Autophagy: Turning Stress into Health

Caveman Doctor is going to shift gears here and progress from his days as a member of H. erectus to H. sapien in an effort to get a little more cerebral.  This article gets a little (ok a lot) sciency, however, I think the topic should be discussed at length because there is a lot of info going around on Paleo and caveman discussing pathways to autophagy, including intermittent fasting and exercise, without a lot of science.

Autophagy Autophagy: Turning Stress into Health

What is Autophagy?

Our cells are constantly breaking down, repairing themselves, and regenerating.  However, this process is by no means perfect, and often some parts are unfixable.  Also, often cells are just too old and beat up, and much like an old 1985 Yugo, sometimes it’s better to just totally replace the old piece of junk.  Of note, the Yugo may actually be the worst car ever.  Well, autophagy is the process that takes this old Yugo, strips off the pleather seats and interior, and reuses the metal to build a brand new Ferrari.  In fact, the process of autophagy uses structures called lysosomes, which are able to tear apart and reuse our cellular parts or even completely destroy unusable Yugo-esque parts1,2.  This garbage is converted to amino acids, the building blocks of proteins, which can then be transported throughout the body for use.  This process helps rejuvenate cells and clear out the junk that builds up.
 
Autophagy is important not only in that it removes detrimental cells and machinery, but also in how it removes these parts.  Autophagy kills these cells in a contained environment, doing it safely and effectively.  This “hazmat” type programmed destruction is much unlike its counterpart, necrosis.  When necrosis occurs, the kill is uncontained and leaks inflammation and damaging chemicals into the surrounding environment, which can in itself lead to further cellular damage and cancer3.  While autophagy would be like pulling out a weed in your yard, necrosis would be the equivalent of spraying your whole lawn with roundup to kill that one weed.  Autophagy basically kills defective or dying cells in a controlled manner and this alone could be a large benefit of autophagy.
 
“Autophagy is to a club or rock, as necrosis is to a bomb.”
 
 

Autophagy:

  1. Decreases unnecessary cellular processes during starvation or fasting
  2. Rids the cells of clutter, which causes aging of cells and the body
  3. Performs cellular remodeling, which is a form of internal spring cleaning
  4. Suppresses cancer and tumor formation by blocking over-proliferation of cells
  5. Destroys microbes and other infectious elements of cells
  6. Regulates our immune system to fight future infections4
  7. Supplies us with energy during times without food5,6

As a result, autophagy reduces:

  1. Cancer7
  2. Insulin resistance8,9
  3. Infections
  4. Aging
  5. Heart Disease
  6. Neurodegenerative diseases (Parkinson, Alzheimer’s, etc.)10
  7. Inflammation4

Judging by the list above, I likely don’t need to spend too much time convincing you of the importance of autophagy.  When old cellular products and garbage build up, this clutter causes disease, aging, and malfunctioning within our cells.  Also, when errors happen within the DNA of cells or they start reproducing more than they should, autophagy destroys these cells that would otherwise lead to cancer11.  However, when is autophagy turned on and how does our body know how much remodeling is necessary?  Can it happen too much or too little, just as if we don’t replace old cars, the streets would be cluttered with old rusting frames, and if we replace every car on the road with a Ferrari?  This would be somewhat wasteful; amazing but wasteful.
 

The main processes that turn on autophagy:

1. Fasting
2. Ketosis
3. Exercise
4. Acute Stress (which includes fasting and exercise)
 
Interestingly, the caveman experienced all of these frequently, and call it evolution if you like, but we have experienced these states regularly for the past several millions of years, and our bodies have used them to become more efficient.  In fact, these processes likely protect us from many types of chronic diseases.  The caveman often went without food for long periods of time, and in order to stay alive, engaged in frequent high-intensity and short-duration exercises when he was lifting heavy objects, attacking animals, and running from predators.  It is a testament to Nature that she turned something that may seem so bad (no food for days, running from a bear, etc.) into something that can be so beneficial for our health.
 
