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  • Writer's pictureRyan Allen

Self-eating and cellular renewal: a brief introduction to autophagy

In my recent post about metformin, I briefly alluded to the broad, potentially beneficial impacts that come from one’s body being in (or simulating) a fasted state. I recognize that this may seem counterintuitive or even controversial for a lot of people; this was my knee-jerk response as well. However, there certainly has been a lot of accumulating evidence across numerous fields that has made a convincing case, and a lot of it has actually started to make more sense. After all, looking at this through an evolutionary lens as I often like to do, we can understand that our ancestors for years and years didn’t always have an idea of what or when their next meal would be. They would have to hunt or forage for food, probably going through significant periods of both feast and famine. Looking at it this way, it’s reasonable to assume that we would have evolved at least some solution(s) to keep ourselves stable and healthy despite this fluctuation.

Figure 1: Computer illustration of lysosomal fusion with an autophagosome. Autophagy causes defective cellular components to be enveloped in a membrane (an autophagosome), which then fuses with a lysosome, allowing the parts to be digested. (Image: Britannica)

It turns out that one of the main “solutions” is this cellular process known as autophagy. For me, this is certainly among the most fascinating concepts I have learned in undergrad and yet another incredible result of millions of years of evolution. So, what is it? Well, autophagy literally means “self-eating,” and that’s pretty much what it is. The cell basically has numerous “sensors” to detect when it is deprived of energy or nutrients (among these are AMPK and mTOR, also mentioned in my most recent post). The molecular pathways that follow from these sensors are eventually able to stimulate autophagy, which is the process by which components of the cell (typically defective ones) are engulfed in a membrane and eventually digested by the cell’s lysosome.

Why does this matter? Well, on top of fasting’s clear use as a healthy strategy for weight loss and counteracting obesity (your cells are “eating away” their dysfunctional parts, almost using themselves as a fuel source), autophagy seems to have countless connections to chronic disease prevention. Perhaps a basic example of autophagy may show how it can be useful. Take the mitochondria, vital organelles that I was just discussing before in the context of metformin. Mitochondria are believed to have derived from bacteria through a hypothesis known as the endosymbiotic theory. One such piece of evidence for this is the fact that mitochondria have their own DNA—called mitochondrial DNA or mtDNA—which resembles the DNA of bacteria. If one has damaged mitochondria, this mtDNA can leak out into the cytoplasm of the cell, and the immune system will recognize it as something bacterial inside our cells. This triggers inflammation, and if the damaged mitochondria (or any other defective, useless cellular debris) persist inside our cells, then, we would be in a state of chronic inflammation. While a deeper dive into this concept will have to wait for future blog posts, it suffices to say that chronic inflammation is relevant to the pathology of many killer chronic diseases. To prevent this, autophagy can remove these no longer beneficial and now harmful mitochondria, via a subtype of autophagy known as mitophagy.

In addition, there have been suggestions of autophagy’s role in ridding the body of harmful protein aggregates. One may recognize these aggregates from the pathology of Alzheimer’s disease, a neurodegenerative disease strongly associated with the accumulation of beta-amyloid protein in the brain (alluded to in this post). Autophagy also may play a part in combatting fat buildup in the liver (another common element of many chronic diseases) as well as an intriguing, complicated role in cancer. All of these things undoubtedly warrant whole blog posts themselves at some point.

There is so much still to discuss on autophagy, but it has clearly become apparent that this is a crucial mechanism for survival. As I mentioned previously, it is even suspected by some to be a key mechanism of metformin for generally lessening the effects of aging. However, as I mentioned before, it is important to remember that like almost all things in biology, autophagy is presented on a spectrum. We of course do not want to have no autophagy, but we also do not want to starve ourselves forever or take any action to stimulate overwhelming amounts of autophagy. The idea is that we are most likely all not getting enough in our current society. This then brings up the obvious question, how can we stimulate “healthy” levels of autophagy?

Probably the most obvious way which I’ve already made clear is to fast. The optimal dosage on this, though, is still unclear. In other words, how long you should fast, with what frequency, etc. are all yet to be completely determined, however there are varying degrees of fasting or time-restricted feeding (TRF) that I encourage all to cautiously try at some point (many of which are not severe, but always mention such an idea to your doctor before engaging). Exercise has also been shown to stimulate autophagy, with the Zone 2 aerobic exercise that Nick has discussed probably being the most potent as it in many ways resembles a deprived or fasted state. Of course, certain drugs that also mimic this state such as metformin would act to induce autophagy, as well as potentially certain dietary strategies like Dr. Valter Longo’s fasting-mimicking diet (FMD) or even a ketogenic diet. Lastly, sleep may contribute to autophagy. As we’ve already discussed and as is affirmed by Dr. Matthew Walker, sleep basically cleans up a bunch of our cellular “detritus,” and there seems to be a link between autophagy and circadian rhythms on the whole.

In conclusion, then, autophagy may constitute some of the main molecular reasoning behind the importance of sleep, exercise, a good diet, etc. for our health. It truly is like a way for our cells and our bodies to renew themselves, which could be very powerful if we manage to harness it correctly.


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