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.

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 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 wouldn’t look so hot. 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 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. Although we don’t yet have clinical trial evidence for this, 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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92 comments

  1. Ferris
    Dr. Sarah Ballantyne (Paleo Mom) said Keto is dangerous. I got off of it due to her comments. Any truth to this?
    Reply: #90
  2. Gentiann
    It seems that's her allegations are not supported by science.
    Check, on this site, the science of low carb and keto diets.
  3. 1 comment removed
  4. Vicente
    The linked study of leucine "Excess Leucine Intake Enhances Muscle Anabolic Signaling but Not Net Protein Anabolism" is completely misinterpreted here. Apart from the fact that it had only 14 participants total, it never says anything such as "small amounts of leucine could stop autophagy cold". On night-fasted participants that were given "carbonated drinks representative of high-quality protein containing 18% and 35% leucine" mixed muscle fractional synthetic rate was "elevated in both groups 60 min following nutrient ingestion". The article even concludes saying that "future studies are required to determine whether the seemingly small _improvements_ in net muscle protein balance with higher leucine translate into clinically meaningful changes in skeletal muscle mass over time and whether nutrients (EAAs and/or leucine) play a regulatory role in the control of human skeletal muscle autophagy. However, taken in the context of the current literature regarding the amount of leucine able to elicit a maximal protein anabolic response, our results are in agreement with others that indicate ~1.8 g in an amino acid mixture is sufficient." Anyone care to explain?
  5. 1 comment removed
  6. Russell Aleksic
    Can someone please tell me if I can drink plain water, green tea or black coffee during AUTOPHAGY. No rude comments please. TIA
    Replies: #57, #72
  7. Josie
    Russell,

    Please also check out DELAY, DON'T DENY (Gin Stephens). She discusses CLEAN fasting (plain water, plain seltzer water, black coffee, plain tea - black or green - NO FRUIT FLAVORS). Clean fasting, no sweetener, drink your water and coffee, etc, during your fasting time, and have a small snack a bit before your main meal. or you can do OMAD - one meal a day - but that has done wonders for me. I love this website, Dr. Fung, and all the info coming out on Intermittent Fasting. Once you get over the worry about not eating, and start listening to your body, you will get used to it and FEEL SO MUCH BETTER. I didn't think I could do black coffee, but I started getting off of the sweetener and cream, and boom, I'm drinking my coffee black. You can do it!

  8. MR
    So does this translate into improved life expectancy in Pakistan, for example, vs western countries?
  9. Mamatha
    Such an interestin concept explained easily. Never knew that body has a auto cleaning mechanism which leads to anti aging results.....I like it. Thank you
  10. Connie
    Autophagy has been linked in helping Alzheimer’s, but is there evidence it would also help Lewey Body Dementia?
    Reply: #61
  11. Kristin Parker Team Diet Doctor

    Autophagy has been linked in helping Alzheimer’s, but is there evidence it would also help Lewey Body Dementia?

    Nothing concrete yet, but this study looks very promising!
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243049/