 

The Pathways:

While this is not meant to resemble a chapter from a text book, several cellular pathways inhibit autophagy and can lead to cancer, including IRS, mTOR, PI3K, AKT, among others.  Interestingly, intermittent fasting inhibits these pathways, leading to autophagy.  A separate pathway, AMPK, is upregulated during fasting and exercise, and as Nature likely intended, it actually increases autophagy by blocking mTOR and some of the pathways listed above.  A concise schematic of these pathways is below.  Also take note of the effect of insulin-like growth factor (IGF), its receptor, and the likely effect of increasing insulin sensitivity (all relating to carbohydrate intake).
 

autophagy pathways copy Autophagy: Turning Stress into Health

Abbreviations: IF = intermittent fasting, IRS = insulin receptor substrate, IGF-1 = insulin-like growth factor 1, IGF1-R = insulin like growth factor 1 receptor, PI3K = phosphatidylinositol 3-kinase, mTOR = mammalian target of rapamycin, LKBA = liver kinase B1, AMPK = AMP-activated protein kinase.

Molecular Pathways Affected by Intermittent Fasting. The IF icon indicates pathways affected by IF. IGF-1R, AKT, IRS, mTOR and PI3K are decreased with IF. LKB1 and AMPK are increased with IF, and AMPK activation increases autophagy.
 
These are also the pathways that we are currently trying to hone in on with targeted cancer therapy as many (including myself) see these pathways as key in the formation and progression of tumors.  While many drugs target these pathways, we can decrease them naturally through diet and exercise, hopefully before cancer even starts, but likely during treatment as well.
 
 

Healthy Stress:

Just as we have previously discussed here and here, acute stress may have many benefits on our bodies.  Acute stress provides us with a stimulus to create more beneficial cellular components (like in our immune system) or a stimulus to remove more harmful ones (like faulty cells and cancer).  The two natural ways to cause healthy, acute stress are through diet and exercise.
 
 

Exercise:

A healthy and naturally way to stress the body to elicit autophagy is through exercise.  Animal studies have shown that acute exercise turns on autophagy in skeletal and cardiac muscle cells12.  Autophagy also is turned on in the pancreas (where insulin is made) and the liver (where ketones and other energy sources are made) during excercise.  And briefly to avoid too much science here, BCL2 is turned off as well.  BCL2 is a very important protein that stops apoptosis (the killing of our cells) and autophagy.  While killing our own cells may sound bad, this targeted assassination is how our body effectively eliminates mutated cells that could eventually form into cancer.
 
Studies ran mice on treadmills, and interestingly autophagy was turned on after 30 minutes of exercise, but plateaued after 80 minutes.  This further lends credence to those of us who avoid long, chronic cardio, and instead engage in acute, high-impact exercise, which provides the benefits of the chronic cardio without the detriments in terms of excess stress and pounding on our body.
 
One other more controversial (and interesting) theory is that of Michael Ristow, who has showed through his research that exercise causes mitochondrial stress.  The mitochondria are the powerhouses of our cells and turn our ingested fats, carbohydrates, and protein into energy.  In response to the acute free radical damage and stress within our mitochondria during exercise, Ristow has showed that they create more catalase13 and other free-radical fighting substances, which leave our cells more able to fight and recover from damage.  According to his research, exercise is a type of military training that prepares our cells for the constant battle against free radicals and oxidative damage.  Coincidentally, his research also shows that glucose restriction works similarly as exercise to extend lifespan14 and glucose consumption correspondingly shortens it15,16.  Needless to say, his work is met with much controversy.
 
 

Diet:

Intermittent Fasting:
The literature is abundant with sources showing that calorie restriction (20-40%) activats and shuts off many cellular pathways that increase longevity and decrease many chronic diseases.  Interestingly, a method of periodic calorie restriction may actually provide the same or more benefits and is much easier to accomplish.  Intermittent fasting (IF), involves periodic fasts of anywhere from 12-18 hours, to as long as 72 hours.  For those of you low-carbers out there, this often occurs without you knowing it as eating a diet based on fat and protein, often leaves us less hungry, making short-term fasts quite easy.  Once the rebound hunger pangs of insulin fluctuation are removed, it’s not hard to skip a breakfast here or there, resulting in a 15 hour fast.
 
Ketosis:
The other easier method of calling upon your cells to clean up their mess is through ketosis.  When we eat a low-carbohydrate diet (below 50 grams of carbohydrates), our liver starts producing ketones.  Though, if consuming generally low levels of carbohydrates, a period without food here or there leading to a dip below 50 grams in a day, or a hard workout will likely knock you into ketosis every now and again.  If you are curious, you can check with Keto-Strips.
 
