What a funny concept; cellular mechanisms that digest parts of our own cells. Yet these “self-digestion” mechanisms are crucial and intimately linked to healthy longevity. Their role is to make it possible to (1) reorient part of the available resources or even to (2) unclog a cell cluttered with proteins or organelles (structures of the cell which have different functions) which are no longer functional. Using a factory analogy, autophagy can thus (1) salvage unused or underused materials and make them available to another section of the factory. These digestion and recycling mechanisms can also (2) recover damaged materials or devices in order to recycle them into new machines that will be available for this factory.
The most interesting thing is that these processes are essential to life, they have a great implication in development, defense against cancer, in healthy longevity, and they can be induced by fasting, physical activity, diet, or supplements.
Recycle to adapt
Biology is largely based on optimizing the use of resources to allow species to survive. Thus, one of the great laws of biology is that what is not used disappears. For example: if we do not use our muscles enough, muscle mass decreases. Have you ever wondered how this is possible? Why doesn’t the body keep unused muscle mass? It is that during evolution, access to sufficient resources was a daily challenge. In order to allow a fine adaptation to our lifestyles, the body has developed the ability to significantly grow more muscle that we need the most, while being able to reorient the materials used if the demand for this muscle capacity decreases. This is a fine coping system, which works wonderfully when you are young. Autophagy is the same principle, for all things needed for recycling as well as damaged cellular devices.
Three operating modes tailored to your needs
There are mainly 3 types of autophagy: macroautophagy (macro = coarse; for large needs) microautophagy (for small recycling) and autophagy related to the use of molecular chaperones (proteins having the role of repairing other proteins and if they are unsuccessful, the damaged proteins are degraded by autophagy).
For microautophagy, the small components to be recycled are directed to the lysosome and are directly digested by an invagination form of the lysosomal membrane. The lysosome is a cellular organelle that is used to digest, very much like a stomach or garbage disposal. Microautophagy is considered to be the main type of autophagy responsible for the turnover of organelles and proteins in all cells. It is also used to redirect certain resources. For example, when there is a deficiency of amino acids, the cytosolic proteins, present in the cell, are destroyed by this type of autophagy to recover essential amino acids.
Macroautophagy is one of the most studied types of autophagy and is linked to several diseases in humans. This type of recycling usually considers components like damaged organelles or misfolded proteins, like microautophagy, but it incorporates protein aggregation into its transport mechanism to effect extensive degradation. Like microautophagy, it also works with selective and non-selective mechanisms. Macroautophagy creates a phagophore which, when completed, is called the autophagosome, which surrounds the component to be recycled (what is called cytoplasmic/autophagic cargo) which will be sent to the lysosome for disposal. We could draw a parallel with the trucks that collect our recyclable materials. These are transport vehicles that pick up damaged materials from the recovery device (lysosomes). This autophagosome is a double-membrane vesicle that fuses with the lysosome membrane to expel these components to eliminate them.
Autophagy through the use of a chaperone protein works very differently from the other two types. Chaperone proteins are used to reactivate misfolded proteins. You could define the chaperone a bit like a person who aims to watch/supervise something. If it does not succeed in making the protein functional again, it will remain attached to it to form an identification complex and it will cause its recovery to be recycled.
A chaperone complex is needed in order to identify soluble proteins to be supplied to the lysosome for destruction. These only work with selective mechanisms which are much more complex since chaperone proteins (like heat shock proteins) are recognized by a lysosomal receptor (lysosomal membrane protein), which work together, in many cases, for recycling. It is as if an employee of a used car dealership had identified those that could be destroyed in order to reuse the metal parts and then gave the signal to “destroy” them.
Autophagy by molecular chaperones is of great interest from a human health point of view because it could help to direct the specific recycling of certain proteins. For example, the proteins involved in Alzheimer’s disease.
We could present a 4th type linked to specific functions such as autophagy of mitochondria (mitophagy), cellular lipids (lypophagy), or foreign bodies such as viruses and bacteria (exophagy).
