The Impossible Guide To Autophagy
Introduction to Autophagy
Table of Contents
The 2016 Nobel Prize in Physiology and Medicine went to researcher Yoshinori Ohsumi for his work on the mechanism behind Autophagy. Autophagy has been shown to help increase endurance, decrease osteoarthritis and increase lifespan in various models. But what exactly is autophagy and what can it do for you?
Autophagy is defined as “consumption of the body’s own tissues as a metabolic process occurring in starvation and certain diseases.”1 It means that sometimes, the cells in the body will eat themselves for fuel in times of starvation and in certain diseases. However, this discovery is fairly recent and is only currently starting to get widespread research attention. While the knowledge of autophagy in humans is very new, there are important discoveries to know to understand autophagy.
Brief History of Autophagy
To understand autophagy, a bit of cell biology is needed. According to cell theory, the cell is the basic unit of life. Inside of each cell are smaller pieces called organelles. These function a lot like organs do in humans, with each performing a certain job. Everybody should remember the mitochondria is the powerhouse of the cell from high school biology. While these larger organelles have been known for a long time, some organelles were only discovered recently. Christian de Duve, 1974 Nobel Laureate, noted that the lysosome contained many enzymes (proteins that make the cell run smoothly) and organelles that were degradative, making the lysosome the recycling center of the cell2. The lysosome is a small bubble full of different enzymes that floats around and can do a remodel of the cellular interior by recycling unwanted material.
Once the discovery was made that cells had the ability to perform autophagy, further research began to suggest that autophagy happened regularly in many plant, animal and fungal species and that it was used for many different purposes. Researchers found that rat livers increased this activity when they were starved3, suggesting the link between autophagy and metabolism when the cell is stressed (more on potential applications i.e. intermittent fasting later). In 1966, Duve noted that autophagy could be useful “as part of self-rejuvenation of long-lived cells,” “self-clearance of dead cells,” as nutrition when nutrients were scarce. He also noted autophagy could be useful during intial development4. With all of these potential uses of autophagy, how would researchers narrow down exactly how it helps organisms and what genes control it? More importantly, why does it matter to us and how can we use it to our advantage to be healthier and more fit?
The answer to those first two questions is yeast. Yeast is actually quite closely related to humans since they are also animals, and yeast is a very simple model to study. That’s where 2016 Nobel Prize of Physiology and Medicine winner Yoshinori Ohsumi comes in. His lab was one of the first to discover what specific genes could increase or decrease the degrading power of the autophagosomes, specialized lysosomes designed for recycling parts of the cell. This discovery allowed many other labs to begin to isolate autophagy-related genes (ATG)5. Once these genes were identified, specific tests could begin on exactly how autophagy affects cells under different circumstances. Within 2 years of Ohsumi’s discovery, there were 4 more major findings that helped to shed light on how autophagy functioned and what it did for the yeast.
How Autophagy Impacted Animal Models
Following soon afterwards came studies in mice, cows and rats. These studies found that the majority of the genes that controlled autophagy were very similar across animal species, with the same gene controlling autophagy in breast cancer cells6 as it did in yeast cells. Once it was established that the genes were pretty much the same across all complex organisms, it allowed scientists to do research in worms, mice, plants and everything in between.
Scientists soon showed that autophagy was important in development and extended life span in worms7 and in survival of baby mice directly after birth8. The mice were unable to find fuel inside their cells immediately after birth and before first feeding, and subsequently passed away. Researchers also found that the same mechanism that cells use for autophagy can be an immune response against tuberculosis9, streptococcus10 and other bacteria that attack inside of cells. These exciting results were soon followed by more studies that showed autophagy is important in controlling homeostasis (equilibrium within the body), inflammation, metabolism, immunity, and guarding against cardiac, neural and skeletal diseases. Autophagy accomplishes this by breaking down and removing unwanted material from the cell and recycling necessary materials when the cell is stressed11.
