for another very interesting article :-)
  7. Ian
    Yoshinori Ohsumi is a true scientist. Good on the Nobel Prize organization!

    I haven't found another site on Yoshinori Ohsumi that talks about using fasting as a technique, however. One site says, "It could give us a way to make Parkinson’s disease drugs that work by controlling autophagy.... It could provide new ways of fighting Diabetes and a host of other diseases. Of course, those advancements are still some ways off."
    http://futurism.com/self-cannibalization-nobel-prize-in-medicine-goes...

    Sheesh!

    Reply: #16
  8. Ian
    Hi Deborah,
    Dr. Longo is talking about refeeding as part of the process, interesting.
  9. Josef
    What fasting protocol do you recommend for Autophagy? I don't need to lose weight, but this cell regeneration sounds very appealing. Thank you.
  10. Cat
    What other lifestyle practices support autophagy. Sleep? Meditation?
  11. ANTHONY
    I have just finished reading 'The doors of perception' by Aldous Huxley and he briefly describes fasting as a way of opening new forms of reality. Very interesting stuff !
  12. Audrey Gregis
    Very cool! And now I know why my nutritional cleansing protocol works so well, as I have experienced. Thanks for a great article!
  13. Derek Davidson
    Brilliant article once again, thank you Dr Fung
  14. KKOFFI
    Wow. Life lessons.
  15. Moira
    Thank you for sharing.
  16. Moira
    Thank you for sharing
  17. Nils
    Re: the question about things (in addition to fasting) that support or can induce both apoptosis and autophagy:

    1) Drinking green tea.
    2) Taking PQQ (found in green tea) (take along with a little fat, and with some CoQ10 for best results)
    3) Green tea polyphenols have been shown to induce cell death (apoptosis) in prostate cancer cells, breast cancer cells and other cancer cells.
    4) Taking quercetin along with resveratrol.
    5) Partial fasts: avoiding carbohydrates.
    6) Partial fasts: avoiding protein for a few days (see Valter Longo's research)
    7) Exercise.
    8) Exercise while fasting (about two hours before a meal)

  18. Alex
    There is a saying in Islam "fasting is healing".
  19. Chyma
    How do i do this? How long do i fast? What fo i eat after coming off fast?! Im already lchf
    Reply: #31
  20. shanbanu
    Congrats well explained phenomenon dr. Now I know why I feel so good after one month of Ramdhan fasting!!
  21. justin
    first off.. the study linked to ingesting amino acids like Leucine supposedly stopping autophagy "cold" only has a sample size of 14 which makes it null at being able to prove anything. Second, word for word the study states the group taking Leucine "indicate autophagy decreased more" which by the wording "decreased more" just means it decreased, not that it stopped it "cold". Third, the study only tracked the participants 180min after ingestion of Leucine.

    I don't mean to sound negative but either one of two things is happening:

    1. The author's of this website are toying with your emotions by over-exaggerating claims to make themselves sound confident and therefore get you to believe them

    or

    2. they searched the web for "scientific studies" using the words "decrease" and "autophagy" and just linked it to this post to make it seem like they have done extensive research knowing full well the majority of people on here wouldn't understand anything the study is saying.

    Either way, i just ask the genuine visitors to this site be careful on what you believe as "scientific fact"

  22. Tim
    Some people can't read...

    "And it doesn’t take much. Even a small amount of amino acid (leucine) could stop autophagy cold. "

  23. justin
    and some people don't understand marketing.. anyone who does understand it knows that a reader emotionally attached to whatever topic is being discussed (such as health) will essentially take that "could" and hold it to be a dire truth..

    In layman's terms.. to your brain Tim, "could" means the exact same as "will".

    and you mistake my intentions, I am merely trying to point out that the vast majority of people who read "could stop autophagy cold" if you take any amino acid will most likely take it as a 100% true scientific fact and avoid any trace of amino acids during fasting for as long as they live... and that shouldnt be the case.

    All I am asking is that just because there is a "Dr." in front of someone's name doesn't mean you should have blind faith in what they say. Trust but verify.

  24. Tim
    In layman's terms.. to your brain Tim, "could" means the exact same as "will".

    Obviously it doesn't, since I pointed it out...and the definition of 'fasting' is not to eat anything. Amino acids, or otherwise...so your point is moot.

  25. justin
    haha thats because after reading my comment you paid more attention to its detail otherwise you would have never thought twice about it but I wont further argue psychology cause I guarantee you're going to respond with another childish remark. Good article Dr. Fung. I am just trying to get people to think about things in a different light/point of view.
  26. Tim
    haha thats because after reading my comment you paid more attention to its detail...

    Your misquote was obvious...and off topic, since the article was about fasting to induce autophagy. Raise insulin, decrease glucagon - decrease autophagy...lower insulin, increase glucagon - increase autophagy. A sliding scale...It's all right there in the article.

