26 January 2018

Aging and mitochondria: new data

Mitochondria are self-renewing structures that have evolved from symbiotic bacteria into fully integrated intracellular organoids. Their main function is to produce chemical energy, the by-product of which is reactive oxygen species and other oxidants that damage biomolecules.

Most of the DNA of the original bacterial genome of the precursors of modern mitochondria migrated to the cell nucleus, while only a small amount of DNA remained inside the organelles themselves. When studying different species with significantly different lifespans, the researchers found clear correlations between the longevity of individuals of different species with certain combinations of mitochondrial activity (metabolic rate) and the composition of mitochondria (resistance to oxidative damage). This is convincing evidence, independent of many other supporting facts, in favor of the fact that mitochondria are important determinants of aging and longevity.

There are many methods for studying the complex mechanisms of mitochondrial contribution to aging, and until specific recovery technologies successfully eliminate this factor, the extent to which various age-related changes in mitochondria are associated with aging will remain the subject of active debate and study.

From the point of view of researchers working within the framework of the SENS (Strategies for Engineered Negligible Senescence, "strategies for achieving negligible aging by engineering methods"), damage to mitochondrial DNA is the most important of the primary causes of aging. They appear during replication or as a result of damage caused by active molecules and can lead to the appearance of mitochondria that are both defective and abnormally rapidly replicating compared to normal organelles. Cells are filled with defective mitochondria and themselves lose the ability to function normally, producing a large number of damaged and damaging molecules that contribute to the development of age-related diseases.

On the other hand, the dominant part of the scientific community draws attention to nonspecific disorders of mitochondria in aging tissues, characterized by a decrease in the ability to create an energy reserve, a violation of the dynamics of fusion and division, as well as other structural changes. From the point of view of SENS researchers, this may be a secondary or even later consequence of other forms of cell and tissue damage.

Of the two articles recently published in the public domain, the first is a general high-quality review of the data available to date on the role of mitochondria in the aging process. When reading it, it seems that this area of research is rapidly moving away from the theories generally accepted over the past decades, the inconsistency of which has already been proven, but the direction of its further movement is not fully defined.

The second article analyzes the causes and mechanisms of DNA damage. Currently, there is a fairly active debate about whether errors in DNA replication or the activity of reactive molecules, including in large numbers generated by the mitochondria themselves, are the main cause of this. This article defends the opinion that replication errors are a very important cause, especially relevant for stem cell populations, since they contribute to the age-related extinction of stem cell activity. The causes of errors are undoubtedly of interest, but in reality they have practically nothing to do with potential methods of repairing damage or eliminating this problem. If we had at our disposal a method of reliably repairing mitochondrial DNA damage in almost any cells, replacing these cells or providing backup copies of protein products of this DNA, then the cause of these damages would be completely irrelevant.

Aging mitochondria Pierre Theurey, and Paola Pizzo, The Aging Mitochondria // Genes 2018


"On average, the life expectancy of a healthy person is 80 years, and one of the main risk factors for human morbidity and mortality is aging. Many evolutionary and mechanistic theories have been developed to explain the causes and mechanisms of aging of living organisms. However, from a mechanistic point of view, among all theories, a special place is occupied by theories according to which mitochondria play the main roles in the aging process. For the past 50 years, mitochondria have been central to the leading hypothesis known as the free radical theory. Even though the research community is already leaning towards a more complex explanation of aging, given the complex interrelation of the underlying mechanisms, mitochondria remain of exceptional importance due to their dominant role in the homeostasis of cells in almost all tissues. Thus, as far as can be judged from the description of molecular and cellular mechanisms, mitochondria are involved in each of the important aspects of aging: the extinction of stem cell functions, physiological aging of cells, "inflammaging" (age-related chronic systemic inflammation) and many others.

For a long time, researchers have described mitochondrial disorders in aging tissues of many organs. In particular, this issue has been actively studied in skeletal muscle tissue and heart tissue, since sarcopenia (age-related muscle degradation) and heart failure are the two main causes of deterioration in the physical condition of the elderly. Not only in these two tissues, but also in others, including in the tissues of the liver, brain and adipose tissue, mitochondrial disorders are detected during aging. In particular, there is a decrease in the number and density of mitochondria, as well as the activity of mitogenesis, while contradictory inconclusive results have been obtained with respect to the dynamics and composition of mitochondria. It is important that mitochondrial function disorders, such as decreased ATP production and respiratory chain activity/capacity, are regularly described for different aging tissues.