There are four major types of autophagy that the cell can undergo: bulk macroautophagy, selective macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). The majority of autophagy is done by the two types of macroautophagy. Bulk macroautophagy is the primary method that cells use to recycle organelles and nutrients when the cell is starving, and is responsible for a significant portion of the “clean-up” function that autophagy is used for. The other part of the “clean-up” function is selective macroautophagy. The cell uses this method primarily to remove harmful molecules from the cell after metabolism and other cellular processes. The other two types of autophagy, microautophagy and CMA, have smaller roles that are generally more tissue specific and not was well understood.
How Autophagy Impacts People
So autophagy is really important on the cellular level, but how can you increase autophagy in your body? Current theories on increasing autophagy amount to putting the cells in the body under a moderate amount of stress. What constitutes a moderate amount of stress depends on your current health and fitness state, but the methods of stressing the body are pretty much the same: calorie restriction12 and endurance exercise13.
On a cellular level, in instances of calorie restriction, cells are starving. When the cells feel this stress coming on, they begin to increase the activity of lysosomes in order to continue to power the cell. In this process, the lysosomes take older or degenerating organelles and recycle them to fulfill the nutrient requirement. This process serves two purposes: to immediately provide materials to rebuild and feed the cell while also making the cell more efficient by getting rid of older organelles. This cellular remodeling helps to create healthier cells that have the potential to live longer, since it is like renewing the interior of the cells. At the bodily level, this occurs by intermittent fasting and in ketosis. By removing a constant supply of carbohydrates to the cell either by restricting intake time or volume, the cells are forced to perform autophagy to survive. This is another potential benefit to intermittent fasting and ketosis that occurs on the cellular level. This also offers a possible reason that children born during times of famine live longer and weigh less than their counterparts born during times of feast14. The genetic mechanism for autophagy isn’t completely understood, but the potential for modification by your ancestors’ experiences might impact how your body does autophagy to start. That’s not to say the body’s propensity for autophagy can’t change, since it undergoes more remodeling and recycling when it is not constantly bombarded with food, leading to healthier cells.
Exercise is most affected by autophagy since it produces so much waste in the body. In exercise, the body produces many harmful byproducts, such as lactic acid, that need to be degraded and removed from the cell before they accumulate and cause damage. Properly functioning autophagic machinery is needed to allow muscles to work over long periods of time15. Autophagy allows damaged mitochondria to be repaired and keeps the cell from dying by replacing these energy producing centers16. It is unclear whether or not endurance exercise can induce autophagy in cells that are deficient or if it can stimulate autophagy in cells that have undergone exercise. Researchers believe that this process is responsible for the increased metabolism that happens post exercise17.
There are several degenerative diseases that are linked to a lack of autophagy that are common as people age: osteoarthritis, cancer and Parkinson’s disease. Current research suggests that autophagy reduces as people age, and the lack of cellular remodeling causes cartilage death and the development of osteoarthritis. This suggests that an increase in autophagy and maintaining the autophagic machinery in each cell as people age could help to prevent degeneration of cartilage and the disease process.
Parkinson’s is another degenerative disease that likely stems from a lack of autophagy in the brain and brain stem to clear out “Lewy bodies” that cause the disease. These bodies muck up the cell function by decreasing the effectiveness of the lysosome, which reduces the cell’s ability to clean up with autophagy. As a result, damaged mitochondria and other organelles accumulate and the cell can no longer support itself sufficiently. In the brain and brain stem, this inability to clear out damage causes the swelling and poor function that characterizes the disease18.
How autophagy impacts cancer is a little complicated, since cells that have high levels of autophagy are less likely to get cancer. However, it is unclear if the higher levels of autophagy are preventing the cancer directly or by changing other processes in the cell that allow cancer to occur19. The flip side is that successful tumor cells also have higher levels of autophagy, since it can remove many of the harmful metabolites that accumulate through the tumor cell’s rapid growth20. This discovery has yielded some ideas for anticancer drugs that could potentially be less harmful than current methods of fighting cancer21 like chemotherapy or radiation.
