Autophagy is the process by which our cells recycle their components. Most of the time it runs quietly in the background, but when cells are stressed, autophagy becomes more important. Read on to learn about autophagy, its definition and how it works, autophagy regulation, and what factors increase it.
What is Autophagy?
Autophagy (from the Greek for self-eating) is the regulated process by which a cell degrades its dysfunctional or foreign components. The cell can then recycle useful chemical components for further purposes [1].
This allows autophagy to regulate the balance of protein composition in a cell, prevent the buildup of toxic waste products, maintain cellular organelle function, remove invading pathogens, and sustain cells during periods of low energy input due to fasting or starvation [2].
The scientific importance of understanding autophagy was highlighted when Yoshinori Ohsumi won the 2016 Nobel Prize in Physiology or Medicine for his discoveries of the mechanisms for autophagy.
Mechanism of Autophagy
Essentially, autophagy is the creation of a ‘garbage bag’ (autophagosome) that collects cellular components and then takes them to the cell’s ‘recycling center’ (lysosome) to be broken down into their parts which can then be recycled into new components.
Autophagy-related genes (ATG) are responsible for producing the structures that carry out autophagy. The VPS34 complex initiates the autophagosome, ATG9 contributes to its expansion, and the ATG12-ATG5–ATG16L1 complex recruits ATG8 proteins which complete formation and are involved in targeted capture [3].
Other genes are involved in turning autophagy on and off. These genes can detect changes in the cell. mTOR responds to the level of nutrients in a cell and decreases autophagy (by disrupting ULK1 preventing the formation of the VPS34 complex) when there are plenty of nutrients available. AMPK monitors the energy levels in a cell (the amount of ATP) and activates autophagy when they are low. HIF1A detects oxygen levels and turns on autophagy (targeting mitochondria) when they are low (hypoxia) [4, 5].
Sirtuin genes (activated by resveratrol) can inhibit mTOR which increases autophagy [6]. Low levels of NAD+ are also reported to increase autophagy [7].
Research Limitations
Unfortunately, the mechanisms of autophagy are extremely difficult to study in humans, so the vast majority of research discussed in this post was undertaken in animals and cells. This lack of clinical evidence means that very few conclusions can be reliably drawn about autophagy and human health.
The Purpose of Autophagy
When things are running smoothly in a cell, autophagy occurs at a low level, helping to recycle worn-out cellular components. It’s a type of ‘maintenance’ mode.
But when things become stressed in a cell (not enough nutrients or energy, dysfunctional components, or invasion by microbes), autophagy is turned up in order to help protect us. A ‘stress response’ mode.
Aging & Lifespan
Activation of autophagy counteracts the age-associated accumulation of damaged cellular components and enhances the metabolic efficiency of cells [8].
Autophagy is a response to stress that helps cells to become more resilient and conservative with their energy.
In particular, autophagy can be activated to remove dysfunctional mitochondria (mitophagy) which produce a lot of harmful reactive oxygen species (ROS) that degrade the cell [9].
These processes are reported to extend the lifespan of several species [10].
Psychiatric Distress
Typical functioning of autophagy provides protection against the development of psychiatric disorders. Disruptions to autophagic processes have been associated with increased risk for some psychiatric conditions [11].
Post-mortem studies of the brains of individuals with depression and schizophrenia identified deficiencies in essential autophagy pathways [12, 13].
Neurodegeneration
Many neurodegenerative disorders stem from the accumulation of deformed proteins in and around neurons, inducing gradual brain cell death and subsequent loss of mental faculties [14].
Autophagy protects us by removing these proteins.
In Huntington’s disease it removes the huntingtin (HTT) protein [15], in Alzheimer’s disease it removes amyloid ꞵ (created from the APP protein) [16], in Parkinson’s disease it removes ⍺-synuclein (SNCA), and in dementia it removes microtubule-associated protein tau (MAPT) [17].
