Epigenome of aging
In the article (see references in its original), published in the open access journal Aging, the authors discuss the future directions of aging therapy by destroying cells that have entered the phase of physiological aging, or manipulating the activity of these cells. The accumulation of cells that have entered the phase of physiological aging is one of the fundamental causes of aging. Such cells constantly appear in intact and fully functional tissues of young people, while some of them avoid destruction and cause problems. Over time, their number gradually increases and becomes sufficient to lead to a fatal outcome. Of course, the physiological aging of cells is not the only destructive cause of aging. To date, it is generally believed that cells that have entered the phase of physiological aging accelerate the death that occurs as a result of other forms of damage, and are never the direct cause of aging. Aging is a "collective killing" that occurs as a result of the interaction of many individual processes.
Selective destruction of cells that have entered the phase of physiological aging demonstrates good results as an approach to eliminating their contribution to the aging process. The number of such cells is relatively small and a sufficiently large number of methods of their destruction have already been developed or are under development. According to the results of all the assessment methods used, the condition of old mice improves significantly even after partial elimination of cells that have entered the phase of physiological aging. Apparently, the future of this direction lies only in the search for more effective methods of removing such abnormal and unwanted cells.
However, some experts oppose the destruction of cells that have entered the phase of physiological aging. They prefer to focus on modulating the bad behavior of such cells or finding ways to return them to their normal state. However, most likely, this direction is a more difficult way to obtain fewer positive effects, as well as associated with higher risks for patients. The process of physiological aging is started with a specific purpose, it protects against the development of cancer, promotes regeneration after damage, and also ensures compliance with the limits of the possibility of proliferation, characteristic of most cells. In all such cases, the need for physiological aging and the characteristic behavior of cells for it is short-term and the cells that have entered it must subsequently be eliminated. If a cell enters the phase of physiological aging due to damage to DNA molecules, which is accompanied by an increased risk of cancer, its destruction looks more attractive than attempts to return it to normal, at least at the present stage of development of this direction.
The article "Epigenome of cells that have entered the phase of physiological aging" (Na Yang and Payel Sen) is published in the journal Aging.
Excerpts from the article The senescent cell epigenome:
"In the initial description of the phase of physiological aging of cells in cell culture in vitro, parallels were drawn with the aging of tissues and organisms. Critics have questioned the correspondence of the described process to what is happening in a living organism, considering it an artifact. Physiological aging has gained popularity as a "pro-aging" phenomenon with the discovery of biomarkers such as p16 and beta-galactosidase in numerous aging tissues. Mechanistically, the idea that cells that have entered the phase of physiological aging are the cause of the appearance of inflammatory characteristics of aging also attracted close attention after the discovery of the secretory phenotype associated with physiological aging (from the English "senescence-associated secretory phenotype", SASP).
The formation of the field of physiological aging took place in four important stages: (1) studies to confirm the concept have demonstrated a significant improvement in the indicators of healthy life expectancy and average life expectancy of mice as a result of targeted destruction of cells that have entered the phase of physiological aging, (2) the development of small senolytic molecules as a therapeutic strategy for cleansing the body of cells that have entered the phase of physiological aging, (3) demonstration of the ability to senolytics improve the physiological functions and the average life expectancy of old mice and (4) the successful conduct of preclinical studies of senolytics in relation to a number of age-associated conditions. Below is a discussion of potential alternatives to senolytics that can use epigenetic proteins as "switches" to activate/inactivate specific mechanisms in cells that have entered the phase of physiological aging for their effective destruction.
Inhibitors of the physiological aging-associated secretory phenotype (SASP)
Despite the impressive success of senolytics, experts still have fundamental doubts about their specificity and safety. In addition, the potential effectiveness of senolytics in the treatment of age-related diseases still needs to be tested. Another class of molecules promising as a means for anti-aging anti-aging therapy are inhibitors of the physiological aging-associated secretory phenotype (SASP). The concept of destroying the pro-aging population of cells that have entered the phase of physiological aging while preserving the antitumor population of these cells looks like a very attractive therapeutic approach for elderly people who have a high risk of developing cancer. Both rapamycin and metformin have demonstrated their positive effect on the secretory phenotype associated with physiological aging and are currently on the way to clinical trials as anti-aging drugs. An alternative is the use of small molecules to inhibit epigenetic enzymes, which play a key role in the activation of genes associated with physiological aging secretory phenotype (MLL1 and BRD4), in order to prevent its harmful effects.
Activation of autophagy
Autophagy is a process of self–destruction that ensures the removal and recycling of damaged cell components. According to the fundamental publication, at the basic level autophagy is necessary to maintain the resting state of stem cells, as well as to prevent the entry into the phase of physiological aging of satellite cells of skeletal muscles of mice. Moreover, autophagy fades with aging, a low-calorie diet activates autophagy and a violation of the autophagy process is characteristic of Alzheimer's disease. Thus, enhancing the overall activity of autophagy (indiscriminately) is a viable approach to slowing down aging. However, studies have shown that autophagy-stimulating strategies are associated with the problem that autophagy of "nuclear" substrates can actually contribute to the entry of cells into the phase of physiological aging, aging of the body and the development of inflammation.
Destruction by the immune system
Cells that have entered the phase of physiological aging are naturally destroyed with the help of immune mechanisms, the main role in this case belongs to macrophages. However, the immune cells themselves undergo progressive extinction of functions (aging of the immune system), which makes an active contribution to the accumulation of cells that have entered the phase of physiological aging. Moreover, it has been suggested that a certain population of such cells is resistant to the action of immune mechanisms. Therefore, epigenetic interventions that stimulate immunological surveillance in aging tissues, or therapeutic approaches using antibodies that deprive cells that have entered the phase of physiological aging of resistance to immune mechanisms, can also be promising rejuvenation strategies.
Anti-aging therapy
The principles of regenerative medicine can be applied to aging and age-related diseases. It has been demonstrated that the expression of pluripotency factors in cells that have entered the phase of physiological aging allows these cells to enter a new cell cycle with restored telomere length, as well as a normal profile of gene expression, the level of oxidative stress and age phenotype. Epigenetic factors that provide enhanced reprogramming can be used to rejuvenate aging or cells that have entered the phase of physiological aging. However, regenerative therapy of elderly people should be carried out with great caution because of its potential pro-tumorogenicity (the ability to increase the risk of developing tumors).
Other potential methods of epigenetic therapy
Based on the observations made by the researchers , the following conceptual themes are formulated:
(1) gradual euchromatization of the genome,
(2) loss or disorganization of structural heterochromatin due to
(3) destruction of the nuclear plate and changes in the morphology of the nucleus, as well as
(4) loss of spatial organization of the genome.
These large-scale changes are manifested by serious transcriptional changes that eventually activate programs such as the secretory phenotype associated with physiological aging and contribute to the appearance of transcriptional noise. Systematic screening of epigenetic factors is highly likely to identify potential targets, the impact on which will prevent or eliminate the harmful effects of physiological aging.
Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Fight Aging!: Future Directions for the Senescence Field.