  27. 1 comment removed
  28. Dave Beavers
    So after fasting, in combination with a LCHF diet, then it is ok to eat all of the meat you want?
    What I have been reading about LCHF diets point exclusively to eating foods high in fat and protein (meats, cheeses, etc.) and avoiding starches, sugars, bread, pasta, etc., and pretty much leads me to believe that beer and wines are mostly out.
    I have seen in recent labs that I have developed an insulin resistance, albeit small (according to my doctor), but suffer extreme fatigue after meals (short lived), that often seem to be remedied by sugar intakes. Not sure why that is, but it is.
    I also have this spare tire at 49 that has seemed incorrigable, and I have plans for retirement so I feel like I need to get serious about adopting a plan that is going to deliver me to the best physical and mental states that I can exist in, and LCHF seems to be the way to go.
    I welcome any input folks have.
  29. Dale Dewar
    I pick up on Dave's comment about experiencing extreme fatigue and sleepiness after my first meal ... after fasting from the evening before... my second meal is at 8pm and my first at noon ... I only experience the fatigue after the noon meal ... why?
  30. Lou
    I follow Gin Stephens, Delay, Dont Deny book. I fast average of 20 hrs daily eating in a 4 hr window. Some days is 16/8 others 23/1. Very flexible and freedom to eat whatever you desire in your eating "feast" window. Highly recommend the book and GB page by same title
  31. Michael
    Great article Dr. Fung...Because each individual is different, fasting, low carbohydrate diets and Ketogenic diets have many benefits, how does one determine the right balance between fasting and eating if they are strictly focused on the benefits autophagy? Does this occur in a short 1 day fast, or is a longer 4-7 day fast needed? What factors determine when the benefits of autophagy kick in, and when does it become counter productive?
  32. IRF
    Now I know why 30 day fasting is mandatory in Islam.
  33. Muhammed Yusuf
    Just do Islamic fasting, it's one of the benefit is autophagy.
  34. MtnGrl
    Mormons fast once a month for 24 hours, some do it more often for spiritual reasons. The leaders of that church live well into their nineties, fully functioning until almost the very end. I can't help but wonder if fasting is one of the reasons they stay healthy and live so long. Well, that and not smoking or drinking alcohol.
  35. Mohamad Hamdan
    Any references for this article, even the references of the studies are not shown
  36. Maria Jasmine Freeman
    I have been fasting daily- enforced by a horrid menopause with continuous resultant vomiting-for almost ten years( yes 10 years), for more than 20 hrs each day, and I feel v healthy apart from my menopause symptoms.
    More, a recent article has shown that fasting resulted in reduction of the cyst size in polycystic kidney disease mice, while this did not occur in mice on normal diet!!
    Fast, any time you can!
    Maria Jasmine Freeman
  37. Ernesto
    Simply Awesome! Thanks!
  38. Robin Smith
    Thanks for the amazing report.
    I know that, Muslims must fast the whole day time during the holy month of Ramadan besides some optional days during the week.
    It seems to my they are right about fasting.

    The question is what kind of fasting and for how many hours.

  39. Jone
    How fast can you get the benefits in Autophagy? Minimum vs maximum?
  40. Swancoug
    It is unlikely that the 24 hour fast of Islam is long enough to lower insulin and raise glucagon enough to initiate autophagy in between helpings of honey baclava at midnight. As antecdotal evidence I’ll point out that the Islamic world has higher rates of type 2 diabetes than even the US with all our booze and Big Macs. It takes at least three days for even the most metabolically healthy of us to lower insulin levels significantly.
  41. Abdelwahab Hassan
    In fasting as a Muslim you starve yourself from dawn to sunset for 30 days
    Everyday we discover amazing things about Islam in spite of all trials to distort it
  42. Ted
    Does the Autophagy state clear up clogged arteries?
  43. Trust2try
    Islam teach to fast for 30 days and other optional fasting after the Ramadhan. And to add, Islam also teach to eat less or in moderate amount in everything.
    Prophet Muhammad (PBUH) emphasized the habit of eating less as a method of preventing sickness and disease. Prophet Muhammad (PBUH) said:

    “Nothing is worse than a person who fills his stomach. It should be enough for the son of Adam to have a few bites to satisfy his hunger. If he wishes more, it should be: One-third for his food, one-third for his liquids, and one-third for his breath.”

    – Tirmidhi & Ibn Majah

    ** " from the article i read, it said the "breath" may refer to the gas that emitted from the food" (Allah knows best)

    https://religionatlums.wordpress.com/about/eating-habitssunnah-of-the...
    https://www.al-islam.org/message-thaqalayn/vol-14-no-2-summer-2013/ea...

  44. Ellie
    What about people who are diabetic? My doctor says not to skip meals cause it just sends blood sugars higher.
  45. Kevin Mason
    Do people doing keto and IF go into Autophagy faster than people on a standard diet and IF.
  46. Jean Mahy
    Does fasting have any effect on those of us with a familial tendency to DVT? Since my 4th DVT April 2017, I have been taking 20mg of Rivoroxoban daily with food. The medical profession would like me to take this for life. I'm not happy with this.
  47. Nvs
    I Islam fasting liquids including water is prohibited so I don't think it comes in the same category as healthy fasting
  48. Pankaja B
    How does this process relate to diabetic patients ?

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