Infectious Diseases
Autophagy contributes to fighting infectious diseases in three ways; [14]
- Direct removal of microbes from inside of cells (xenophagy)
- Removal of toxins created by infections
- Modulation of the immune response to infections
Infectious microbes (such as Mycobacterium tuberculosis and the Group A Streptococcus), viruses such as HIV, and protozoans are removed through the processes of autophagy [18, 19, 20, 21].
Inflammation
Autophagy can both increase and decrease inflammation responses within the body. It increases inflammation by presenting evidence of pathogen invasion and turning on the immune response [22].
Autophagy then decreases the inflammation brought about by an immune response by clearing the cell of antigens that are stimulating the response. Additionally, autophagy also removes pro-immune response molecules produced by the cell in response to an invasion [23].
Muscle Performance
When exercising, we place stress on our cells. Energy use goes up, and cellular components may get worn out faster. Autophagy is then increased in order to: [24]
- maintain energy use balance within the cell
- reduce the amount of external energy required (by more efficiently recycling existing energy molecules)
- ensure that degraded cellular components are removed before they begin to cause any trouble
Cancer
Autophagy plays a role in preventing the onset of cancer and inhibiting the growth of early-stage cancers. Autophagy suppresses pro-cancer processes such as chronic inflammation, DNA damage response, and genome instability [2].
Mice genetically engineered to have impaired autophagy are reported to have increased rates of cancer [25].
Unfortunately, the protective roles of autophagy may also be hijacked by established tumors. As tumors grow the cells in the middle become isolated from the blood supply and begin to undergo nutrient and energy stress. Activation of autophagy can provide support to these cancerous cells. However, autophagy seems to be broadly beneficial before cancer cells can fully develop [26].
Factors That May Trigger Autophagy
Autophagy is an essential cellular process that is activated when cells are under stress. As such, mild or “hormetic” stress can be beneficial if it activates autophagy without doing significant damage [27].
Alternately, some compounds in food or supplements can trigger the mechanisms of autophagy.
Note that the relationships between autophagy and lifestyle or diet are very difficult to demonstrate in human subjects. As such, the evidence for many such links are limited to animal or cell studies, making it impossible to tell whether these factors will increase autophagy in humans.
Use caution and talk to your doctor before starting any new supplement, exercise regimen, or lifestyle change.
Mild stressors that may trigger autophagy include:
Other factors that may trigger autophagy include:
- Diet/Foods
- Herbal remedies
- Supplements
- Active plant compounds
- Cancer therapy drugs
Lifestyle Factors
1) Aerobic Exercise
Aerobic exercise has been demonstrated to induce autophagy in muscle tissues and the brain in animals, probably due to the prolonged stress associated with physical exertion [28].
Not only does exercising make you feel great and improve your health in other ways, but it also activates autophagy to ensure your cells fully recover from the process.
2) Intermittent Fasting and Caloric Restriction
Intermittent fasting and caloric restriction activated autophagy in animals [29].
A lack of nutrient influx activates autophagy to increase the recycling of cellular components, ensuring cells continue to properly function with less requirement from external resources [29].
This can be achieved either by going for a period without any food (fasting) or by reducing the amount of food you eat (caloric restriction). Short-term fasting has been demonstrated to induce profound neuronal autophagy and may be a good method for combating neurological conditions [30].
3) Ketogenic Diet
The ketogenic diet reduces carbohydrate intake and increases fat intake, resulting in a shift of energy use from glucose to ketones. This shift mimics the process that occurs during fasting and may thus lead to an increase of autophagy [31].
According to animal studies, ketogenic diets may promote autophagy in the brain, which some researchers have suggested is a vital mechanism for preventing neurodegenerative diseases. However, this link has not been demonstrated in humans [32].
People who struggle with fasting or caloric restriction are often drawn to the ketogenic diet.
For more information on ketosis and the ketogenic diet, check out this post.
4) Sleep
Autophagy is activated during sleep. The circadian rhythm not only helps control your sleep cycle, but it is also linked to autophagy. The internal biological clock affects the rhythm of autophagy [33].
In mice, sleep interruptions negatively affected autophagy. When the animals’ sleep was disrupted, an interruption in autophagy protein transmission followed [34].