  12. Curtis S.
    I have been doing an autophagy diet with only eating Keto since October 22nd. I lost 60 pounds in 2 months and had nothing but positive effects from it after the initial rough 5 days of feeling hungry. I did not go to the gym during this time or have any heavy activity. I recently went off the diet a little during Xmas....I ate twice a day and added some carbs and I gained 8 pounds back and feel more sluggish. I will continue my weight loss journey and “getback on the train” as my goal is to lose 100 pounds in 5 months and lose 30% of my starting weight. Good luck to those who can accomplish eating once a day on a keto diet, as this takes will power and learning the difference between hunger and head hunger.
    Replies: #67, #68
  13. Susan
    How long do you need to fast before the body begins autophagy? Could I fast for 18 hours, eat in a 6 hour period or do I need to do a 24 hour fast?
    Replies: #64, #74, #88
  14. Kristin Parker Team Diet Doctor
    That is going to vary from person to person. You can experiment with either method.
    Replies: #65, #69
  15. Victoria
    Does black coffee stop autophagy?
    Reply: #66
  16. Kristin Parker Team Diet Doctor
    Generally speaking, black coffee is acceptable during fasting, as is bone broth.
    https://www.dietdoctor.com/intermittent-fasting/time-restricted-eating
  17. Bakar
    Hi, please do share what an autophagy diet is. I am on keto and lost a few pounds but you are amazing.
  18. Julie
    Hi Curtis
    Congrats on the weight loss. Can you please clarify what you mean by an autophaging diet? I presume you are talking about intermittent fasting, but but what regimen are you following? 16:8, 24 hours fasts ? Longer fasts ?
    Reply: #71
  19. Julie
    Hi Kristin
    You said the length of time fasting in order to stimulate autophagy varies from person to person. How do you know if your body has begun autophagy to judge this?
    Reply: #70
  20. Kristin Parker Team Diet Doctor
    There are no external symptoms of autophagy. Dr Fung does have more in depth articles on his IDM Program website. They don't exactly answer your question but do give more in depth information about autophagy and fasting.
    https://idmprogram.com/fasting-and-autophagy-fasting-25/
  21. Kristin Parker Team Diet Doctor
    You can read more about the different regimens here - https://www.dietdoctor.com/intermittent-fasting
  22. Andrea
    Hi all, I am really unclear on whether black coffee stops autophagy (whilst on a prolonged water fast). Can one of the Team Diet Doctors please advise? I see so many conflicting opinions on the internet and books I have read. Many thanks, Andrea
    Reply: #73
  23. Kristin Parker Team Diet Doctor
    Generally speaking, black coffee is acceptable during fasting, as is bone broth.
    https://www.dietdoctor.com/intermittent-fasting/time-restricted-eating
    Reply: #77
  24. JD
    Good question & here is the answer. If you are in ketosis, then autophagy is taking place because you emptied all sugar from liver & then emptied sugur from cells. The easiest way to tell is get ketone strips to pee on at end of you fast & see if in ketosis. It took a few days for me, now I can eat anything I want & be in ketosis at end of fast.
  25. 1 comment removed
  26. Crystal
    Dr. Fung says too much autophagy can damage as well...how much is too much? How often should we being doing this process for optimal results? I am at goal weight but see I still have more actual fat to lose. However, I am also wanting to do this for health benefits.
    Reply: #78
  27. Andrea
    Hi Kristen, I understand black coffee is okay for fasting but my question is specific to autophagy? Dies black coffee stop autophagy? I have read many conflicting medical opinions. Many thanks
  28. Lisa I
    I would also love to know the answer to this question. Anyone have any links/resources for this?
    Reply: #79
  29. Kristin Parker Team Diet Doctor
    Dr Fung recommends shorter fasting periods once you've reached maintenance.
    https://www.dietdoctor.com/intermittent-fasting/questions-and-answers...
  30. Monique
    Kristin, I really got a lot of helpful information from Dr. Fung! If an obese person wants to lose weight, they should try intermittent fasting and eat few carbs, correct? I realize this is a very simple "explanation" on my part, but this is how I'm summarizing it for myself.

    Thank you.

    Reply: #81
  31. Kristin Parker Team Diet Doctor
    People who are just starting out sometimes find that incorporating fasting right away is too difficult as they are still too hungry too often. Many people have success starting with keto or low carb high fat and then incorporating fasting after a couple of months, once they are fat adapted and naturally able to go longer without getting hungry. A good place to start is with the 2 week challenge. It is free and automatically created to help people eat keto macro ratios without having to track carbs or calculate anything.
    https://www.dietdoctor.com/low-carb/get-started
  32. rania
    that is not a new discovery , prophet Mohammad peace be upon him guided Muslims into fasting Ramadan month each lunar year to sustain health .
  33. Ruth
    Hi day 4 IT 8:16, not finding it too hard but is it normal to feel tired? No rude comments please
    Reply: #85
  34. Carol
    Be sure to have some salt and magnesium Dr Phinney says Keto flu is just mineral imbalance.
  35. Kristin Parker Team Diet Doctor

    Hi day 4 IT 8:16, not finding it too hard but is it normal to feel tired? No rude comments please

    Make sure that when you are eating, you are getting enough electrolytes, especially salt.

