Written and Medically Reviewed by Dr Babar Shahzad, BSc and MBBS on January 23, 2020.
Autophagy is a cell-renewal process that has recently become associated with intermittent fasting.
In this article, you’re going to learn about the autophagy process, how it might benefit you, and how to induce autophagy yourself.
What Is Autophagy?
Autophagy is a cell renewal process whereby damaged cells or cell parts are removed and replaced, creating a healthier and more functional cell. Autophagy means “eating of self,” and while that doesn’t sound ideal, it is a critical process to keep your cells acting efficiently.
By removing damaged cell parts, autophagy plays a housekeeping role and may clear damaged cell structures such as mitochondria, endoplasmic reticulum, and peroxisomes. Autophagy may also remove intracellular pathogens and is thought of as a survival mechanism (1).
How Does Autophagy Start?
Autophagy can be induced by starvation, specifically by an increase of glucagon. When we eat, our insulin levels increase, and our glucagon levels decrease. Conversely when we don’t eat, or fast, our insulin levels go down, and our glucagon levels go up (2). This glucagon increase is known to be one of the most effective stimulators of autophagy.
Autophagy was first discovered when scientists were examining a rat liver and added glucagon (a peptide hormone) to it. The researchers found that it resulted in the degradation of mitochondria and other structures within the cell. This is the first recorded viewing of glucagon-induced autophagy (3).
Another key player in autophagy regulation is the target of rapamycin (TOR) kinase. TOR acts as a signal that tells when nutrients are available. When TOR is activated, it inhibits or stops autophagy by communicating growth-promoting conditions. However, TOR kinase is repressed by signals that sense nutrient deprivation, and when TOR is deactivated, autophagy increases. The increase of autophagy ensures that cells adapt to nutrient deprivation through reduced growth and increased catabolism (the break down of cell molecules (4).
Further reading: One Meal a Day: What Benefits Does It Bring?
What Are The Benefits Of Autophagy?
Research has shown us that autophagy is an essential cellular mechanism that plays a housekeeping role by removing long-lived and damaged proteins, cell organelles, and regulating growth and aging. Autophagy is crucial to many biological functions like cell differentiation, development, and defense against pathogens and has emerged as a possible modulator of disease progression (5).
The disruption of autophagy can lead to cellular dysfunction and proteotoxicity that can then result in the onset of neurodegenerative diseases, cancer, pathogen infection, and metabolic disease. Therefore, targeted and controlled autophagy activation may be able to provide promise as a therapeutic tool against such diseases (6).
The benefits of autophagy may include:
- Anti-aging effects thanks to the removal of damaged cell structures and DNA protection
- Possible protection against the mutation and loss of function that can result in diseases such as cancer, heart disease, and auto-immune disease.
- Autophagy’s role in eliminating toxins and promoting cell viability may be able to fight diseases such as Huntington’s, Alzheimer’s, Parkinson’s, and ischaemic heart disease (7).
How To Induce Autophagy:
Since autophagy is closely regulated by nutrient deprivation, one of the best ways to induce autophagy is by intermittent fasting.
Intermittent fasting is a time-restricted eating plan with a no-eating ‘fasting’ period and an eating ‘feeding’ period. There are different intermittent fasting routines, and they mainly vary between when and for how long you fast or feed. For example, one of the most popular intermittent fasting routines is the 16/8 diet. 16/8 is a daily routine that requires you to fast for 16 hours and eat during the remaining 8 hours.
The main benefits of intermittent fasting are:
- Weight loss (8)
- Increased growth hormone (9)
- Decreased insulin and fasting blood sugar (10)
- Reduced oxidative stress (11)
- Improved cardiovascular (12) and cognitive health (13)
How Intermittent Fasting Induces Autophagy
By implementing a system of fasting, intermittent fasting is creating a lengthier period when you do not eat, therefore decreasing insulin levels and increasing glucagon levels which encourages an increase in autophagy.
Intermittent fasting has been shown to induce autophagy, and one study (14) looking at mice models even found that short-term fasting resulted in a dramatic increase in autophagy in the brain. Neuronal autophagy is incredibly vital in fighting degenerative diseases such as Parkinson’s. It was commonly thought that food restriction didn’t induce autophagy in the brain due to it being a metabolically privileged site. The researchers found otherwise. The researchers observed increased neuronal autophagy in cortical neurons and Purkinje cells, which are important neurons and nerve cells critical to brain function.