Foods
5) Coffee
Coffee has been demonstrated to increase autophagy in mice [35].
A large meta-analysis of over 340,000 people in the UK found that only heavy drinkers (over six cups a day) experienced a higher rate of cardiovascular disease than nondrinkers, while moderate coffee drinking (one or two cups a day) was associated with decreased rates of CVD [36].
While this study did not investigate autophagy specifically, it demonstrates that moderate ingestion of coffee is, at least, not harmful to the heart. Furthermore, impaired genes and mechanisms of autophagy have been associated with CVD in animals [36, 37].
No studies have investigated whether this speculative relationship between caffeine, autophagy, and CVD holds in humans.
6) Green Tea/EGCG
According to a mouse study, active ingredients in green tea may activate autophagy. In particular, polyphenols such as epigallocatechin-3-Gallate (EGCG) activated autophagy in the livers of mice given 3.2 g EGCG per kg diet; the researchers settled on this dose as a rough equivalent to a human drinking ten cups of green tea per day [38].
People would have to drink a lot of green tea to achieve this kind of intake, and the link between EGCG and liver autophagy has not been demonstrated in humans.
To learn more about the benefits of green tea, check out this post.
Natural Supplements
7) Resveratrol
Resveratrol is a polyphenol found at low dosages in grapes, wine, peanuts, and soy [39].
Several studies have reported an autophagy-inducing activity of resveratrol in cells [40, 41].
In rats, caloric restriction and resveratrol together (but not either one alone) promoted autophagy in the heart. However, this benefit has not been demonstrated in humans, and resveratrol is infamous for its low bioavailability [42].
For more on the health benefits of and controversy surrounding resveratrol, check out this article.
8) Curcumin
Curcumin is the most active phytochemical in turmeric and has many health benefits [43].
In a mouse study, curcumin activated autophagy and reversed some of the damage caused by osteoarthritis [44].
In cells, autophagy is reported to be activated by curcumin (via the AMPK signaling pathway) [45].
For a deep dive into the health benefits of curcumin, check out this post.
9) Vitamin D
Vitamin D is obtained through diet, supplements, and synthesized in the skin upon exposure to sunlight [46].
In mice and in isolated cells, vitamin D induced autophagy in pancreatic β‑cells, providing a possible avenue for use in diabetes. More studies are required to determine whether the relationship between vitamin D, pancreatic autophagy, and diabetes holds in humans [47].
10) Omega-6 and 3 Polyunsaturated Fats
Supplements containing omega 6 and 3 polyunsaturated fats may increase autophagy [48, 49].
In a study of rats with traumatic brain injury, omega-3 fatty acids promoted autophagy and prevented the death of neurons. In worms, omega-6 fatty acids increased the total lifespan by activating autophagy and slowing the processes of aging. Needless to say, these results have not been repeated in humans and should be taken with a grain of salt [50, 51].
An excellent source of omega fatty acids is fish oil. For more about the health benefits of fish oil, check out this post.
11) Nicotinamide
Nicotinamide is a member of the vitamin B family and an ingredient for making the essential energy molecule nicotinamide adenine dinucleotide (NAD).
In a mouse study, nicotinamide delayed the progression of cognitive decline and Alzheimer’s by increasing autophagy in neurons [52].
In particular, its ability to induce autophagic recycling of mitochondria could be beneficial to cellular health [53].
For more information about where to find nicotinamide supplements and further health benefits check out this post on nicotinamide riboside.
12) Lithium
Lithium is a chemical element that is reported to have many health benefits when used as a supplement.
Several studies have demonstrated that lithium is a part of an autophagy-promoting signaling pathway in mammals. Lithium appears to induce autophagy by inhibiting inositol triphosphate (IP3), a protein that plays an important role in neuronal plasticity [54, 55].
In animals, lithium has been reported to enhance the degradation of aggregate-prone proteins that cause Huntington’s disease, Alzheimer’s, and dementia. Some researchers attribute these effects to an increase in autophagy [55].