Aging because we accumulate damaged equipment
Where does the link between aging and autophagy come from if the latter is used for cellular recycling? Autophagy is part of what are called maintenance and repair mechanisms. These mechanisms work perfectly well when you are young, but as you get older their effectiveness decreases. There is therefore the recycling of waste to keep cells functional by avoiding clutter and nutritional recycling caused by the need for resources.
Thus, if the body lacks resources, it will reduce growth and development by inhibiting MTOR (mechanistic target of rapamycin; the conductor of development, the most important metabolic pathway that causes the organism to age) and it will stimulate autophagy to try to recover the available materials. This is extremely beneficial because:
- It slows down aging, and
- Makes cells more functional.
Another relevant example is the efficiency and health of the mitochondria. Our small, intracellular energy powerhouses have the ability to pollute our cells and increase the risk of many diseases if they are not functioning properly. Normally, when mitochondria are not functioning well, their membrane potential decreases and they will release oxidative molecules that can cause DNA or protein damage (pollution). It is the autophagy mechanisms that replace damaged mitochondria.
As we age, our cells tend to become congested, malfunctional, and produce oxidative molecules as autophagy works less well. Stimulation of autophagy makes it possible to make cells functional again, to rejuvenate them. This rejuvenation process also has a significant impact on inflammatory mechanisms.
Autophagy and inflammasome
The inflammasome is a complex of proteins that regulate innate pro-inflammatory reactions through the activation of caspase-1 and the production of IL-1β and IL-18. There are different types of inflammasomes. The production of inflammasomes is stimulated by the decrease in autophagy and causes an increase in inflammation. The increased production of oxidation caused by the dysfunction of mitochondria also stimulates the production of inflammasome and pro-inflammatory molecules. This increase in inflammation throughout the human body accentuates the problems or the rate of development of autoimmune diseases, cardiovascular diseases, type II diabetes, degenerative diseases, and cancer. Thus, autophagy has an important role to play in keeping cells functional and controlling inflammation.
Self-digest when hungry
Two lifestyle habits are linked to the stimulation of autophagy: physical activity which stimulates maintenance and repair mechanisms in general, and fasting which creates a situation of resource deficit. As mentioned previously, the lack of resources stimulates autophagy in order to quickly recover the available resources. Note that as you age, the action of MTOR, previously mentioned, decreases autophagy and accelerates aging. Reducing calorie intake, through fasting or calorie restriction, stimulates autophagy in two ways: by inhibiting MTOR and by stimulating repair mechanisms. In addition, inhibiting MTOR would reduce the buildup of cellular proteins that tend to make our cells dysfunctional as we age. It also reduces the need for autophagy, or the task required for autophagy to be able to meet the demand.
One of the keys to healthy longevity is our ability to stimulate autophagy. Note that stimulation by physical activity is dependent on the level of intensity. In other words, high intensity physical activity is necessary for the stimulation of autophagy. Another option would be to stimulate autophagy through diet or supplementation.
Stimulate autophagy thanks to plant molecules
Several plant extracts or molecules have demonstrated the ability to stimulate autophagy and/or reduce the creation of inflammasomes. The best known are surely spermidine (a polyamine) and resveratrol (a polyphenol from the stilbenes family). We should also mention quercetin, epigallocatechin gallate (EGCG; a polyphenol of the flavanol family, the most abundant in green tea), catechin (polyphenol, a flavone also in green tea), and hydroxytyrosol (the most important polyphenol in olives).
Interestingly, neuronal cells are particularly sensitive to the accumulation of cellular debris or dysfunctional organelles. This speeds up cell death and reduces neurogenesis (the production of new cells). Thus, the previously mentioned plant polyphenols and spermidine, which stimulate autophagy, have significant benefits in the prevention or treatment of degenerative diseases. Several are also known to improve mitochondrial functions or stimulate apoptosis (programmed cell death that is used to replace damaged cells). These processes are all interrelated.
An integrative health approach aimed at autophagy
Integrative health aims to consider prevention above all else, considering the range of approaches that can be used. It is interesting to note that the stimulation of autophagy can involve the integration of several solutions. I previously mentioned physical activity, fasting, diet, and supplementation. The most productive approach will surely be to integrate all of these facets by implementing all 4.
Originally published in the Vitalité QC magazine: https://vitalitequebec-magazine.com/en/home/
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