Autophagy

Caloric restriction (CR) activates autophagy.  Intermittent fasting (IF) is basically kind-of-like the opposite of CR.  I’m not knocking IF.  The animal studies of autophagy, based on “chronic nutrition depletion,” more accurately reflect CR which results in decreased body weight or metabolic rate.   IF generally includes refeeds, resulting in weight maintenance.  Also, in the few human studies on it, weight loss (CR) but not fasting (IF) has been shown to induce autophagy.

If you’re actually losing weight over the long-term with an IF protocol, and thus are CR by definition, then I suspect you may be autophaging, too (yeah yeah, I know, that’s not really how autophagy works, but you get the picture).

Disclaimer: I’m relatively autophagy-agnostic; not really confident racing to maximize it is a great thing based on Human Studies.

Book: Autophagy in Health and Disease

 

autophagy-image

 

Exhibit A: autophagy in skeletal muscle

Tl;dr: “a little exercise is a better than a lot of fasting”

A1) Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle (Moller et al., 2015)

The protocol: participants either fasted for 36 hours or received a glucose infusion before and during exercise (cycling at 50% max for an hour).

“In the present study, we demonstrate that short-term aerobic exercise activates autophagic signaling through ULK1 in human skeletal muscle, independently of nutrient background.”

They really should’ve stressed that the deck was stacked to show fasting activated autophagy… 36 hours of fasting is pretty long but it had no effect.

 

 

A2) Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation (Schwalm et al., 2015)

Protocol: shorter fast (overnight), but longer exercise – 2 hours at 55% or 70% max.

“In summary, the most effective strategy to activate autophagy in human skeletal muscle seems to rely on exercise intensity more than diet.”

Higher intensity = more autophagy, but again: no effect of fasting.

 

A3) more support for long-term CR (as opposed to IF) (Yang et al., 2016)

30% CR for 3-15 years!

“The CR individuals consumed a diet with a high nutrient-to-energy ratio, which supplied more than 100% of the recommended daily intake for all essential nutrients.  All processed foods, rich in refined carbohydrates, free sugars, and partially hydrogenated oils, were strictly avoided by the CR practitioners.” A+!

“We found that CR significantly upregulated many autophagy genes, including ULK1, ATG101, beclin-1, APG12, microtubule-associated protein 1 light chain 3 (LC3), GAPRAP/GATE-16, and autophagin-1.  Consistent with some of these gene expression changes, we found that beclin-1 and LC3 protein expression levels were significantly higher in the skeletal muscle of the CR volunteers than in the WD control subjects.”

 

 




 

Exhibit B: autophagy in adipose tissue (where elevated autophagy is theoretically no bueno)

Defective regulation of adipose tissue autophagy in obesity (Nunez et al., 2013)

Protocol: obese humans before and 1 year after bariatric surgery.

“human obesity was associated with increased autophagy, and body mass reduction led to an attenuation of autophagy in the adipose tissue.”

*Of note, bariatric surgery-induced weight loss is more similar to CR than IF; these patients eat frequent, small meals.  In fact, IF may even be detrimental to autophagy in this #context.  You may experience a slight increase in autophagy during early IF (not supported by evidence, but let’s just say theoretically for now), but when you compensate for the caloric deficit via refeeding, any theoretical benefits may be reversed.  Again, I’m not knocking IF.

However, to be clear, I still don’t think the calorie bombs experienced by people eating 1 meal per day or restricting food intake to a small window are very healthy.  There is some evidence showing all your calories in the morning are beneficial… but this was compared to all your calories in the evening, not 3 regularly-spaced meals (eg, see studies by Jacobs & Hirsch).

I don’t advocate grazing (eg, 6 meals per day) because chronic calorie influx or IF because re-feed calorie bombs (among other things)…  I mean, neither method seems particularly friendly to any tissues or organs involved in metabolism and nutrient partitioning…  regardless of whether you’re keto, LCHF, #carbthefuckup, or whatever.