Autophagy Conclusions (Actionable Takeaways)
There is a significant amount of research that is being done to help understand this process in greater depth, since it helps every organism from trees to mushrooms to people to function. Currently, the best strategies to increase autophagy are through diet and exercise. It is suggested that intermittent fasting could help to increase autophagy by forcing cells to clean themselves up in order to provide nutrition. Now this is not a suggestion to stop eating for weeks at a time to do a cleanse: that would cause your body to start to eat itself on a tissue level. That is extremely unhealthy. But eating within a certain time window each day could stimulate autophagy to begin, leading to overall healthier and longer-living cells.
Another suggestion for diet would be to try a keto diet. The keto diet, if done correctly, reduces the amount of simple energy circulating around the body. While this is a dramatic oversimplification of keto, it could stimulate autophagy by allowing cells the opportunity to recycle damaged organelles instead of bombarding them with simple carbohydrates all the time. An increase in fat consumption also can increase autophagy by increasing lipophagy22 (the fat specific part of autophagy).
Exercise can induce autophagy sometimes, so regular exercise could help to increase this very important cellular process. At the end of the day, a healthy diet and consistent exercise are the same prescriptions that have been made by holistic medical plans for longevity for years. Autophagy seems to be an important part of the puzzle as to why these behaviors yield such positive health results. There is a reason that people who perform these activities are known to live longer, healthier lives.
Autophagy Sources & Citations:
5) A unified nomenclature for yeast autophagy-related genes. Klionsky DJ, Cregg JM, Dunn WA Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y
10) Autophagy defends cells against invading group A Streptococcus. Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S, Yoshimori T, Science. 2004 Nov 5; 306(5698):1037-40.
7) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Meléndez A, Tallóczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B, Science. 2003 Sep 5; 301(5638):1387-91.
9) Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V
14) Bygren, L., Tinghög, P., Carstensen, J., Edvinsson, S., Kaati, G., Pembrey, M. E., & Sjöström, M. (2014). Change in paternal grandmothers´ early food supply influenced cardiovascular mortality of the female grandchildren. BMC
3) Cytolysomes and mitochondrial degeneration. NOVIKOFF AB, ESSNER E J Cell Biol. 1962 Oct; 15():140-6.
18) Esteves AR, Arduíno DM, Silva DF, Oliveira CR, Cardoso SM (January 2011). “Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD”. Parkinson’s Disease. 2011: 693761
4) Functions of lysosomes. De Duve C, Wattiaux R Annu Rev Physiol. 1966; 28():435-92. Dev Cell. 2003 Oct; 5(4):539-45.
1) Google (n.d.). Autophagy Definition.
16) Grumati P, Coletto L, Schiavinato A, Castagnaro S, Bertaggia E, Sandri M, Bonaldo P (December 2011). “Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles”. Autophagy. 7 (12): 1415–23.
13, 15, 17) He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B, et al. (January 2012). “Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis”. Nature. 481(7382): 511–5.
21) Jin S, White E (2007). “Role of autophagy in cancer: management of metabolic stress”. Autophagy. 3 (1): 28–31.
2, 11) Levine, B. and Klionsky, D. (2018). Autophagy wins the 2016 Nobel Prize in Physiology or Medicine: Breakthroughs in baker’s yeast fuel advances in biomedical research.
19) Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B, et al. (December 1999). “Induction of autophagy and inhibition of tumorigenesis by beclin 1”. Nature. 402(6762): 672–6
22) Liu K, Czaja MJ. Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ. 2012;20(1):3-11.
12) Morselli E, Maiuri MC, Markaki M, Megalou E, Pasparaki A, Palikaras K, Criollo A, Galluzzi L, Malik SA, Vitale I, Michaud M, Madeo F, Tavernarakis N, Kroemer G, et al. (2010). “Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy”. Cell Death & Disease. Genetics,15(1), 12. doi:10.1186/1471-2156-15-12
20) Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E, Domingo D, Yahalom J (January 2001). “A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles”. Cancer Research. 61 (2): 439–44.
6) Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B J Virol. 1998 Nov; 72(11):8586-96.
8) The role of autophagy during the early neonatal starvation period. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N Nature. 2004 Dec 23; 432(7020):1032-6.
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