For more on how lithium affects human health, check out this post.
13) Spermidine
Spermidine is a polyamine compound found in a wide range of foods [56].
Spermidine levels decrease as humans age, generating a correlation between spermidine and many of the markers of aging. Furthermore, diets rich in spermidine have been associated with reduced rates of cardiovascular disease and cancer. Spermidine has been found to activate autophagy in animals; some researchers have therefore suggested that it could induce autophagy in humans and thereby delay aging [57].
It has been reported to assist with age-related declines and prolong the lifespan of several organisms through the activation of autophagy [58].
Some of the foods with the highest reported levels of spermidine are dried soybeans and one-year-old cheddar cheese [56].
14) Trehalose
Trehalose is a sugar that contributes to protecting the body.
It induces autophagy and has been reported to inhibit cytomegalovirus infection and have neuroprotective properties. Much of the research on trehalose and autophagy has been done in cells, but one study of maternal diabetes in animals found that trehalose maintained healthy levels of autophagy even in the presence of excess glucose [59, 60, 61].
15) Other Compounds and Extracts
Many compounds have been associated with increased autophagy in cell studies. The compounds in this list have not been demonstrated to increase autophagy in animals, let alone humans; the evidence of their usefulness is therefore of very low quality and should not be used as grounds to take them for any medical purpose. We include them here because we think it’s interesting to see what compounds might be of interest to future research.
These compounds and extracts include:
- Corynoxine, isolated from Uncaria rhynchophylla, promotes the clearance of alpha-synuclein via mTOR pathway [62].
- Cedrol, found in the essential oil of conifers, induces autophagy and cell death of lung carcinoma cells [63].
- Amla extract from Indian gooseberry (Emblica officinalis) induces autophagy and inhibits ovarian cancer proliferation [64].
- Black hoof mushroom (Phellinus linteus) extract induces autophagy and inhibits breast cancer cell growth [65].
- Extract of European black nightshade (Solanum nigrum) induces autophagy and inhibits colorectal carcinoma cells [66].
- East Indian sandalwood oil induces autophagy and cell death in proliferating keratinocytes [67].
- Neferine from the Indian Lotus (Nelumbo nucifera) induces autophagy through the inhibition of PI3K/Akt/mTOR pathway [68].
- Anacardic acids, found in the shell of the cashew nut (Anacardium occidentale), induce autophagy and inhibit lung carcinoma (A549) cells [69].
- Naringin, found in citrus fruits (especially grapefruit), induces autophagy-mediated growth inhibition of cancer cells [70].
- Astin B, from Aster tataricus, induces apoptosis and autophagy in liver cells [71]
- Oridonin, purified from the herb Rabdosia rubescens, induces autophagy and cell death in prostate cancer cells [72].
Drugs
These medications have been found to induce autophagy in cells or animals; clinical trials (and therefore human evidence) are sorely lacking. We recommend strongly against taking any of these drugs without a doctor’s prescription. If you are already taking one, however, it may be interesting to note a potential effect on autophagy.
25) Drugs that Trigger Autophagy
Some drugs target the autophagic pathway. They can increase autophagy to help clear troublesome targets (e.g. bacteria and dysfunctional proteins) from within cells or they can use autophagy as a means of inducing the death of cancer cells.
Always consult a physician before taking any medication.
- Sirolimus, also known as rapamycin, induces autophagy by inhibiting mTOR [73].
- Fentanyl is a potent, synthetic opioid pain medication that induces autophagy via activation of the ROS/MAPK pathway [74].
- Carbamazepine, a medication used primarily for the treatment of epilepsy and neuropathic pain, induces autophagy and has been shown to act on multidrug-resistant Mycobacterium tuberculosis [14].
- Metformin, a diabetes drug, is an autophagic promoter that has been trialed in Alzheimer’s treatment and reported to improve anxiety-like behaviors [75, 76].
- Imatinib, a chemotherapy medication used to treat cancer, induces autophagy in chronic leukemia cells [77].
