Genes Involved in Autophagy

Autophagy is a general term for cellular pathways that move something from the cytoplasm of the cell into the lysosome for degradation. The term comes from the Greek ‘auto’ (self) and ‘-phagy’ (to eat). So when you see articles touting ‘autophagy diets’ as the latest and greatest for longevity or beautiful skin, realize that the term is just a general one that applies to a cellular process that goes on all the time in our cells.

Let me see if I can explain a bit of the biology behind this, and then I’ll go into how your genes play a role in autophagy.

What is autophagy and why is it so important?

Back to high school science class: the lysosome organelle is inside almost every cell in the body. It is made up of a membrane that surrounds a bunch of different enzymes for breaking down proteins. This is a way our cells can clean up after themselves and also how they get rid of foreign invaders like bacteria.

The autophagy pathway involves forming an organelle called an autophagosome, which is a vesicle that engulfs the things inside a cell that needs to be gotten rid of. My mental image is that the autophagosome is like a trashbag forming around the cellular junk that needs to be taken out. Then that trashbag (autophagosome) meets up with the lysosome, which is like throwing the trash into a big vat of bubbling acid (yep, I watched too much TV as a kid) with enzymes in it that break apart the trash. Perhaps add in a bit of chomping PacMan action to complete the mental picture?

So what kind of “junk” is in our cells? This can be anything from unused or misfolded proteins to lipids to damaged organelles such as damaged mitochondria. Autophagy – or the creation of an autophagosome around the damaged organelle – then leads to its disposal via the lysosome. Additionally, intracellular bacteria and viruses are also engulfed and then destroyed (a specific type of autophagy called xenophagy).

Autophagy is also a way to recycle some of the proteins by breaking them down into amino acids that the cell can then reuse. Thus, autophagy is normally triggered when our cells are stressed, such as when we are in starvation mode, or there is cellular stress from exposure to a toxin.[ref]

How does autophagy work?

Let me make sure this is clear with all the info about degradation and destruction: autophagy is considered to be a cytoprotective process – protective of the cell. It’s a good thing! Back to the analogy – taking out the trash and recycling the plastic bottles makes your home a better place. This is a natural part of our body’s cellular processes.[ref]

Zooming back out to the big picture here: why do we care about autophagy? It is important in a couple of ways:

• First, when the mitochondria in a cell stop functioning optimally, they need to be destroyed so that new mitochondria can be formed. Also, mitochondria that aren’t functioning optimally are more likely to create reactive oxygen species (ROS) which can cause cellular damage.
• Second, a decrease in or problem with autophagy is associated with neurogenerative diseases such as Parkinson’s and Alzheimer’s.[ref] The proteins that cause these neurodegenerative diseases can be cleared in part through autophagy.
• Additionally, autophagy plays a role in clearing intracellular (inside the cell) pathogens. This comes into play with inflammatory bowel diseases where genetic problems with autophagy have links to increased risk of IBD.
• Finally, autophagy also plays a role in hair loss[ref] and the aging effects on the skin.[ref] Age spots and lighter patches are likely due to autophagy not happening efficiently enough in skin cells.

Like most cellular processes, there is an optimal window of activity. Too little autophagy leaves a ‘dirty house’ and too much can lead to cell death.

Regulators of autophagy:

How does the body regulate this process? There are several factors that come into play here. mTOR (mammalian or mechanistic target of rapamycin) is one of the negative regulators of autophagy: a decrease in mTOR causes an increase in autophagy. Insulin-like Growth Factor 1 (IGF1) causes a decrease in mTOR activity under conditions of mild starvation. This then upregulates the creation of autophagosomes. Additionally, autophagy can be activated by AMPK, which increases with which can directly activate autophagy and also inhibits mTOR.

So what is mTOR? Basically, it is the signaling pathway that tells cells that it is time for growth. mTOR is activated when there is plenty of A/TP and amino acids (especially leucine and glutamine[ref]) available in the cell. This then signals cell growth. If you are a bodybuilder, anabolism (building up muscles and cells) is what you want, and there is a lot of information in the bodybuilding community regarding activating mTOR. There are questions, though, about whether it is good to always activate mTOR. These questions come into play when looking at its role in cancer (when you don’t want cell growth), as well as the necessary function of autophagy for getting rid of defective mitochondria, etc.

Again, our body needs a balance between anabolic processes (signaled by mTOR) and catabolic processes (such as autophagy).

Fasting – and a lack of specific amino acids – induces autophagy. This would have been a natural state of the body in the past when food wasn’t readily available at all times. Back when there wasn’t a 24-hour Mcdonald’s drive-thru available, people sometimes went hungry for a little bit! So it seems that our bodies are naturally prone to balancing out the times that we build up cells with the times that we clean up and break down unneeded components.

Lifehacks for increasing autophagy

If you carry some of the autophagy-related genetic variants above — or you just want to make sure that you clear out old mitochondria for optimal functioning — here are some research-backed ways of increasing autophagy.

Fasting:

A fasting-mimicking diet is a low-calorie, low-protein diet that is thought to increase autophagy and protect against toxins, improves health, and protect against diabetes, cancer, and heart disease.[ref] Read more about the fasting-mimicking diet in the book The Longevity Diet.

Intermittent Fasting

Intermittent fasting decreases mTOR and increases autophagy.[ref][ref]

There are various ways that people define intermittent fasting. For some people, it is fasting for a whole day once or twice a week. For others, it is taking an 18 to 24-hour break from eating.

Exercise:

Research shows that exercise can increase autophagy.[ref] A recent study found that the autophagy benefits are seen with more intensive exercise that is done in a fasted state.[ref] One more good reason to get active first thing in the morning!

Supplements and dietary changes for increasing autophagy:

*Always check to make sure supplements don’t interact with any medications you are taking.

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