Autophagy: Definition, Process, causes & Supplements

Cells employ a crucial mechanism known as autophagy to eliminate damaged components, ensuring their continued functionality and promoting overall cell health. Two significant factors that can trigger autophagy are stress and nutrient deficiency. Physical exercise, fasting, and calorie restriction actively support this process. Additionally, there are supplements like spermidine and resveratrol that have been shown to enhance autophagy, potentially leading to improved cellular health. Embracing these lifestyle strategies and incorporating autophagy-promoting supplements may contribute to the well-being and rejuvenation of your cells.

What is Autophagy?

Autophagy, quite literally meaning "self-eating," is a cellular process crucial for recycling and reusing damaged components within the cell. Functioning as a diligent housekeeper, autophagy plays a pivotal role in eliminating misfolded proteins and ensuring the removal of damaged cell organelles such as mitochondria, endoplasmic reticulum, and peroxidases. 

Notably, this essential process can be induced through fasting, adding another layer to the fascinating interplay between our dietary habits and cellular health. The steps of autophagy are initiation, phagophore nucleation, elongation, autophagosome formation, autophagosome-lysosome fusion, and cargo degradation.

Importance of Autophagy

Autophagy is important because it plays a major role in homeostasis, helping the body produce healthier cells and eliminating or clearing damaged cells. It also plays a role in preventing diseases such as cancer, diabetes, autoimmune disorders, infections, and neurodegenerative and cardiovascular diseases. As autophagy decreases with age, it becomes challenging to eliminate damaged cells.

The accumulation of damaged cells also leads to various diseases. Some supplements help in increasing autophagy, aiding in the degradation of proteins required for the survival of cells. It is a nonselective degradation process where cytoplasmic organelles are engulfed, including mitophagy, reticulophagy, xenophagy, and aggrephagy. Cytotoxic drugs induce both autophagy and apoptosis.

Types of Autophagy

There are three types of autophagy in eukaryotic cells-macroautophagy, microautophagy, and chaperone-mediated autophagy.

Macroautophagy

Macroautophagy is the process in which large portions of the cell are enclosed in vesicles known as autophagosomes and subsequently degraded by lysosomes. Autophagosomes are double-membrane structures that surround cellular components. These autophagosomes then fuse with lysosomes for demolition.

Microautophagy

Microautophagy, a less common form of autophagy, is characterized by the absence of autophagosomes. Instead, lysosomes directly engulf cellular components. The lysosomal membrane protrudes towards the cytoplasmic contents and encloses the cellular components.

Chaperone-mediated autophagy

Chaperone-mediated autophagy is a process in which heat shock proteins are eliminated. This pathway involves lysosomal degradation and does not require autophagosomes. Chaperone-mediated autophagy plays a crucial role in proteostasis, the maintenance of proteins, and overall cellular health.

Causes of Autophagy

Autophagy is caused by nutrient deprivation, growth factor depletion, and hypoxia. Environmental stress and lifestyle habits also cause autophagy.               

Natural Triggers

Autophagy is stimulated by natural elements such as fasting, exercise, and specific foods like turmeric and green tea. Exercise triggers AMPK activation, whereas fasting causes a cellular stress response. Turmeric and green tea's bioactive ingredients, such as EGCG and curcumin, alter signalling pathways to improve cellular upkeep and cleaning while promoting autophagy.

Environmental factors

Certain environmental chemicals can alter autophagy, which is a cellular mechanism that recycles malfunctioning or damaged cell components. Certain substances have the potential to cause cellular stress and dysfunction by interfering with autophagic pathways. Determining the effect of environmental exposures on cellular health and disease susceptibility requires an understanding of these interactions (Pesonen & Vähäkangas, 2019).

Can you induce autophagy?