Ketones are a source of fuel for our bodies and brains when carbohydrates are not around.  They are an evolutionary product, if you will, that provide our cells with readily usable energy sources.  They also appear to have properties that protect our brain from damage and aging.  In fact, there are even trials showing that they improve cognitive performance in patients with Alzheimer’s disease17.
 
This process seems to trigger to our cells that it’s clean up time (similar to fasting) by activating our lysosomes to break down old and faulty proteins18.  The nice thing about this innate “green technology” is that you get the benefits without fasting.  Sometimes the body will even start to break down protein, and while most of us do not want this to happen, our body does reach for the non-essentials first and the junk in our cells before going after the good stuff.  The great part about a caveman diet is that with the amount of protein and fat we consume, we can use our food to produce the glucose (and ketones) necessary without breaking down our own body sources of protein, like lean muscle.  Cavemen don’t want to lose their muscle that they use for strength activities, and they are even a little vain and like looking a little (or a lot) muscular.
 
As a side note:
There is much data linking calorie restriction, fasting, longevity, and many health benefits.  Interestingly, while animal studies have shown a decrease in insulin and insulin-like growth factor (IGF) from long-term calorie restriction, the same has not occurred in humans.  Short term restriction has shown decreases in IGF19,20, which is likely a cause of many malignancies, including prostate cancer.  However, when we are placed on long term calorie restriction, IGF levels normalize21.  My view is that ketosis occurs during short term fasting (and not long term calorie restriction) because this often occurs with a diet that is chock-full of carbs, knocking the follower in and out of ketosis.  The ketosis may be what really provides the benefits here.  This is where short term fasting can be beneficial and NOT necessarily overall calorie restriction.
 
The other issue, which a group that I work with has found, is that if you load up on carbohydrate-rich food in the non-fasting period, the results may not be as good due to insulin and IGF levels shooting through the roof.  Perhaps if you load up on caveman/Paleo-type foods during the rebound period, it doesn’t matter as much.  I would bet my money on this (and am betting my health on it).
 
 

In Summary:

Autophagy is a process of cellular recycling that effectively removes old, damaged, and faulty equipment in our body, potentially stopping cancer, insulin resistance, diabetes, infections, heart disease, Alzheimer’s, inflammation, and even aging.  Combining fasting, intense exercise, and a low-glucose lifestyle is likely a near-perfect combination of turning on autophagy while minimizing excessive damage.  It’s no surprise that they are all the same mechanisms that we have naturally experienced in nature for millions of years.
 
The real endeavor here is to channel this innate process of spring cleaning within our body for maximal health benefits, without overdoing it and experiencing unnecessary stress.  My answer for this, like many things, is to apply the stresses for which autophagy likely was created; the same stresses we experienced during millions of years of fasting, sprinting, lifting heavy objects, and avoiding those causes of excess inflammation like chronic stress, sugar and excess carbohydrates, distance running and exercise that excessively stresses the body.
 
The advantage of a caveman diet and lifestyle is that we are naturally engaged in all of these.  Now we can add autophagy onto the long list of health benefits.
 
SIGNATURE2 Autophagy: Turning Stress into Health
 
 

Reference:

1.         Mizushima N: Autophagy: process and function. Genes & development 21:2861-2873, 2007

2.         Mizushima N, Levine B: Autophagy in mammalian development and differentiation. Nat Cell Biol 12:823-830, 2010

3.         Mizushima N, Levine B, Cuervo AM, et al: Autophagy fights disease through cellular self-digestion. Nature 451:1069-1075, 2008

4.         Levine B, Deretic V: Unveiling the roles of autophagy in innate and adaptive immunity. Nature Reviews Immunology 7:767-777, 2007

5.         Lum JJ, Bauer DE, Kong M, et al: Growth Factor Regulation of Autophagy and Cell Survival in the Absence of Apoptosis. Cell 120:237-248, 2005

6.         Kotoulas OB, Kalamidas SA, Kondomerkos DJ: Glycogen autophagy. Microscopy Research and Technique 64:10-20, 2004