The key feature of mitochondria described by the researchers is an increase in the number of somatic point mutations and deletions of mitochondrial DNA (mtDNA). Given the proximity of mtDNA to the main source of reactive oxygen species (ROS), oxidative damage was considered the main cause of mutations in mtDNA. According to the mitochondrial free radical theory of aging, oxidative damage to mtDNA is the main mechanism influencing the proteins of the respiratory chain, inducing a violation of its functions and increasing the production of ROS, which forms a "vicious circle". However, this theory was seriously questioned and the scientific community had to adapt the working hypotheses in such a way that they corresponded to the more complex interweaving of aging mechanisms, the central link of which is mitochondria.

The proliferative cycle causes the development of age-related mitochondrial defects and promotes the aging of stem cells
Ren et al., Proliferation Cycle Causes Age Dependent Mitochondrial Deficiencies and Contributes to the Aging of Stem Cells // Genes 2018


In addition to the nuclear genome, a typical animal cell also has from 100 to 1000 copies of mitochondrial DNA encoding subunits of electron transport chain complexes. In the process of converting energy into ATP molecules and carrying out biosynthesis, mitochondria generate free radicals that damage the surrounding DNA, proteins and lipids. The mitochondrial genome lacks protective histones and effective damage repair mechanisms. Therefore, mtDNAs are particularly predisposed to the accumulation of mutations. The situation is aggravated by the fact that inefficient electron transfer chain complexes synthesized due to mtDNA mutations generate an increased amount of free radicals, which further increases damage to mitochondria, forming a vicious circle on the principle of feed forward control.

According to the generally accepted hypothesis, the accumulation of mtDNA mutations throughout life causes an age-related extinction of energy metabolism and a violation of tissue homeostasis. Mice of the mitochondrial "mutator" line, characterized by an increased rate of mtDNA mutagenesis, demonstrate premature aging, which, in principle, reinforces the correlation between mtDNA mutations and aging. However, the level of mtDNA mutations detected in various tissues of normally aging people or experimental animals is too low to cause any pathological consequences. This refutes the causal role of mtDNA mutations in physiological aging, especially in the aging of postmitotic tissues.

DNA replication is the source of mutations. In adulthood, most tissues consist of postmitotic (non-dividing) cells, which are characterized by a low rate of mitochondrial and mtDNA renewal, which may explain the low frequency of mtDNA mutations in postmitotic tissues. Therefore, it is possible that the search for the relationship between mtDNA mutations and aging was initially aimed at a false goal.

On the other hand, it can be assumed that mutations of mtDNA in actively dividing cells, such as cancer and stem cells, can reach high values during aging. In fact, an increasing amount of data demonstrates the accumulation of mtDNA mutations in aging stem cells. Stem cells are an essential component of tissue homeostasis and the process of damage repair. The age-related decline in the functionality of stem cells contributes to the development of several manifestations characteristic of aging, such as the impaired ability of tissues to recover and an increased predisposition to the development of cancer and infectious diseases, therefore, it is attributed an important role in the process of natural aging.

In this study, the authors applied a physiological approach to manipulating the division cycle of embryonic stem cells regardless of the chronological age of fruit flies and analyzed its effect on the aging of embryonic stem cells and the reproductive physiology of females. As a result, it was demonstrated that an increase in the number of division cycles played an important role in the age-dependent extinction of egg survival and contributed to an age-related decrease in female fertility. In addition, an increase in the number of mtDNA mutations and a violation of mtDNA replication in aging ovaries were revealed. A strong correlation between the extinction of stem cell activity and mitochondrial dysfunction in aging ovaries indicates that mtDNA mutations caused by proliferative cycles can contribute to the aging of stem cells.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Fight Aging!: Recent Papers on the Mitochondrial Contribution to Aging.

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