  36. Johnda
    I find the fasting idea quite interesting. My husband and I just started keto, and we are not eating nearly as often. We're trying to only eat when we're hungry, and sometimes that's just one meal a day. We're drinking a lot of water now, too. These changes just kind of started on their own. We're not trying to fast, but we're definitely getting a lot more hours between meals than ever before.
  37. Sharon H
    Can you take electrolytes during fasting hours without breaking fast? I take Dr. Bergs electrolyte powder, otherwise I get leg cramps.
  38. David Miller
    Autophagy is also achievable through intermittent fasting just as easily as longer fasts. Autophagy begins when liver glycogen is depleted, around 12-16 hours into a fast. The rate of autophagy peaks there, and then drops after about 2 days.
  39. Don Michel
    I have started doing doing 3 40 hour fasts each week (two weeks in). This has proven to be quite easy for me, and I think I could maintain it forever. But, is this enough to maximize results, or would I be better off doing one longer fast each week?
  40. g Kaplan, MD
    Yes,
    Paleo provides animal protein which cancers need to thrive, ultimately killing the host.

    This Nobel Laureate explains how the human body, if it has not exogenous animal proteins, during fasting, will cause cancer cells to die off a they starve themselves to death. Normal cells wont die for they are programmed to have a circadian cycle which allows them to go without food during that period.
    Eating a non processed whole plant diet keeps cancer in check, as vegetable proteins are less nourishing to cancer than plant based ones.
    BEWARE, plant based diets require B complex vitamins, or anemia and demantia can ensure!!

  41. Mary White
    Josie, same for me; after I got over worries that I could harm myself without three meals every day I began eating one meal per day (dinner) and have never felt better at any other time in my life. Fasting has changed my life for the better, and I owe that to Dr. Fung's books. As a child I hated to eat breakfast and lunch; I've always had very slow digestion and eating more than one meal makes me feel terrible. I think I always was destined by nature to require fasting for my health; we're all different and we all must find what keeps our metabolisms running smoothly. Having to manufacture digestive chemicals three times a day doesn't feel "right" to me.
  42. Ellen
    Glucogan is produced by the pancreas which signals or stimulates stored glucose to be released into the blood when blood glucose is low. So how does this theory work, if autophagy is activated by glucogan and decreased by glucose?
  43. Lan
    Does Apple Cider Vinegar stop the Autophagy process? Thank you in advance.
  44. 1 comment removed
  45. sara abdul
    my inquiry is " in autophagy proceger i can consume water when i "m thirsty or not allowed "
    Reply: #96
  46. Kristin Parker Team Diet Doctor

    my inquiry is " in autophagy proceger i can consume water when i "m thirsty or not allowed "

    Dr Fung recommends water or bone broth. Tea or black coffee with a tiny bit of cream may also be ok.

  47. Frank
    I have a question about fasting and tea sweetened with stevia. It is said that any sweeteners activate insulin release and therefore stimulate mTOR, shutting off autophagy, but just how does the body know to associate sweet tastes with insulin, and would this even matter prior to the fast having gone long enough for autophagy to get going in a big way?

    How would sweet tasting herbs like stevia that have no significant carb, amino acid, or fat content even trigger insulin, or is that a hypothesis, based on artificial sweeteners that do contain amino acids? And if they do, perhaps by depleting insulin stores early in the fast, might they even bolster autophagy later?

    I also wonder what effect nutrient co-factors such as vitamins that provide no significant "fuel" would have. Might they actually facilitate autophagy by enabling easier processing of the cells being consumed?

    I've been in a pattern of fasting for typically about 19 to 24 hours while only drinking water and teas, sometimes with stevia, and only taking vitamin C buffered with correct ratios of minerals (slightly more Mg than Ca and/or about 3:1 K/Na), then doing a short (about 15 to 30 imutes including warm-up and cool-down) and extemely intense HIIT and/or strength workout, then slamming a power drink and pigging out while my body is in muscle building mode.

    The results have been phenomenal in terms of fitness and generally feeling great. I don't feel hungry when my body is ready to go in fasting mode, which it typically about the 3rd or 4th day after a workout. I've found it quite unnecessary and in fact not beneficial to do such intense workouts - however short - more frequently than the 3rd day after, and haven't even noticed any negative effects if going a week without working out when my day-to-day activities include incidental exertion, such as lifting, drumming, dancing, snow shoveling etc.

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