 




 

Exhibit C: autophagy in liver

No nutritional studies on liver autophagy in humans; however, it might be regulated similar to muscle as it seems to move similarly in both tissues in diseases states (eg, Vanhorebeek et al., 2011 & Vescovo et al., 2012).

 




 

Exhibit D: autophagy in brain

No human studies on this, although CR has inconsistent effects on autophagy in mouse brain (eg, Mizushima et al., 2014,  Alirezaei et al., 2010, & Kaushik et al., 2012).   And exercise activates autophagy in mice similar to humans, at least according to this study (He et al., 2012), so it may activate autophagy in human brain as well… although I wouldn’t assume anything about autophagy in human brain at this point.

 

Conclusion: studies showing beneficial effects of autophagy are primarily animal studies.  Human studies are correlative at this point.  That said, if you want moar autophagy, best bet is CR and/or exercise.  Maybe not so much with IF.  Please don’t hate me for this.

 

calories proper

 

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  • Tuck

    Nice post. Facts are hard things. 😉 I think the cyclic ketotic effects of IF are probably beneficial on their own, autophagy would have been a nice bonus, but not necessary. I’m a big fan of fasted exercise myself, and I’ll stick with that protocol. Makes one feel great, and that’s not a bad indicator of health benefits.

    “human obesity was associated with increased autophagy, and body mass reduction led to an attenuation of autophagy in the adipose tissue.”

    I suspect this is a bit of a confounder. Omega-6 metabolite 4-HNE is also a great promoter of autophagy, as it damages the cells to the point where they self-destruct, through carbonylation, among other means. The obese have high levels of 4-HNE, especially in adipose tissue, so I suspect this is a destructive form of autophagy, as the body is unable to repair damage fast enough and cells die. This is not a beneficial process, and reducing it a good thing.

    As the first paper below makes clear, bariatric surgery reduces oxidative stress, and ameliorates the negative effects of excess 4-HNE and related prooxidants throughout the body…

    “What distinguishes adipose tissue of severely obese humans who are insulin sensitive and resistant?”
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575680/

    “Oxidative stress and protein carbonylation in adipose tissue — Implications for insulin resistance and diabetes mellitus”
    http://www.sciencedirect.com/science/article/pii/S1874391913001838

    “Cafeteria diet-induced obesity causes oxidative damage in white adipose”
    http://www.sciencedirect.com/science/article/pii/S0006291X16304260

  • Sky King

    Hmmmm…. And how does one reconcile that with studies like this one:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3106288/

    It would be quite amusing to watch you debate this subject with Yoshinori Ohsumi, a cellular biologist from Japan, who became this year’s Nobel Prize winner in physiology and medicine “for
    discovering the mechanisms of autophagy.”

    http://www.pravoslavie.ru/english/97617.htm

    But I’m sure Ohsumi must be very busy these days, so perhaps a debate on this subject with Dr. Fung may be more feasable?

    https://www.dietdoctor.com/renew-body-fasting-autophagy

  • Human. Studies.

    • Tuck

      So you want to see a study where people are injected w/ 4-HNE and adipose autophagy is induced?

      I don’t think that’s going to happen anytime soon, as it’s a known mutagen and carcinogen. Not going to pass the IRB…

      Infusion is generally unwitting, since most don’t seem to recognize the implication of what they’re doing… 😉

      There’s a spiffy overview here, though:

      http://www.sciencedirect.com/science/article/pii/S0925443915000241

      See “3.1. Effect of HNE on autophagy”

      Still rodents. It’s too difficult to study in vivo in humans from a cause-and-effect perspective, because the effects happen inside the cells and organelles.

      Closest I’ve seen is use of “minced human visceral adipose tissues”. Good heavens…

      • “It’s too difficult to study in vivo in humans from a cause-and-effect
        perspective, because the effects happen inside the cells and organelles.”

        disagree, can be studied in humans just as easily as in animals via biopsies.
        Liver, adipose, and muscle samples are accessible via biopsy.