Yes, it is possible to induce autophagy through stress conditions such as calorie restriction, fasting, and exercise. Certain foods and medications can stimulate autophagy through various mechanisms. The most common mechanism is calorie restriction. Reducing caloric intake by 10-40% can trigger the activation of autophagy inducers. Research indicates that long-term calorie restriction increases the expression of autophagy-related genes such as Atg5, Atg7, Atg1, and others, as well as molecules involved in the elimination of misfolded or dysfunctional proteins and organelles. Calorie restriction and fasting have been shown to enhance health, promote longevity, and stimulate autophagy (Jamshed et al., 2019).

Intermittent fasting and extended fasting also improve autophagy activity. In a recent study, researchers analyzed markers related to longevity such as creatinine and cystatin C. A group of 11 overweight adults engaged in early time-restricted feeding and followed a normal eating schedule. After four days, there was a 22% increase in the production of the autophagy gene LC3A. Regular exercise also induces autophagy in muscle tissue. Some researchers argue that exercising after fasting shows greater autophagy activation (Brandt et al., 2018).

Lifestyle practices

Autophagy can be induced by low-carbohydrate diets, exercise, and intermittent fasting. Long-term fasting, in particular, triggers autophagic processes as cells prepare for a shortage of nutrients. A low-carb diet and exercise, particularly intense workouts, also encourage autophagy by altering metabolic pathways and cellular energy levels.

Dietary approaches

Dietary strategies that trigger autophagy include low-carb or ketogenic diets, fasting, and calorie restriction. Under these circumstances, the body responds to stress by reducing insulin signalling and increasing the activity of AMP-activated protein kinase (AMPK). This promotes cellular renewal and health by activating autophagy, a cellular process that gets rid of damaged parts.

Fasting and autophagy

Autophagy induction is a cellular process essential for preserving cellular homeostasis and eliminating damaged proteins and organelles. Extensive research has focused on understanding how fasting and calorie restriction affect this process, which is particularly linked to immunological response, longevity, and cellular repair.

Studies consistently indicate that both calorie restriction and fasting effectively promote autophagy. In times of nutrient scarcity, cells utilize autophagy as a survival strategy to recycle biological components and generate energy. This involves the production of double-membraned vesicles called autophagosomes, which absorb and transfer biological material to lysosomes for destruction.

The practice of intermittent fasting, wherein individuals alternate between eating and fasting periods, has shown promising outcomes in boosting autophagy. A brief fast, typically lasting 16 to 24 hours, depletes the cell's energy reserves, activating the sirtuin and AMP-activated protein kinase (AMPK) pathways, subsequently inducing autophagy. Furthermore, calorie restriction achieved by consuming fewer calories per day overall has been linked to increased autophagic activity, likely through nutrient-sensing pathways such as mTOR.

Research also suggests that the duration and intensity of fasting or calorie restriction may influence the extent of autophagy induction. Long-term fasting appears to enhance the autophagic response, potentially yielding more significant positive effects on cells. However, striking the right balance is crucial because severe calorie restriction or overly extended fasting can have detrimental effects on health (Bagherniya et al., 2018).

Symptoms of Autophagy

Effect	Explanation	Source
Increased Ketone Levels	When the body lacks carbohydrates, it produces ketones from fatty acids. Ketone body synthesis is associated with promoting autophagy (Camberos-Luna et al., 2015).	Camberos-Luna et al., 2015
Reduced Appetite	Autophagy is linked to decreased appetite, likely due to altered insulin and glucagon levels. Rising glucagon during autophagy has been shown to reduce appetite (Kanasaki et al., 2019).	Kanasaki et al., 2019
Fatigue	Autophagy, among other factors, is associated with fatigue. Techniques inducing autophagy, like fasting or a ketogenic diet, have been linked to fatigue and low energy levels.	-
Bad Breath	Entering ketosis, indicated by bad breath, results from increased ketone levels during autophagy. The smell, often metallic or fruity, is caused by acetone, a specific ketone (No specific source mentioned).	-
Weight Loss	Autophagy influences hunger-regulating hormones (ghrelin, insulin, and glucagon), leading to reduced appetite and potential weight loss (Kanasaki et al., 2019b).	Kanasaki et al., 2019b
Improved Brain Function	Autophagy is crucial for brain function and nerve cell health. Ketones, a brain energy source, may enhance autophagy, contributing to improved brain function (Jensen et al., 2020).	Jensen et al., 2020