- Bortezomib, an anticancer drug, induces autophagy in head and neck carcinoma cells [78].
Factors that Decrease Autophagy
The following substances have been found to decrease autophagy in animal or cell studies, but this is not necessarily (by itself) a reason to avoid them. This section should not be used as grounds to either take or avoid a given supplement or medication. Talk to your doctor before starting any new supplement, and do not under any circumstances discontinue treatment with a medication before seeking your doctor’s advice.
Supplements
Disclaimer
- Eugenol, a phenolic acid found in clove (Syzygium aromaticum), was identified from a screen of 86 traditional Chinese medicines to have the strongest ability to decrease autophagy [79].
- Bafilomycin A1, a macrolide antibiotic derived from Streptomyces griseus, has been reported to inhibit autophagy [80].
- Elaiophylin was identified from a screen of North China Pharmaceutical Group Corporation’s pure compound library of microbial origin to have the best ability to decrease autophagy [81].
- Oblongifolin C, a phenolic acid from the Asian tree Garcinia yunnanensis, inhibits autophagy and has been described as having anticancer properties [82].
- Matrine, an alkaloid found in plants from the Sophora genus, is reported to be an autophagy inhibitor (via modulation of the lysosomal process) [83].
Drugs
The Genetics of Autophagy
Autophagy is tightly controlled by turning on and off autophagy-related genes (Atg). Individual genetic differences can strongly influence this process.
Go to SelfDecode to learn how you can have your own genetic makeup analyzed for autophagy-related conditions.
Genes Involved in the Mechanism of Autophagy
Autophagy begins with the creation of a phagophore from membranes enriched with phosphatidylinositol 3-phosphate (PI3P) [4].
This enrichment is assisted by a group of proteins called the ‘VPS34 complex’ (VPS34, the regulatory subunit p150, BECLIN 1, and ATG14) [3].
Expansion of this membrane region is facilitated by ATG9 which cyclically introduces more lipids to the bi-lipid membrane [90].
The phagophore structure takes shape via the action of the proteins CapZ and WHAMM [4].
During maturation the ATG12-ATG5-ATG16L1 complex recruits ATG8 proteins (particularly cleaved LC3B and GABARAP). These assist with morphing into the ‘bag’ shape of the autophagosome [3].
Among the ATG8 family members, LC3A, B, and C are mostly involved in autophagosome formation while GABARAP, GABARAL1, and GATE-16 are involved later in the maturation step [91].
While autophagy is generally viewed as a random process, engulfing cellular components indiscriminately, it appears to also have the ability to target specific components for degradation [3].
LC3 is reported to have a second function wherein it selectively incorporates cellular components that are exposing a specific structure (the LIR motif) [92].
Targeting of old parts of the endoplasmic reticulum and nuclear membrane is facilitated by FAM134 reticulon protein family [93].
NDP52 and OPTN are the main molecules involved in targeting mitochondria [94].
Components (proteins and bacterium) tagged for degradation (with ubiquitin) are targeted by p62 [95].
The cargo of an autophagosome is broken down and recycled by the contents of a lysosome. Attachment and fusing together of the two is facilitated by an interaction between ATG14, STX17, and SNAP-29 [4].
Genes Involved in Autophagy Activation
The majority of autophagy is controlled by mammalian target of rapamycin (mTOR). When nutrients are limited, mTOR is inactivated, which in turn induces autophagy [96].
mTOR suppresses the ULK complex (ULK1/2, ATG13, FIP200) which turns on the VPS34 complex and initiates phagophore ‘budding’ [97].
AMPK is a key sensor of intracellular energy under conditions of starvation or environmental stress. It can turn on autophagy by acting upon the ULK complex [98].
AMPK can also inactivate mTOR via the tuberous sclerosis complex (TSC) which prevents mTOR from blocking autophagy [99].
There are additional mechanisms for turning on and off autophagy that do not involve mTOR/AMPK. The inhibition of inositol monophosphatase and disruptions to the endoplasmic reticulum (causing the creation of faulty proteins) can both turn on autophagy [100, 99].