  • Chantelle

    Hi Bill … great article again as always. Couple of questions –

    Wouldn’t IF be another form of CR? For instance, if someone fasts for the entire day and then eats dinner, chances are they won’t eat as much as if they were eating 3 meals a day … so in effect, they would be restricting calories by a decent amount.

    Also, there are so many articles and books on fasting and autophagy – all citing gold star studies. Did you find otherwise?

    Thanks so much for your insight … I always learn something new when reading your posts 🙂

    • Hi Chantelle, thanks!

      IF is another form of CR *if* weight loss occurs… but many people are weight stable on IF.

      All of the studies I found on fasting and autophagy were really CR because weight loss occurred. And more specifically, they were *not* IF because people were eating many small meals per day (in one case).

      • Martin Tornberg

        If someone fasts for the entire day, then it stands to reason that there would be some degree of weight loss that would start to occur after one has finished digesting the last meal (unless one is drinking a lot). So there would be a few hours during which there would be a bit of weight loss – weight that would probably be gained back at dinner-time (unless there is some CR). During the weight-loss hours, there would be beneficial autophagy taking place.

        • “During the weight-loss hours, there would be beneficial autophagy taking place.”

          Not exactly sure it works like that. The studies showing an impact of CR on autophagy were 1 year (Nunez) and 3-15 years (Yang).

          Evidence for the short-term regulation of autophagy is primarily from exercise studies.

          Do you have any human studies that support your statements?

          • Martin Tornberg

            None that I can think of, but I’m not a researcher in this field, I’m just a regular “lay person” interested in nutrition, so I tend to get my info from articles and blog posts (such as yours) rather than directly from research studies. My comments are thus based less on studies and more on what I’ve read, as well as my inferences. I have done periodic fasts from time to time, as well as doing some shorter “intermittent fasting”, and I’ve always felt that I’ve derived benefits from them. It seems to me that there is a benefit to allowing oneself to be hungry for a while and deplete the body’s glycogen stores. Since learning about autophagy, I have basically assumed that part of that benefit is due to autophagy, which makes sense to me for 2 reasons – 1) it seems intuitive, and 2) I recall reading that autophagy can be activated by glucagon, which indicates autophagy is pretty easily initiated, at least to some degree, and would be likely to start getting initiated when we allow ourselves to get hungry (and allow glucagon to get released).

          • Martin Tornberg

            According to https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901114/, “it is well known that nutrient depletion induces autophagy” and “It is also well known that, for example in liver, glucagon activates autophagy”. This suggests to me that autophagy commences relatively quickly if one is in a fasted state, or even in a non-fasted but nutrient-deprived state (such as by eating very low-carb, ie being deprived of glucose, or by eating very low-protein meals, ie being deprived of sufficient amino acids).

          • a review of animal studies vs. actual human studies measuring autophagy

            ^^^the latter is stronger support, scientifically, imo

            Autophagy occurs all the time, it’s just slightly tweaked, for example, after exercise or chronic CR. And there is some direct evidence in humans that a bout of fasting doesn’t do it.

            I understand the IF/autophagy dogma is robust, some people on Facebook actually insulted me for writing this post! (which I almost predicted when I wrote “Please don’t hate me for this” lol)

          • Martin Tornberg

            OK, so you’re saying shorter-term fasting or the IF variety doesn’t boost autophagy, only longer-term or “chronic” CR boosts it? Do you have any evidence of this? At what point would the autophagy boost kick in? I mean, a bout of fasting is a bout of CR, and fasting is the most intense form of CR there is, so if CR activates autphagy after a certain time period, then water fasting should activate it even faster, and dry fasting should activate it the fastest of all. It seems like what you’re really trying to say is that the most common forms of IF, in which one is merely fasting for 16-18 hours, isn’t enough to trigger an extra level of autophagy – a longer period is needed, long enough for the body to feel truly calorie restricted. OK, how long then, and what makes you think that it takes so long to get into the CR state that you believe is needed to trigger extra autophagy? Do you have a theory (and/or any evidence) with respect to what triggers the extra autophagy? If it’s merely a rise in glucagon, as I believe certain studies have indicated, then it doesn’t seem as though it should require such a long period of fasting or “chronic CR” to trigger it.