Autophagy in the brain occurs through changes in autophagosome (a fundamental structure in autophagy), and by decreased TOR activity.
The ketosis diet is a high-fat, low-carb diet that may also be able to induce autophagy.
The ketosis diet aims to induce ketosis, a natural metabolic state that uses ketones as a primary energy source for the body. Ketosis can help with weight loss (15), possibly reduce epileptic seizures (16), and have a therapeutic effect on conditions such as heart disease (17), type 2 diabetes (18), Alzheimer’s disease (19), and acne (20).
To enter ketosis, you typically need to eat as little as 20 to 50 grams of carbohydrates per day. While on this extremely low-carb diet, insulin levels decrease, and fat stores release fatty acids for energy. These fatty acids are oxidized in the liver and turned into ketones, a molecule that can then be used for energy.
How Ketosis Induces Autophagy
Ketosis requires an intense reduction in calorie intake, which reduces insulin levels and therefore increases glucagon levels, leading to an increase in autophagy.
Ketogenic diets have been known for their neuroprotective properties. One study (21) looking at rat models found that when rats were fed a ketogenic diet, there was a reduced activity of the TOR kinase in the hippocampus, an area of the brain. TOR acts as an autophagy blocker, so the ketogenic diet may be able to increase autophagy by decreasing TOR levels.
Other studies have also shown that ketones, the molecule produced by the liver during ketosis, are found to increase the neuronal levels of hypoxia-inducible factor-1⍺ (HIF-1⍺). This increase might occur through the succinate-mediated inhibition of prolyl hydroxylase activity. HIF-1⍺ reduces the level of oxygen in a cell, allowing for autophagy to occur in old or damaged cells.
There is also research suggesting that ketones activate Sirt1 in neurons by increasing cytoplasmic and nuclear levels of the NAD obligate cofactor. Sirt1 is closely associated with insulin regulation, and may, therefore, play an active role in inducing autophagy as decreased insulin results in increased glucagon. So ketosis may further induce autophagy through ketones activating and increasing HIF-1⍺ and Sirt1 (22).
One non-dietary option for inducing autophagy is exercise. It is thought that physical exercise might induce autophagy in areas of the body that are involved in metabolic regulation processes. One study (23) found that exercise-induced autophagy in areas including muscles, the liver, pancreas, and adipose tissue in mice.
Researchers concluded that “treadmill exercise also induces autophagy in the cerebral cortex of adult mice.”
Furthermore, the authors concluded that “autophagy may in part mediate the beneficial effects of exercise in neurodegeneration, adult neurogenesis, and improved cognitive function.”
How Exercise Induces Autophagy
More research is required to determine the exact mechanisms and neurons that upregulate autophagy in response to exercise. However, previous studies suggest that exercise increases Sirt1 levels, which is closely associated with insulin regulation, and also increases AMPK activation (24). AMPK is a protein kinase that increases glucagon levels (25). Exercise may increase autophagy levels by decreasing insulin levels, and thus growing glucagon to induce autophagy, and also by increasing AMPK activation to increase glucagon levels directly.
Who Might Not Be Suitable For Autophagy
While autophagy is highly beneficial, certain conditions may not work well alongside some of the techniques used to induce autophagy.
If you are or have any of the following, it is not advised for you to undergo intermittent fasting and/or the ketogenic/ketosis diet, as restricted eating could have adverse effects.
- Pregnant or breastfeeding
- Looking to become pregnant
- Heart Disease
- Eating disorder
Also, increased exercise may be of concern to the above. Anyone looking to induce autophagy through intermittent fasting, ketosis, or exercise is advised to consult a doctor if they have any concerns.
Autophagy is a cell renewal process that works as your body’s housekeeper. Autophagy may be able to delay the effects of aging, protect against mutation and loss of function, and help in preventing diseases such as Parkinson’s, Alzheimer’s, cancer, and heart disease.
Autophagy is induced mainly through a reduction in insulin and an increase in glucagon where glucagon then acts to induce autophagy. Other mechanisms, such as a reduction in TOR kinase, which blocks autophagy, also works to increase autophagy in the body.
Diet and exercise routines offer the easiest route to increasing autophagy, with intermittent fasting, ketosis, and increased exercise all increasing glucagon and autophagy levels.