 

Side effects of autophagy

Damaged or malfunctioning cellular components are recycled as part of the natural cellular process known as autophagy. Although autophagy is generally thought to be advantageous for general health, it's vital to remember that research on the topic is still developing. Even though autophagy has been linked to several health benefits, it's important to remember that everyone will react differently, and further study is required to understand its implications completely. These are a few possible autophagy-related side effects or things to think about.

Effect	Reason
Initial Discomfort	As the body adjusts to the autophagic process, some people may experience mild side effects or initial discomfort.
Symptoms of Detoxification	Detoxification through autophagy can lead to symptoms like headaches, exhaustion, or flu-like symptoms as toxins and damaged cells are eliminated.
Risk of Nutrient Deficiency	Prolonged or intense autophagy, breaking down cell components for recycling, may result in nutrient deficiencies without balanced nutrition.
Effect on Muscle Mass	Overautophagy, especially during fasting, may harm muscle mass by breaking down muscle proteins.
Energy Levels	The body may change how it uses energy during autophagy, leading to a temporary drop in energy as it adjusts to different sources of energy.
Immune System Implications	While autophagy is linked to immune system advantages, excessive or protracted autophagy may negatively impact immune performance. More research is needed for a comprehensive understanding.
Individual Variability	Individual responses to autophagy vary significantly based on factors such as age, health, and genetic predispositions.
Hormonal Changes	Autophagy may impact hormone levels, affecting mood, energy levels, and other aspects of health differently for each individual.
Drug Interactions	Caution is advised for individuals on medication, as the effects of autophagy on drug metabolism and interactions with other drugs are unclear.

 

Supplements for autophagy

There are ways to boost your autophagy by taking supplements that trigger it. Some of the supplements are:

• Spermidine

Spermidine is a polyamine found in the ribosomes, the cellular machinery responsible for protein synthesis, within the human body. It exhibits benefits similar to fasting by inducing autophagy in various organs such as the liver, heart, and muscles. Spermidine activates the Atg genes responsible for self-cleanup processes and enhances the acetylation process by reducing the expression of certain proteins. Fasting also induces autophagy.

• Coffee

It is rich in antioxidants and triggers autophagy. A study shows drinking coffee decreases the risk of diseases as it flushes out the toxins in our bodies (Pietrocola et al., 2014).

• Tea

Tea, especially green tea, also induces autophagy and possesses antioxidant and neuroprotective properties. It helps protect your cells from damage and keeps you feeling full for a longer period. 

• Resveratrol

It is a polyphenol, a potent antioxidant that fights diseases and detoxifies the body. It is present in red wine, grapes, soy, and peanuts.

• Vitamin D

It is responsible for calcium absorption in the body and triggers autophagy in pancreatic cells, reducing the risk of diabetes.

• Essential fatty acids

Omega-3 fatty acids, denoted as "3," and omega-6 fatty acids, denoted as "6," are necessary as they induce apoptosis and autophagy via the mTOR pathway in cancer cells. There are even fish oil supplements that induce autophagy.

• Curcumin

It is a compound found in turmeric, that triggers autophagy and reduces cellular damage. It exhibits anti-cancer effects by inducing autophagy, a process vital for cell degradation.

Although the precise mechanism is unclear, studies suggest curcumin's potential in treating prostate cancer warrants further exploration (Zhu & Bu, 2017b).

Conclusion

To summarize, autophagy is an essential cellular function that helps maintain health and reduce the risk of diseases. Various factors, including fasting, exercise, and certain supplements such as spermidine, resveratrol, and coffee, can induce autophagy. Despite its potential benefits, individuals may respond differently, experiencing varying effects. Consequently, more research is necessary to fully comprehend the implications of autophagy.