          • Martin Tornberg

            There is one sense in which I think you may be right. If an “IF’er” consumes all calories in a 6 hour window, say 1pm to 7pm, then compared to a “normal eater” who also eats breakfast, the IF’er should certainly experience more autophagy from 9am-1pm (due to having skipped breakfast), but that IF’er might experience less autophagy during the afternoon, evening, and most of the night, due to the much heavier calorie consumption during that time, so it is possible that overall, the IF’er doesn’t experience any more autophagy. I’m skeptical of this, though, because if that’s the case, then where are the benefits of IF coming from? Perhaps the benefits are because most IF’ers are also doing some CR and losing weight? And then the benefits cease after the weight loss ends? That’s possible, I suppose, but I’m still skeptical – I am at a stable weight personally, I do IF about 3 times a week, not for weight loss, and it feels beneficial to me, so if the benefit is not from autophagy, what’s it from? I guess it could be placebo / psychological, or from some mechanism independent of autophagy, but I doubt it.

          • “There is one sense in which I think you may be right.”

            O_o

          • please re-read this blog post

  • DarthCoder_Net

    Excellent post. From what I’ve read, almost all of the health benefits of any diet comes from the CR not the composition of the diet. This fits right in with that line of thinking. I’m not saying all diets are equal for long term health. Humans are amazingly complex.

    • agree, weight loss trumps diet composition in most cases

      • tkent26

        So… you could do CR on soda and twinkies, and everything would be okay?

        • DarthCoder_Net

          Look up The Convenience Store Diet. Prof. Mark Haub health improved on twinkies, oreos, chips, sodas and protein shakes. The key was that he was limiting it to 1800 cals/day. He lost 27 lbs in 10 weeks and had better blood lipids. I’m not saying better foods wouldn’t have made more improvements but his health markers did improve.

    • tkent26

      In many cases, the CR is unconscious, and comes as a secondary and downstream effect from changing composition.

  • Man

    Why should people hate you for this ? This is very interesting information because when a paleo or primal guru throws to his followers that autophagy from IF is something good and to be practiced via regular IF, well, people will simply believe that and echo the rumour in various forums. So you are providing a very good service.

    Personally, I tried them all: daily IF, no breakfast, one-meal-a-day, 6 meals-a-day, no food for 50+ hours, etc. After observing how little health benefits I derived, I settled back to 3 meals / day with a good breakfast, a medium lunch and depending on physical activity, some early evening food that would prevent me from being hungry when I go to bed.

    i find this rhythm so natural and beneficial that I don’t see why I should deviate willingly from it again. However, when this is said, I now know that IF is OK, i.e. if I skip a meal or 2 now and then, I won’t starve and my dick won’t shrink 😀

  • Martin Tornberg

    I love your articles and generally they are clear and sensible, but in this case, it seems to me that you are misunderstanding something. My own reading / research suggests that autophagy commences around 12 hours after our last meal (although it could be more or less, depending on our metabolism and the size of the last meal). As long as one does IF for long enough to commence autophagy, one should be able to get at least some of the benefits of autophagy during that window of time. This is just common sense. If you compress your eating window to 8 hours so that you can fast for 16 hours, then you should be able to get a few hours of autophagy in. Of course, a similar effect might be achieved by spreading one’s meals out and avoiding snacking; ie, with breakfast at 7am, lunch at 1pm and dinner at 7pm, you may be in mild autophagy for an hour or two prior to each meal, after having finished digesting the prior meal. You have not provided any evidence that autophagy is not useful. The usefulness of autophagy – a sort of cellular clean-up process – is basically common sense; is there a reason why you are arguing against it? Am I missing something? What is your point in this article? Usually your articles are very insightful, so I feel like there must be something I’m missing here that you’re trying to convey?

