Intermittent Fasting, Autophagy, and mTOR – Part I
Rob, a reader from Ireland, pointed me to a worrying post regarding the potentially negative aspects of intermittent fasting and asked about my opinon of it. Ok, I’m being generous here by throwing in the modifier potentially, because the post’s author definitely holds the viewpoint that fasting will kill you … I’m paraphrasing here and exaggerating a bit for effect, but not much since the actual quote from the posts’s conclusion is:
It has been said that extraordinary claims require extraordinary evidence, so, without further ado, let’s dive in to the “proof” of Kiefer’s pudding.
If you Can’t Dazzle Them With Brilliance, Baffle Them With Bullsh*t
Try as I might, I can’t follow Kiefer’s argument, mostly because I find it muddled and contradictory. Things start off on the wrong foot when he asks the reader to suspend all disbelief and “imagine a purely destructive process that’s critical for building the very thing it destroys.” Call me pedantic, limited, or lacking in imagination, but to me a purely destructive process only destroys, it doesn’t build. If it destroys and builds, then it’s not purely destructive, but rather, complex, subtle, and nuanced.
If you are in a charitable mood, you might be tempted to let Kiefer off the hook and chalk all of this up to enthusiastic overstatement – maybe he didn’t really mean that autophagy is purely catabolic. Except that apparently, he really does mean it as he repeats this mantra throughout his post : “by definition and function, autophagy destroys tissue, making it purely catabolic.” Not to nitpick, but even if we were to concede that autophagy is purely catabolic (it isn’t), autophagy does not destroy tissue. Autophagy is active at the cellular level, while tissues are collections of cells. This is a very important distinction for reasons that will become apparent later, I raise this issue here to point out that Kiefer might be a bit sloppy in either his understanding, or explanations, or both.
This stance on autophagy as purely catabolic is especially surprising when you realize that in his citations, Kiefer refers to a paper by Masiero et al. entitled “Autophagy is required to maintain muscle mass.“ I understand that Kiefer is a busy man as he is trying to build his nutritional conselling business, and he may not have had the time to read the full paper, or maybe even the abstract. But I would hope that he at least had the time to read the title! Trying to characterize something that plays a critical role in maintaining muscle mass as purely catabolic smacks of expending a lot of effort in pounding a square peg into a round hole.
But why is Kiefer doing this? After all, he’s not dumb, far from it, as he tells us himself, “he’s smart as f*ck.” Mostly, he’s trying really hard to create an association in your mind between autophagy and pure catabolism so that in the subsequent discussion, whenever you see the word autophagy, he would ideally like you to picture your body melting into a puddle of catabolic goo. Because if he can sell you this purely catabolic disease, he can then sell you his cure, and it will only cost you $89. The last thing Kiefer wants is for you to think of autophagy as complex, subtle, nuanced, and worst of all, tightly regulated:
More recent research has altered the original view of autophagy as a nonselective process by revealing the existence of molecules involved in selectivity of autophagosome cargos. … Autophagy is tightly regulated to prevent its unbalanced activation, which may cause damage to cells. Studies have identified at least two signaling complexes that participate in the fine-tuning of autophagic activity under conditions of stress and other physiological circumstances in which autophagy is needed.
Selective autophagy includes a pathway for targeting specific hydrolase proteins ( the Cvt pathway ), one for processing protein aggregates (aggrephagy), another for processing ribosomes (ribophagy), yet another one for mitochondria (mitophagy), as well as pexophagy, a pathway for specifically targeting peroxisomes. That is certainly a lot of pretty specific pathways. As Shakespeare might have said, “if autophagy be the food of the nutrient deprived cell, play on, give me excess of it!”
Over time, I’ve learned a thing or two from my wife, especially at mealtimes, when she habitually leaves her favourites to savour slowly at the end, so I’ve saved my favourite selective autophagy pathway for last – macrolipophagy:
If at this point you want to take some time to bask in the glow of the work of Singh et al., by all means, please take all the time you need. I’ll wait.
