Stimulating autophagy

Autophagy stimulation is a key area in longevity and health research. The body has a complex system of regulation of this process, and it can be influenced by both natural and (potentially) pharmacological methods.

Here are the main mechanisms and factors that stimulate autophagy and improve the functioning of lysosomes.

1. Energy stress (‘Turning on hunger’)

This is the most powerful and natural incentive. When a cell doesn’t get enough energy, it turns on a ‘recycling mode’ to get rid of the old one and produce new energy.

Potassium starvation: The most effective method. The lack of nutrients (especially amino acidsAmino acids are the fundamental building blocks of proteins and play a key role in biological processes. There are a total of 22 standard amino acids used for protein synthesis in living organisms. and glucose) leads to a drop in blood levels.:
- Insulin and IGF-1 (insulin-like growth factor 1).
- mTOR (target of rapamycin in mammals). mTOR is the main ‘brake’ of autophagy. When its activity is high (with an abundance of food), the cell grows and divides, and autophagy is suppressed. Fasting slows down mTOR, removing this ‘brake’ and triggering autophagy.
- Activation of AMPK (AMP-activated protein kinase). This is the’ energy level sensor ‘ of the cell. When the level of ATP (the energy currency of the cell) is low, AMPK is activated and involves energy production processes, including autophagy. AMPK directly suppresses mTOR.
Interval fasting and diets that mimic fasting: More practiced approaches that give the same effect as prolonged fasting, but in a milder form.

2. Physical activity

Physical activity creates moderate stress for muscle cells and other organs.

Mechanical damage and oxidative stress: During exercise, damaged proteinsProteins are high-molecular organic substances consisting of alpha-amino acids linked in a chain by a peptide bond. In living organisms, the amino acid composition of proteins is determined by the genetic code. During synthesis, 20 standard amino acids are used in most cases. Many combinations of them determine the great diversity of properties of protein molecules. Proteins play a key role in the immune response and can perform transport, storage, catalytic, structural, and receptor functions. Proteins are an important part of the nutrition of animals and humans. The main sources of proteins are meat, poultry, fish, milk, nuts, legumes, and grains. and organelles are formed in the cells. This serves as a direct signal for their utilization through autophagy.
Energy consumption: Exercise depletes glycogen and ATP stores, which, like fasting, activates AMPK and inhibits mTOR.

3. Cellular stress

Any moderate stress can ‘shake up’ the cell and start cleaning processes.

Oxidative stress: The formation of reactive oxygen species (ROS) serves as a signal to trigger autophagy.
Hypoxia (lack of oxygen): Activates special proteins (HIF) that can induce autophagy.
Heat stress: Rising temperatures are also a trigger.

How to improve the performance and number of lysosomes?

Stimulating autophagy is only half the battle. It is important that the ‘processing plants’ — lysosomes-work efficiently.

1. Synthesis of new lysosomes (Lysosomogenesis)

A cell can increase the number of lysosomes when it realizes that the need for recycling has increased. The main ‘regulator of lysosomes’ — transcription factor EB (TFEB) – is responsible for this process.

How is TFEB activated?
- During starvation and stress, when mTOR is inactive, TFEB moves from the cytoplasm to the nucleus.
- In the nucleus, it ‘sits’ on genes encoding lysosomal enzymesEnzymes are proteins that accelerate chemical reactions in the body. They ensure the occurrence of metabolic processes such as food digestion, energy release, cell formation, and many others. (cathepsins) and lysosomal membrane proteins themselves.
- This leads to a massive synthesis of new,’ fresh ‘ lysosomes and enzymes for them.

Factors that activate TFEB (and hence lysosomogenesis):

Same as for autophagy: fasting, exercise, oxidative stress.
Some polyphenolsPolyphenols are a group of natural organic compounds that contain several phenolic groups (aromatic rings with hydroxyl groups -OH). They are widely distributed in plants and play an important role in their protection from ultraviolet radiation, pathogens, and oxidative stress., such as curcumin and resveratrol, can also promote TFEB activation.

2. ‘Rejuvenation’ of existing lysosomes

For lysosomes to work well, you need to maintain their internal environment.

Acidity (pH): Lysosomes require an acidic environment (pH ~4.5-5.0) to activate enzymes. With age and with diseases (for example, neurodegenerative diseases), the pH in lysosomes can increase, and enzymes stop working.
- What helps? Adequate functioning of the proton pump (V-ATPase), which pumps protons into the lysosome. It requires energy (ATP) and certain lipids to work.
Zinc and other cofactors: Some lysosomal enzymes require zinc and other trace elements to function.

Practical conclusions: what ‘helps’ autophagy and lysosomes?

Strategy	Mechanism of action
Interval fasting (for example, 16/8)	Insulin/glucose reduction, mTOR inhibition, AMPK and TFEB activation.
Regular physical activity	Energy consumption, AMPK activation, direct stress from damage.
A protein-restricted diet (especially animal-based)	Decreased mTOR activity (leucine and other amino acids are powerful mTOR stimulants).
Consumption of foods rich in polyphenols (green tea, turmeric, berries, red grapes)	Antioxidant effect, potential activation of pathways leading to autophagy (sirtuins, TFEB).
Healthy sleep	During sleep, brain cleaning processes are activated, including autophagy (glymphatic system).
Avoiding constant ‘snacking’	Constant food intake supports high insulin levels and mTOR activity by suppressing autophagy.

Important warning: Autophagy is a double-edged sword. Its chronic or excessive activation can be harmful. The ‘more is better’ approach doesn’t work here. Stimulation should be cyclical and moderate (for example, through fasting) to give the cell time to recover.