    • Martin Tornberg

      This article would make more sense to me if you had written something like this:
      “It is still unproven whether IF, in the absence of calorie restriction, actually leads to an increase in the total amount of autophagy that takes place in a 24 hour period. Some degree of autophagy should occur naturally, especially during sleep and before breakfast, when we are in a fasted state every day, to some extent. Autophagy is also known to be increased in response to certain stressors, such as exercise. It stands to reason that since IF is also a type of stressor, IF would also increase autophagy, but the studies that I have seen that demonstrate that IF increases autophagy have used IF in conjunction with calorie restriction, so it is not yet certain whether IF without calorie restriction also results in an increased level of autophagy.”
      Is this what you meant to say?

      • Overnight fasting and 36 hours of fasting didn’t activate autophagy (see studies by Moller and Schwalm), whereas caloric restriction did (see study by Yang).

        I don’t think there’s a “common sense” regarding autophagy just yet.

        • Martin Tornberg

          OK, thanks, but my understanding is that there are different types of autophagy, so perhaps the types that were being measured by Moller and Schwalm (in the studies you mention) weren’t being activated, but I find it hard to believe that there could be 36 hours of fasting without there being autophagy – even in a person who doesn’t exercise. That seems inconsistent with other things I’ve read about autophagy.

          • Martin Tornberg

            Based on how autophagy is described on https://en.wikipedia.org/wiki/Autophagy, it seems like a pretty essential process that must occur – to a greater or lesser extent – for us to live normal lives, since it “allows the orderly degradation and recycling of cellular components.” Since most people don’t fast for 36 hours, it seems to me that most people would be dead within a few months if autophagy did not occur naturally overnight (and certainly within les than 36 hours of fasting). Perhaps you (and Moller and Schwalm) are referring to extra autophagy or some specific form of autophagy?

          • “Since most people don’t fast for 36 hours, it seems to me that most
            people would be dead within a few months if autophagy did not occur
            naturally overnight (and certainly within less than 36 hours of fasting).”

            That’s sort of my point: autophagy doesn’t require fasting. Actually, fasting doesn’t even seem to work like people think it works in this context.

          • jasmine johend

            Liking this post Bill because fasting is the new big thing and the longer duration seems to earn more bragging points. I don’t mean IF or TRF, I mean people fasting for days and days are the new super Jedi masters who are zapping potential cancer cells and disease progression, increasing their longevity and health span etc. I’ve had to turn off my social media, it was just too depressing as I struggle with fasting. Anyway it’s reassuring to know that good old CR and intense exercise can be just as effective.

          • thanks!

            “I mean people fasting for days and days are the new super Jedi masters
            who are zapping potential cancer cells and disease progression,
            increasing their longevity and health span etc.”

            hahaha!

            I’d be cool with skipping dinner once or twice a week, but going for weeks with no food? PASS… especially when the research is almost entirely based on animal studies.

            As far as autophagy goes [in general], I’m still not entirely convinced we want to maximize it, but exercise seems like the easiest way to kick-start it (at least in muscle).

          • jasmine johend

            Martin you might find Dean Pomerleau’s posts in the CRONies forum (Michael Rae contributes as well) here interesting (or not), he provides exhaustive references. He’s moving away from long-term CR to IF in the morning. Some of the other members practice long-term fasts. Interesting reading from people really into it. Luigi Fontana tested some of these CRONies for his studies https://www.crsociety.org/topic/11699-will-serious-cr-beat-a-healthy-obesity-avoiding-diet-lifestyle/

          • Martin Tornberg

            Thanks!

    • Martin Tornberg

      Since other types of stressors, such as exercise, result in an increase in autophagy, why would you think that IF would not result in increased autophagy? And if it doesn’t result in increased autophagy, what, then, do you suppose accounts for the benefits of IF that so many people seem to be experiencing?

