What is Autophagy?

The word autophagy is derived from two Greek words that mean “eat the self.” ^[1] Autophagy is a physiological cellular process that helps to maintain a balance between the making and breaking of cells. It is a natural cleaning process that reuses old and damaged cell parts to optimize the efficiency of cells. Autophagy initiated by the deprivation of nutrition or oxygen in times of bodily stress helps provide an alternate source of energy from the recycled cellular materials. This helps the immune system by clearing toxins and infectious agents. It can also induce programmed cell death (apoptosis) under certain conditions.^[2]

The mechanics of autophagy were not fully understood until the early 1990s, when Japanese cell biologist Yoshinori Ohsumi completed a series of groundbreaking research on yeast, where he identified autophagy and its important genes. His research established a new theory for how cells recycle their contents and revealed the basic role of autophagy in a variety of physiological functions, including adaptation to fasting and its link to benefits in blood sugar levels, inflammation, weight loss, and lifespan.^[3] Ohsumi’s research has won him the Nobel Prize in Medicine in 2016.

Physiology of Autophagy

Autophagy is a balance of cellular functions where misfolded proteins, damaged organelles, and infectious agents are removed from the otherwise healthy cells. The process of autophagy begins with the formation of autophagosome, which then fuses with lysosome that contains enzymes for the degradation of cellular structures.^[4]

Autophagy plays a vital role in creating healthier cells. It is critically acclaimed in many areas of health, including the prevention of several diseases such as cancer, diabetes, autoimmune diseases, infections, and heart diseases. Similar to all the physiological processes, autophagy also declines with advancing age, and the activation of autophagy through various methods helps to improve health and longevity.^[5]

What Induces Autophagy?

Autophagy occurs constantly in our body, but there are various stress stimuli that further induce autophagy. These include fasting, calorie restriction, high fat low carb diets, and exercise. Fasting and calorie restriction are considered the optimal mechanism to improve health and longevity. Calorie restriction is usually described as 10-40% reduction in your daily calorie intake that doesn’t affect the recommended nutritional content.^[3] On the other hand, in intermittent or extended fasting, a person does not eat at all for certain hours of the day, week, or month.^[6]

Although there is still limited data available on effects of nutritional stress-induced autophagy in humans, it has been reported that long-term calorie restriction leads to lifespan extension and better health.

A research in mice indicated that intermittent fasting, or complete food restriction between two meals, induces autophagy in liver, fat, brain, and muscle cells and helps lower blood glucose and lipid levels.^[7]

Fasting and Autophagy

Intermittent or extended fasting under supervision has been reported as a healthy method to shed excess weight and improve health. It helps with hormonal balance and induces autophagy. During fasting, the body uses blood glucose followed by the glycogen from the liver. During extended periods of fasting, the body turns to fat for energy, and this stored form of energy is released in the form of ketones.

Many studies have reported the advantage of ketones over glucose as they protect brain cells against age-related decline, inhibit cancer developing cells, reduce inflammatory diseases such as arthritis, and help reduce insulin levels to protect against type 2 diabetes.^[6]

There is limited data available regarding the optimal length of a fast for autophagy benefits. In a study conducted in 2019, researchers analyzed numerous markers related to longevity, including the expression of the autophagy gene.  A group of 11 overweight adults followed an early time-restricted feeding (eTRF) schedule, which included 10 hours of normal feeding and 14 hours of fasting. This resulted in improved health and longevity outcomes with a 22% increase in the production of the autophagy gene after just four days.^[8]

The length of an ideal fast varies with an individual’s health and age. Only a handful of studies have measured the effects of fasting duration on autophagy in humans. The current evidence from the study on mice suggests that fasting anywhere between 18 hours to 4 days will trigger autophagy.^[9] As mentioned above, exercise and low carb dietary restriction along with shorter fasts also helps to boost autophagy.^[10]

Is Autophagy Healthy or Not?

Too much or too little of anything can be harmful for health. The dysregulation of autophagy can lead to abnormal cell growth or excessive cell death. A halting in physiological autophagy for longer periods can impact cell health and can cause several disorders, including cancer formation. On the contrary, prolonged fasting and overstimulation of autophagy can lead to excessive cell death. According to current research, fasting and calorie restriction are safe ways to induce autophagy, but much more research is required to fully understand the effects of autophagy in humans.^[11]

References:

1. Glick D, Barth S, Macleod KF. (2010). Autophagy: cellular and molecular mechanisms. J Pathol. Link
2. Bagherniya M, Butler AE, Barreto GE, Sahebkar A. (2018). The effect of fasting or calorie restriction on autophagy induction: A review of the literature. Ageing Res Rev. Link
3. The Nobel Prize. Press release. (2016). Accessed on 6th sept, 2022.  Link
4. Xie Z, Nair U, Klionsky DJ. (2008). Atg8 controls phagophore expansion during autophagosome formation. Mol Biol Cell. Link
5. Jing K, Lim K. Why is autophagy important in human diseases? (2012). Exp Mol Med. Link
6. Calorie Restriction and Fasting Diets: What Do We Know? (2018). Accessed on 6th sept, 2022. National institute on aging. Link
7. Wong SQ, Kumar AV, Mills J, Lapierre LR. (2020). Autophagy in aging and longevity. Hum Genet. Link
8. Jamshed H, Beyl RA, Della Manna DL, Yang ES, Ravussin E, Peterson CM. (2019). Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans. Nutrients. Link
9. Pietrocola F, Demont Y, Castoldi F, Enot D, Durand S, Semeraro M, Baracco EE, Pol J, Bravo-San Pedro JM, Bordenave C, Levesque S, Humeau J, Chery A, Métivier D, Madeo F, Maiuri MC, Kroemer G. (2017). Metabolic effects of fasting on human and mouse blood in vivo. Autophagy. Link
10. Brandt N, Gunnarsson TP, Bangsbo J, Pilegaard H. (2018). Exercise and exercise training-induced increase in autophagy markers in human skeletal muscle. Physiol Rep. Link
11. Pallauf K, Rimbach G. (2013). Autophagy, polyphenols and healthy ageing. Ageing Res Rev. Link