7.         Levine B: Cell biology: Autophagy and cancer. Nature 446:745-747, 2007

8.         Yang L, Li P, Fu S, et al: Defective Hepatic Autophagy in Obesity Promotes ER Stress and Causes Insulin Resistance. Cell Metabolism 11:467-478, 2010

9.         Jung HS, Chung KW, Won Kim J, et al: Loss of Autophagy Diminishes Pancreatic β Cell Mass and Function with Resultant Hyperglycemia. Cell Metabolism 8:318-324, 2008

10.       Hara T, Nakamura K, Matsui M, et al: Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885-889, 2006

11.       Jin S, White E: Role of autophagy in cancer: Management of metabolic stress. Autophagy 3:28-31, 2007

12.       He C, Bassik MC, Moresi V, et al: Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481:511-515, 2012

13.       Ristow M, Zarse K, Oberbach A, et al: Antioxidants prevent health-promoting effects of physical exercise in humans. Proceedings of the National Academy of Sciences of the United States of America 106:8665-70, 2009

14.       Schulz TJ, Zarse K, Voigt A, et al: Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell metabolism 6:280-93, 2007

15.       Lee SJ, Murphy CT, Kenyon C: Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression. Cell metabolism 10:379-91, 2009

16.       Schlotterer A, Kukudov G, Bozorgmehr F, et al: C. elegans as model for the study of high glucose- mediated life span reduction. Diabetes 58:2450-6, 2009

17.       Henderson S, Vogel J, Barr L, et al: Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial. Nutrition & Metabolism 6:31, 2009

18.       Finn PF, Dice JF: Ketone Bodies Stimulate Chaperone-mediated Autophagy. Journal of Biological Chemistry 280:25864-25870, 2005

19.       Thissen JP, Ketelslegers JM, Underwood LE: Nutritional regulation of the insulin-like growth factors. Endocrine reviews 15:80-101, 1994

20.       Smith WJ, Underwood LE, Clemmons DR: Effects of caloric or protein restriction on insulin-like growth factor-I (IGF-I) and IGF-binding proteins in children and adults. The Journal of clinical endocrinology and metabolism 80:443-9, 1995

21.       Fontana L, Weiss EP, Villareal DT, et al: Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell 7:681-7, 2008

© Caveman Doctor 2012.  All Rights Reserved

Comments
30 Responses to “Autophagy: Turning Stress into Health”
  1. Tyler Wood says:

    Howdy CD.

    I just finished my first “voluntary” intermittent fasting period, 24 hrs. I’ve been eating the low carb, Paleo style diet for 18 months now along with CrossFit style exercising as well. I wanted to give it a shot. I went from noon to noon the next day as I figured I’d be sleeping for 7-8+ hrs of it so that might make it easier. Overall, not too hard but I could tell I was pretty hungry.

    Questions for you – 1. Is there a minimum amount you can fast (say 6 hrs or so) and still get the benefits? Also, any other fasting schedules/time frames that work for you?

    Thanks, Tyler

    • cavemandoctor says:

      Hi Tyler,

      Congrats on the fast and your lifestyle! The data on this isn’t great. The cancer intermittent fasting people do around at least 24 hours and it varies. Dr. Seyfried recommends doing a 7 day fast once a year. I have never tried either of these and I can’t imagine doing a 7 day fast. I stick with 18 hour fasts periodically. I find the easiest going from dinner to lunch the next day. More than this starts to drive me nuts. I hit ketosis often too which is another form of autophagy as well.

      The minimal time for being considered a fast is a good question. I personally don’t consider it a fast unless it’s 10-12 hour, but really 18, though this is based on no data whatsoever just a personal preference…
      CD

      • Tyler Wood says:

        Great, thanks CD. Now that I’ve done 24 hrs, 18 hrs should be a lot easier. Skipping breakfast and a mid-morning snack doesn’t seem too bad.

        I will be heading out to AHS in a few weeks. Hope to meet you & Roger while I am there.

      • cavemandoctor says:

        Tyler,

        Hope to meet you there as well!

  2. MichaelR says:

    I did not see anything about protein restriction in the diet segment. Do you disagree with the research on protein restriction as it relates to autophagy?