      As a personal side, note – I don’t practice IF every day, I only do it periodically, about 3 times a week, out of concern that doing it daily might be counter-productive by slowing down my metabolism too much and making me sluggish….but I definitely feel that the periodic IF that I do practice has a beneficial, restorative, cleansing type of effect that seems consistent with increased autophagy – and consistent with other people’s experiences with IF, so based on my own experience, I have very little doubt that IF gives me more autophagy.

  • Matthew Klein

    I’m wondering how these results can be reconciled with material presented by Jason Fung, specifically his analysis of “biggest loser” esque data where low cal people regain weight and see a drop in metabolic rate.

  • jord

    hmm.. so CR = autophagy, but IF no autophagy.
    basically eating below maintenance calories.. does protein restriction stimulate it?
    what about eating in a surplus at meal times, then eating in a defecit away from meals to still equal maintenance calories on a weekly basis?

    does this mean at has to be SUSTAINED CR for it to occur? or eating in a defecit for say, 1-2 days?

    • I think the CR must be sustained longer than 1-2 days, otherwise it would’ve increased after 36 hours.

      The effect of depletion of specific nutrients hasn’t been worked out in human yet, but fwiw, exercise seems a pretty potent pro-autophagy intervention.

  • tkent26

    “If you’re actually losing weight over the long-term with an IF protocol, and thus are CR by definition…”

    Except some people losing weight with IF are _not_ counting or restricting calories on their re-feed days, they are eating to satiety.

    Agreed that IF is not useful/necessary for everybody, and that exercise is more useful/necessary than IF.

  • Human study: 72 hours fasting activates autophagy in skeletal muscle http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102031

  • Jason Coates

    So circadian desynchronicity = poor autophagy = metabolic chaos?

  • George

    I reckon if it feels good, do it. If it doesn’t, find another way.
    For me, I am always going to eat the same amount in the (early) evening, when the family eats, whether I eat breakfast and lunch or not. So cuttting one of both of the earlier meals is the way to regulate overall calories and, if I’ve been overeating, to clear my head and have more energy.
    But that’s just me and my life. I have no clue if any of my cells are ever eating themselves, except for the cells on my stomach lining.

  • Carroll Muir

    If CR is the go (rather than IF) what’s to stop permanent suppression of RMR as experienced by Greatest Loser contestants?

  • Jamie Billante

    The author has misread the main study which simply cites that exercise induces autophagy whether fed or fasted, not that fasting doesn’t have autophagic impact. First note that the results are presented at basal level (prior to exercise) which is not to say that autophagy was not already high and present among the fasted group. The reseachers of the “Exercise Authophagic Signaling” themselves aknowledge that fasting increases authophagy – both by referencing source# 29 and their own observation cited with Fig 5. Secondly, if you observe carefully (table 2), glucose and insulin levels were higher and fax oxidation/ burning lower among the non-fasted group – which is intuitive and makes sense. This challanges any linear association the author of the blog makes around lower fat = higher authophagy from fed-state exercise. In fact, using that assumption, authophagy from fasted training is much higher than non-fasted.

    Take aways:
    – Exercise equally increases authophagy from base level (pre-exercise levels), fasted or otherwise
    – Fasting induces authophagy
    – Fasted exercise ameliorates authophagy, with higher fat burning and insulin lowering properties than traning in fed state.

    • “authophagy from fasted training is much higher than non-fasted”

      that’s not what the studies show. This. If you’re going to exercise for autophagy, then fasting beforehand doesn’t add much.

      • Jamie Billante

        Well, it certainly doesn’t test for nor show that IF doesn’t induce autophagy – which is what you state. How is burning more fat while training in fasted state not better which the study does show – table 2?

        • fat oxidation over the course of the week would be more meaningful because the bigger IF refeed meals will shut down fat burning more than smaller regular meals

          • Jamie Billante

            You’re assuming that IF = big refeed, which is incorrect. You can IF and manage your calories for cutting, maintenance or bulking. Also, the macro constituents in your refeed determine whether you perpetuate or shut down fat oxidation.