 

FAQs

1) How long do you have to fast for autophagy?

After a 12- to 16-hour fast, autophagy usually begins, peaking in activation after 24 to 48 hours. Each person's experience may differ in length.

2) What does autophagy do to your body?

By eliminating harmed parts, encouraging cellular renewal, boosting immunity, and possibly lowering the risk of illness, autophagy purifies cells.

3) What are the 5 stages of autophagy?

1. Induction: initiation of autophagy.
2. Nucleation: formation of isolation membrane.
3. Elongation: membrane expansion.
4. Maturation: autophagosome completion.
5. Degradation: lysosomal fusion and content breakdown.

4) How do I know if I am in autophagy?

Reduced hunger, better energy, and enhanced mental clarity are indicators of autophagy. Seek confirmation from a medical expert.

5) What foods do not stop autophagy?

Foods like black coffee and green veggies that are low in carbs and protein are less likely to stop autophagy processes.

6) Does autophagy burn fat?

Through metabolic processes, autophagy potentially aids in fat loss by breaking down cellular components for energy. Direct fat burning, however, is dependent on several variables.

7) Can we drink water during autophagy?

Yes, water is allowed during autophagy. Staying hydrated supports the cellular cleansing process without interrupting the benefits of autophagy.

 

References

Pesonen, M., & Vähäkangas, K. (2019). Autophagy in exposure to environmental chemicals. Toxicology Letters, 305, 1-9.

https://doi.org/10.1016/j.toxlet.2019.01.007 

Jamshed, H., Beyl, R. A., Della Manna, D. L., Yang, E. S., Ravussin, E., & Peterson, C. M. (2019). Early time-restricted feeding improves 24-hour glucose levels and affects markers of the circadian clock, aging, and autophagy in humans. Nutrients, 11(6), 1234.

https://doi.org/10.3390%2Fnu11061234 

Brandt, N., Gunnarsson, T. P., Bangsbo, J., & Pilegaard, H. (2018). Exercise and exercise training‐induced increase in autophagy markers in human skeletal muscle. Physiological reports, 6(7), e13651.

https://doi.org/10.14814%2Fphy2.13651 

Bagherniya, M., Butler, A. E., Barreto, G. E., & Sahebkar, A. (2018). The effect of fasting or calorie restriction on autophagy induction: A review of the literature. Ageing research reviews, 47, 183-197.

https://doi.org/10.1016/j.arr.2018.08.004 

Camberos-Luna, L., Gerónimo-Olvera, C., Montiel, T., Rincon-Heredia, R., & Massieu, L. (2016). The ketone body, β-hydroxybutyrate stimulates the autophagic flux and prevents neuronal death induced by glucose deprivation in cortical cultured neurons. Neurochemical research, 41, 600-609.

https://doi.org/10.1007/s11064-015-1700-4 

Kanasaki, K., Kawakita, E., & Koya, D. (2019). Relevance of autophagy induction by gastrointestinal hormones: focus on the incretin-based drug target and glucagon. Frontiers in Pharmacology, 10, 476.

https://doi.org/10.3389%2Ffphar.2019.00476 

Jensen, N. J., Wodschow, H. Z., Nilsson, M., & Rungby, J. (2020). Effects of ketone bodies on brain metabolism and function in neurodegenerative diseases. International journal of molecular sciences, 21(22), 8767.

https://doi.org/10.3390%2Fijms21228767 

Pietrocola, F., Malik, S. A., Mariño, G., Vacchelli, E., Senovilla, L., Chaba, K., ... & Kroemer, G. (2014). Coffee induces autophagy in vivo. Cell Cycle, 13(12), 1987-1994.

https://doi.org/10.4161%2Fcc.28929 

Zhu, Y., & Bu, S. (2017). Curcumin induces autophagy, apoptosis, and cell cycle arrest in human pancreatic cancer cells. Evidence-Based Complementary and Alternative Medicine, 2017.

https://doi.org/10.1155%2F2017%2F5787218