Autophagy and aging

Fight Aging!, Autophagy is Everywhere in Aging Translated by Evgenia Ryabtseva

For links, see the original article

Specialists engaged in the study of autophagy can reasonably claim that the mechanism of autophagy is involved in almost every aspect of aging. Autophagy is actually a system of cleaning the cell from excess by recycling damaged or unnecessary structures and molecules in the intracellular space. In autophagy mediated by chaperone proteins, chaperones selectively bind other molecules and transfer them inside lysosomes. In macroautophagy, materials intended for cleavage are absorbed by autophagosomes, which subsequently move to lysosomes and merge with them. In microautophagy, lysosomes themselves absorb unnecessary structures.

In all cases, the final stage of the journey is lysosomes – membrane structures filled with an enzymatic mixture that breaks down "recyclables" into components suitable for reuse. The result of a well-functioning autophagy is a cell free of damaged structures and cellular debris, causing fewer problems to the tissue it is part of.

The ability to maintain a minimum level of wear inside cells is a noteworthy determinant of aging. Many of the approaches that slow down the aging process of laboratory animals, such as fruit flies, roundworms and mice, involve the activation of autophagy. Cells respond to stress by increasing autophagy, and this generally does not depend on the type of stress. This is one of the reasons that short-term moderate stress effects have a positive effect on health, which is known as the hormesis effect. Autophagy is an important component of this mechanism, and in some cases even its necessary condition. For example, a low-calorie diet does not have a positive effect on the health and longevity of animals whose cells lack the ability to autophagy.

The authors of an open access article published in the journal Frontiers in Endocrinology (María Carolina Barbosa et al., Hallmarks of Aging: An Autophagic Perspective) analyzed the main manifestations of aging, finding for each of them a relationship with autophagy. Whereas, indeed, almost every aspect of aging can be associated with autophagy and, in particular, given the fact of age-related extinction of autophagy, it is very important to remember that as a therapeutic approach autophagy has a rather limited potential. The approximate limit of this limitation can be demonstrated by the example of autophagy. It is possible to imagine a therapy that stimulates autophagy twice as much as a low-calorie diet, but this will not increase a person's life expectancy for decades. In fact, stress reactions have only a negligible effect on human life expectancy compared to the effects observed in experiments on mice. A low-calorie diet can increase the lifespan of mice by 40%, but it definitely will not achieve such a result when applied to humans. 5 additional years to life expectancy is practically the limit of what we can expect, although the concomitant health benefits are really worth the effort.

Autophagy disorders associated with aging 

(based on the article by Barbosa et al.).

Loss of proteostasis

Proteostasis (balance of the protein composition of cells) is one of the main functions of autophagy in normal tissues. Age-related violation of proteostasis leads to protein aggregation, accumulation of improperly folded protein molecules and, ultimately, to disruption of cell functioning. It is noteworthy that one of the changes leading to a violation of proteostasis is carbonylation under the influence of oxidative stress. To prevent the death or disruption of cell functions, many homeostatic mechanisms are triggered, the main of which are autophagy and the ubiquitin-proteasome system. Since autophagy is considered one of the most important processes of intracellular homeostasis, a violation or weakening of this mechanism can affect the normal functioning of the cell, including causing the development of various diseases and the extinction of normal physiological processes inside the cell.

Mitochondrial dysfunction

Mitophagy is the basic process involved in autophagic degradation of mitochondria. It is necessary for the normal differentiation of certain cell types, such as red blood cells, for embryogenesis, the development of an immune response, cell programming and cell death. Mitophagy is necessary not only to destroy damaged mitochondria, but also to stimulate the synthesis of new ones, which ensures quality control of these organoids. Given the involvement of mitochondria in bioenergetic processes and the synthesis of reactive oxygen species, we can talk about their important role in maintaining cell homeostasis. In addition, a decrease in the activity of mitophagy is observed in aging animals and contributes to the development of aging phenotypes.

Impaired regulation of nutrient recognition

Since mitophagy is a catabolic mechanism, its involvement in cellular and systemic metabolism can be assumed. Metabolic stress reactions can be compromised due to the extinction of autophagic activity. As an important process of regulating the overall status of the cell, autophagy can provide a relationship between metabolic processes to maintain homeostasis in various conditions. In this regard, it has been demonstrated that after the deprivation of nutrients or growth factors, the activation of enzymes of the ULK1 and ULK2 kinase family occurs. They, in turn, phosphorylate and activate several glycolytic enzymes, as well as autophagic proteins. This gives cells the ability to obtain metabolites by capturing glucose, blocking the gluconeogenic mechanism and autophagic degradation of cytosol components (intracellular contents). This is confirmed by the fact that hyperactivation of the mammalian rapamycin target protein (mTOR) has been detected in a number of diseases, including obesity, metabolic syndrome and type 2 diabetes, which emphasizes the importance of strict regulation of autophagy, as well as the mechanism of recognition of nutrients.

Genome instability

Over the past decade, the results of several studies have demonstrated that autophagy or its associated molecules act as "guarantors" of genome stability both directly (modulation of DNA damage repair mechanisms) and indirectly (acting as a homeostatic reaction). Several mouse models provided significant information regarding genome instability and its relationship with healthy and pathological aging.

Epigenetic changes

Taken together, studies on organism models and in vitro emphasize the importance of epigenetic mechanisms throughout life. The relationship between epigenetic changes and autophagy needs to be studied in detail, the results of which will help to understand the regulatory loop linking the processes of development and aging.

Telomere shortening

The activity of the telomerase enzyme can support the progression of the cell cycle by preventing it from stopping due to telomere shortening, which presumably leads to malignancy. An interesting fact is that the increased expression of Beclin1 protein in HeLa cells led to a decrease in telomerase activity after induction of autophagy. This observation is an argument in favor of the hypothesis that autophagy plays an important role in suppressing tumor growth by modulating telomerase activity in somatic cells. This autophagic reaction develops to prevent genome instability and telomere dysfunction, contributing to cell survival.

Physiological aging of the cell

Autophagy regulates the physiological aging of smooth muscle cells of the vascular wall. It is very interesting that autophagy can also mediate the transition of fibroblasts into the phenotype of physiological aging during oncogene activation. Based on this, it was suggested that at each specific moment and in each specific place, the type of autophagy may determine its ability to stimulate or prevent the entry of a cell into the phase of physiological aging.

Depletion of stem cells

Self-renewal is an important mechanism for maintaining a population of tissue-specific stem cells throughout the life of an organism. It is very important that as we age, the activity of stem cells fades. It has been demonstrated that autophagy is a necessary condition for the preservation of hematopoietic stem cells and their ability to remain in the resting phase. Autophagy is also important for maintaining the "stemness" of bone marrow mesenchymal stem cells. In addition, the loss of the Atg7 protein in aging muscle stem cells (satellite cells) of transgenic mice led to a violation of mitophagy and the accumulation of reactive oxygen species. Both manifestations are signs of physiological aging and reduce the regenerative potential of aging satellite cells.

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