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:  Inside almost every cell in the body is an organelle called a lysosome. 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.

Autophagy is the pathway involved in forming an organelle called an autophagosome, which is a vesicle that engulfs the things inside a cell that need 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 then can 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]

Autophagy is necessary for several reasons:

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 are linked 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 for cell growth. If you are a bodybuilder, anabolism (building up of 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 to 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 McDonalds’ 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.

Recap: Autophagy is the natural process by which the cells can clear out damaged mitochondria, recycle proteins, and get rid of intracellular pathogens.  We need a balance of autophagy with anabolic processes.  Fasting is one way to naturally induce autophagy.

Genes involved in autophagy:

More than 30 different genes code for the proteins that form the autophagosome. Researchers are still actively figuring out how all of the bits and pieces of the process go together, but recent genetic studies have shed a lot of light on the pathway.

Genetic mutations in the autophagy genes are linked with several chronic diseases and neurodegenerative disorders, showing that autophagy is an important process in preventing these diseases.[ref]

Image showing the role of the autophagasome in fusing with the lysosome to degrade either an organelle or pathogen in the cytoplasm. Iida, Tomoya et al. Worl Journal of Gastroenterology Creative Commons C/C BY-NC 4 License

A family of genes known as the autophagy-related genes, whose abbreviations start with ATG, codes for several of the proteins integral to autophagy. Several of these genes have variants that have been studied in reference to pathogen susceptibility, autoimmune diseases, cancer, and sepsis.

Note that not all autophagy-related genetic variants are sequenced by 23andMe or Ancestry, so what is listed below is not the complete picture.  Additionally, there are epigenetic modifications of the autophagy-related genes that can also impair their function.[ref]

ATG16L1 gene (autophagy-related protein 16-1):

ATG16L1 is necessary for the initiation of the process to create an autophagosome as well as being integral to the process of closing the membrane. [ref]

ATG16L1 genetic variants have been linked in quite a few studies to an increased risk of Inflammatory Bowel Diseases including Crohn’s disease.  One theory on why the autophagy variant is a risk in Crohn’s is that causes a decreased clearance of bacteria in the cells lining the intestine.[ref]

Check your genetic data for rs2241880 (23andMe v4,v5; AncestryDNA):

  • A/A: normal
  • A/G: increased risk of IBD, decreased risk of gastric cancer
  • G/G: increased risk of IBD[ref], increased risk for palmoplantar pustulosis[ref], decreased risk of gastric cancer, possibly due to the decreased inflammatory response towards h. pylori.[ref]

Check your genetic data for rs10210302 (23andMe v4, v5; AncestryDNA):

  • T/T: increased risk of Crohn’s disease [ref][ref]
  • C/T: increased (slightly) risk of Crohn’s disease
  • C/C: normal (wildtype)

ATG5 gene:

Check your genetic data for rs573775 (23andMe v4; AncestryDNA):

  • A/A: increased risk of lupus* [ref]
  • A/G: somewhat increased risk of lupus
  • G/G: normal

*a second study showed that the increased risk of lupus with the A allele is only for those who also are IL-10 high producer(rs1800896 G allele).[ref]

Check your genetic data for rs6568431 (23andMe v4; AncestryDNA):

  • A/A:  increased risk of cerebral palsy, lower A/G/T5 levels[ref]
  • A/C: increased risk of CP
  • C/C: normal (wildtype)

IRGM (immunity-related G/TPase M) gene:

This gene acts as a regulator of autophagy.  Genetic variants here have been linked to susceptibility to pathogens and IBD.

Check your genetic data for rs13361189 (23andMe v4,v5; AncestryDNA):

  • T/T: normal (wildtype). decreased susceptibility to M. tuberculosis bacteria [ref]
  • C/T: increased(slightly) risk of Crohn’s, increased susceptibility to leprosy
  • C/C: increased risk of Crohn’s disease [ref][ref], increased susceptibility to leprosy [ref], increased risk of Grave’s disease[ref], increased risk of glioma[ref]

Check your genetic data for rs10065172 (23andMe v4; AncestryDNA):

  • T/T: increased risk of TB[ref]increased risk of Crohn’s disease[ref]
  • C/T: increased risk of TB, increased risk of Crohn’s
  • C/C: normal(wildtype)

Check your genetic data for rs4958847 (23andMe v4 AncestryDNA):

  • A/A: increased risk of Crohn’s disease[ref][ref]
  • A/G: increased risk for Crohn’s disease
  • G/G: normal(wildtype)

Lifehacks

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 a few things shown to increase autophagy.

Fasting:

The fasting mimicking diet – a low calorie, low protein diet – increases autophagy and has been shown to be protective against toxins, improves healthspan, protects against diabetes, cancer, and heart disease.[ref] Read more about the fasting mimicking diet in the book The Longevity Diet.

Intermittent Fasting

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

Exercise:

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

Diet and Supplements:

Olive oil has been found to increase autophagy. This may be one mechanism by which the Mediterranean diet decreases the risk of Alzheimer’s disease. [ref][ref]

Resveratrol inhibits mTOR and increases autophagy. [ref] Red wine and grapes are food sources of resveratrol, or you can get it as a supplement.

THC, the active component of cannabis, induced autophagy in glioma (brain tumor) cells in an in vitro study through inhibition of mTORC1.[ref][ref] (Note that this is not an endorsement for using marijuana — just giving you the science here.)

CBD oil, cannabidiol, induces autophagy in intestinal epithelial cells.[ref] I think CBD oil is legal in the US  in most states (from industrial hemp seed), but do check on your local laws to make sure.

Reishi mushrooms have also been found to increase autophagy.[ref]

Lithium inhibits inositol monophosphatase (IMPase), reducing free inositol and myoinositol 1,4,5 triphosphate levels (IP3). Low IP3 increases autophagy. [ref] This may be one reason that higher lithium levels in drinking water are associated with lower levels of Alzheimer’s.  Lithium orotate is available as a supplement.

Luteolin, a flavonoid found in abundance in broccoli, parsley, and celery, was found to activate autophagy after a traumatic brain injury (TBI).[ref] It is available as a supplement as well as in food sources.

Caffeine stimulates the liver to get rid of extra fats through autophagy.  It does this by down-regulating mTOR. The study on this used mice fed a high-fat diet, which increases fatty liver, a problem facing many of us today.  [ref]

More to read:

 

2 Comments on “Genes Involved in Autophagy:

    • Hi Sid,
      I added your email address to my newsletter list. I send out a newsletter with updated posts once or twice a month.
      Debbie

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