In the mid-1950s, Belgian scientist Christian de Duve discovered cellular organelles he called lysosomes. He observed that these elements were capable of "digesting" large amounts of proteins, carbohydrates, lipids, and even other cellular organelles, which were recycled to be converted into raw materials useful for cellular functions.

He coined the term autophagy to describe these processes and won the Nobel Prize in Medicine in 1974 for his work. However, in the years that followed, this knowledge was not extensively explored.

In the 1990s, Japanese biologist Yoshinori Ohsumi, who was a Nobel laureate in 2016, began to investigate how the importance of degradation and recycling of cellular components was vital for certain physiological functions to be carried out.

Autophagy as a tool to purify our organism while generating energy in our cells.

It is essential when the cell is starving or needs energy, since lysosomes, by ingesting components that the cell no longer needs for its function, can recycle them and take advantage of them to provide the cell with energy. For example, in a context of food restriction, such as fasting, lysosomes help generate the nutrients that are in deficit during that day.

Among its benefits, they can generate amino acids that are the raw material to produce new proteins.

During autophagy, lysosomes also destroy viruses and bacteria and get rid of damaged structures. This process is crucial for health, renewal, and cellular survival.

It is postulated that fasting for 12 to 24 hours triggers autophagy, and it is one of the reasons why fasting is linked to better blood sugar control, reduced inflammation, weight loss, and better brain function.

Exercise can also induce autophagy in some cells, allowing them to initiate the repair and renewal process.

Autophagy itself is not a weight loss method, but its induction through fasting and/or calorie restriction can favor fat loss, weight control, cardiovascular health, oxidative stress and hormonal regulation.

Fasting is one of the oldest traditions in the world and has been practiced in various communities for cultural or religious reasons.

It has also been used as a curative method for diseases.

• Hippocrates, considered the father of modern medicine, wrote: “To eat when you are sick, is to feed your sickness.”
• The ancient Greeks believed that fasting improved cognitive abilities.
• Plutarch, a Greek writer, wrote: “Instead of using medicine, better to fast today.”

But are intermittent fasting and calorie restriction synonyms?

Intermittent Fasting involves shortening the eating window, having hours of the day where there is no food intake. During these fasting periods, especially after 12 to 16 hours without eating, the body initiates autophagy to obtain energy by recycling damaged cells and organelles. It has been observed that intermittent fasting is what best mimics ancient human eating patterns.

On the other hand, Calorie Restriction consists of a reduction of the total daily caloric intake, independent of the eating window. It has been shown in people with obesity and overweight that short-term (6 months) calorie restriction significantly improves multiple cardiovascular risk factors, such as insulin sensitivity and mitochondrial function.

Although reducing daily calories effectively translates into a decrease in body weight and even an increase in longevity in many species, including non-human primates, obesity treatments using this method have revealed that the vast majority of people experience difficulties in maintaining the restriction for prolonged periods, which is the cause, in some cases, of the "post-diet" rebound effect.

For this reason, intermittent fasting has gained popularity as an alternative to continuous calorie restriction, and recent research suggests that it offers similar benefits regarding weight loss and cardiometabolic health. Unlike traditional calorie restriction paradigms, intermittent fasting only requires fasting for specific periods of time.

Currently, there are several intermittent fasting protocols. The most common include alternate-day fasting, which consists of fasting for 24 hours every other day, and the 5:2 method, which implies a 24-hour fast twice a week and a very low-calorie diet the other two days.

In this method, fasting can be done on consecutive or non-consecutive days.

Another protocol is time-restricted feeding fasting, which means patients must fast during the time specified within each day and then eat freely for the rest of the time.

The fasting and eating times within each day can be chosen according to personal preferences or lifestyle habits.

Common methods of time allocation are:

1. 16/8: 16 hours of fasting, 8 hours of free feeding.
2. 18/6: 18 hours of fasting, 6 hours of free feeding.
3. 20/4: 20 hours of fasting, 4 hours of free feeding.

Fasting can be broken in three ways:

• Caloric energy intake
• Insulin stimulation
• Activation of anaerobic metabolic pathways (mTOR)

Very low-calorie intakes (≈ 0–5 kcal) do not generate significant changes in glucose, insulin, or mTOR, so they generally do not alter the physiological effects of fasting, especially intermittent fasting.

Based on these mechanisms, the foods or substances that do not break a fast are those that do not alter the pathways indicated above:

• Water
• Coffee, tea, infusions (without sugar)
• Electrolytes like magnesium, zinc, sodium, potassium (without added sugar and carbohydrates)

As we have already mentioned, changing the eating pattern through intermittent fasting results in the activation of autophagy, and also greater life expectancy and greater longevity through multiple processes.

The pathways involved include an increase in AMP (and ADP) and a decrease in cellular ATP, which results in the activation of AMP-activated protein kinase (AMPK), which ultimately inhibits multiple anabolic pathways and stimulates the autophagy of catabolic reactions, thus eliminating damaged proteins and organelles and improving mitochondrial function.

A decrease in circulating amino acids and glucose inhibits mTOR, which leads to lower protein synthesis and promotes autophagy. This includes the elimination of damaged mitochondria (mitophagy) and the generation of new ones (mitochondrial biogenesis) to maintain energy homeostasis.

Through reduced carbohydrate intake, fasting depletes hepatic glycogen, mobilizes fatty acids from adipose tissues, and stimulates hepatic β-oxidation with an increase in ketone production (β-hydroxybutyrate).

In addition, the NAD+-dependent deacetylase activity of sirtuins is activated, which results in autophagy and a reduction of oxidative stress. Together, these pathways lead to longevity and better health.

Implementing a metabolic improvement method that stimulates autophagy can be difficult for some people, because diets are not always compatible with a modern lifestyle. However, in the case of intermittent fasting, since there are diverse protocols, it is more adaptable than other restrictive diets such as ketogenic, protein-based, or daily calorie restriction. Furthermore, since intermittent fasting correlates with the natural circadian rhythm, it could be a more physiological option.

It is important to mention that intermittent fasting is not free of adverse effects; the most common include hypoglycemia, dizziness, and weakness. Furthermore, fasting without adequate protein replacement causes loss of muscle mass.

Fasting is also not recommended for people with hormonal imbalances, pregnant or breastfeeding women, children, older adults, people with immune deficiencies, eating disorders, or nervous system disorders.

If you are interested in starting an intermittent fasting protocol, it is important that you receive medical and/or nutritional guidance from specialized professionals.

1. Vasim, I., Majeed, C. N., & DeBoer, M. D. (2022). Intermittent Fasting and Metabolic Health. Nutrients, 14(3), 631. https://doi.org/10.3390/nu14030631
2. Wang, Y., & Wu, R. (2022). The Effect of Fasting on Human Metabolism and Psychological Health. Disease markers, 2022, 5653739. https://doi.org/10.1155/2022/5653739
3. Marko, D. M., Conn, M. O., & Schertzer, J. D. (2024). Intermittent fasting influences immunity and metabolism. Trends in endocrinology and metabolism: TEM, 35(9), 821–833. https://doi.org/10.1016/j.tem.2024.04.014
4. Zhang, Q., Zhang, C., Wang, H., Ma, Z., Liu, D., Guan, X., Liu, Y., Fu, Y., Cui, M., & Dong, J. (2022). Intermittent Fasting versus Continuous Calorie Restriction: Which Is Better for Weight Loss?. Nutrients, 14(9), 1781. https://doi.org/10.3390/nu14091781