    • cavemandoctor says:

      Not at all. I didn’t expand the article more bc it was getting long-winded for my readers. However, the main points: Intermittent fasting and low-carb/high-fat, which usually includes low protein when done right, are both methods of ramping up autophagy (and both naturally involve decreased protein). I planned on posting more on the topic, if I could find some more time in my schedule.
      -CD

  3. Jack says:

    Great article. Quick questions about mTOR. I thought mTOR was a good thing in terms of building muscle. However, if activated or perhaps go awry, it t can cause cancer?

    How do we maximize mTOR in our favor?

    Thanks
    Jack

  4. Peter H says:

    I am a bit confused on the pathways that inhibit autophagy, like mtor akt, ampk pi3k
    these are all pathways that are important for muscle hypertrophy and are increased with resistance training
    seems like resistance training would be bad bad…

    • cavemandoctor says:

      Peter,
      You are right. These are anabolic pathways that turn on cell growth, reproduction, etc, which is also what leads to cancer (excess cellular proliferation) in a simplified view. This is where it gets difficult to quantify the benefits and risks of channeling these pathways. I try to turn them on before and after my workouts and then take steps to get my body into autophagy at other times.
      Take care!
      CC

  5. jake says:

    Nice! Thank you, and I never understood this very well. Really helps us older cavemen! I remember reading a few years ago and this 80 something guy was really trying to get across how much his one day fasts/week were helping his health. He would go to bed, not eat the whole next day, go to bed, then eat as much as he wanted the next day. He was explaining it on a fitness blog, I think. He couldn’t quite convince everyone just how high this should be on people’s priorities. Your excellent blog post made it to the Evolution Diet Chronicles! Visit my hunter gatherer blog there if you have a chance. Thanks again for helping so many people with your efforts and knowledge.

  6. Lisa says:

    This article is invaluable – scientific but still accessible. I listen to your podcast, as well as that of Robb Wolf and Ben Greenfield, and you all recently ‘encouraged’ me to take the leap into a ketogenic diet (I’ve been primal/paleo for about 6 months). I’ve been fully in ketosis now for about 10 days and while I truly wouldn’t have believed anyone who told me my cravings would disappear, they have and it’s liberating beyond measure (not that it’s relevant but my ration is about 1400 kcal, 8% carb, 15% protein, 77% fat). My energy is stable and consistently high, my sleep is excellent, my gym sessions have been surprisingly good (although short fast burst training seems to be suffering a bit but I’m hopeful I’ll adapt). I haven’t lost a lot of fat but that wasn’t really my goal (I’m a fit 45 yr old female, 125 lbs, bmi of 20) although I’m as vain as the next person who claims they aren’t, lol! Anyway, I’ve been curious about this benefit from ketosis and couldn’t find a succinct and scientific explanation until now. You’re kind of an arrogant jerk sometimes (Mom’s Thanksgiving stuffing comes to mind…) but humility is overrated and we need confident, unwavering voices to help override the prevailing nonsense – don’t you go changing! And thanks for the great info. :)

    • Thanks, well except for the arrogant jerk part… Glad you are feeling great. Make sure pure keto and not periodic is for you (not for everyone).

      If vanity leads to health go for it!

      • I just asked my mother and she said she wasn’t offended and it wasn’t arrogant. Take that

        • Lisa says:

          Yeah, moms are awesome like that: No matter how many times we break their heart, they still land on our side… Kidding! However, I’ve rejected enough food presented by my loving, but woefully misguided, family members over the years to note that no matter how enlightened they claim to be, or how tactfully you decline, messing about with people’s food issues (aka not eating what they put in front of you) makes politics and religion seem trivial by comparison. (That was my longest sentence ever.) Anyhow, back to the subject at hand, I’m still enjoying ketosis and have been able to maintain it despite several holiday events and too many libations. Yay for autophagy, I’ll definitely need it this month!

          • Lisa says:

            Anecdotally (and somewhat tangentially), I spent about a decade living in Yu’pik Eskimo and Athabascan Indian villages in rural Alaska and saw firsthand how healthy their traditional diet is (still followed by many), despite the paucity of plant material. Sadly, the introduction of sugar, particularly soda, has not contributed positively to many people and an epidemic rates of diabetes, severe tooth decay, and the whole cascade of inflammatory diseases are the result.

            • Very interesting! Yeah, it’s a shame. I am in Costa Rica right now and the amount of vegetable oil filling the shelves is painful, especially while there are coconuts hanging from the trees…

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