All of the mentioned pathways make use of macroautophagy, that is, the formation of a bubble-like structure within the cell that encloses the target of autophagy in what’s been termed the phagosome. The phagosome then fuses with another structure containing enzymes that lyse, or breakdown, the phagosomal contents. This is quite important to keep in mind, especially when Kiefer gets a hold of the phagosome and waterboards it into confessing to crimes it did not commit:
Kiefer’s mental model of autophagy seems to be that of a process that is turned off and on much like one operates a light switch. It isn’t. It is an ongoing process, the rate of which rises and falls in accordance with the cellular context and needs, but never actually “turns off.” But let’s ignore that for the time being in order the take a closer look at the paper by Mizushima et al cited as reference 7. We will be looking for a substantive demonstration that macroautophagy is something that treats fast-twitch muscle as exceptional, in the manner described by Kiefer.
In 2003, Mizushima and team published a paper where they revealed that they had figured out a way to make the autophagosome glow in the dark under UV lights. Like all children when presented with a cool new toy, they promptly set about making mice with glow in the dark autophagosomes so they could look at them and count them. Since they knew that a good way to increase the number of phagosomes is to restrict nutrients, they tested their mice in the fed state, after 24 hours of starvation, and lastly, after 48 hours to determine what changes in the number of autophagosomes per unit of surface area could be detected. This is what they found:
The first thing that ought to strike you is that each graph looks different from the others. Different tissues exhibit different responses to food deprivation. This is not unexpected as we know different tissues have different energetic needs as well as different internal structures and therefore different substrates available as autophagy targets.
The second thing that ought to jump out at you is that at time 0, in the fed state, all tissues exhibit varying levels of basal autophagy. Some tissues, like the pancreas, exhibit quite a high level of basal autophagy. In contrast, the heart has some of the lowest basal levels of autophagy recorded by the researchers, although even here they are not zero. So much for “turning off” autophagy.
The third thing that you ought to notice is that in almost all tissues that respond to starvation, including fast-twitch muscle ( EDL M. ) the rate of autophagy after 48 hours is actually lower than after 24 hours. The notable exceptions here are the heart and the soleus muscle, a muscle predominantly consisting of slow-twitch fibers. So, we can toss “macroautophagy stays on for 24 hours or longer only in fast-twitch muscle if we don’t eat” into the trash can too.
Lastly, note that in terms of the Thymus and Lens graphs, none of the observed differences were statistically significant, so, for all intents and purposes we can consider autophagy to be independent of the nutrient availability in these tissues over the timeframe under consideration ( i.e. nutrient deprivation over 48 hours. )
All of these observations put together ought to make you wonder how it is that one can claim that “macroautophagy is transient in nearly all tissues except fast twitch muscle” after having read this paper? It certainly gives me pause. The paper does show that for the most part, cells deprived of external nutrients turn to internal stores, which we knew was the case before we started, so, there is nothing novel here.
In and of itself, however, the fact that we observe the exepected increased autophagic activity, doesn’t tell us very much at all. What we need to know is: what materials are being broken down? Which autophagy pathway is being invoked? Are we talking about damaged organelles, toxic protein aggregates, intracellular parasites, in other words, expendable cellular garbage, or something else, like large supramolecular structures such as whole undamaged organelles of the cell? And if we are talking about whole undamaged organelles of the cell, how many of them are actually LDs, the cellular lipid transporters?
Suffice it to say that up to this point, I am left unconvinced by Kiefer’s argument, to put it mildly, and we’ve hardly scratched the surface. However, I do think that I’ve given you a lot to read and think about, so I’ll stop for now, or else this article won’t ever see the light of day. I’ve already rewritten it four times. It’s about time to publish it.
In closing, I would like to thank Rob for bringing this post to my attention. Ordinarily I would have replied to his email directly to thank him, but it turns out that my contact page was buggy, and did not provide me with his email address. This is now fixed, so I am doubly indebted to him. Cheers, mate!