Stem cells and aging
Antiaging – the effect of stem cells on aging and aging of stem cells
Antiaging — Effect of Stem Cells on Aging and Stem Cell Aging
Jisook Moon and Sang-Hun Bae, College of Life Science, Department of Bioengineering, CHA University, Seoul, Korea.
Chapter from the collection Progress in Stem Cell Transplantation
Edited by Taner Demirer, InTech Publishing House, 2015.
Translated by Evgenia Ryabtseva
1. Introduction
In a broad sense, aging is a normal progressive process, accompanied by an aggravation of predisposition to disease and death. The fact that the aging process is inevitable, but amenable to regulation, makes it an attractive target for research devoted to the study of age-associated molecular changes. The main problem in this case is to decipher the basic mechanisms of aging using traditional experimental approaches, which is due to the complexity of the aging process and the multiplicity of factors contributing to it.
This indicates the need to study aging simultaneously in many aspects. For this reason, the aging process is currently being studied using so-called "-OMICS" (OMICS), including genomics, transcriptomics, proteomics and metabolomics, which allows for a multifactorial study of age-related changes. All this indicates that there is a need for new approaches to deciphering the biological foundations of aging at various molecular levels, the results of which can deepen our understanding of the fundamental aspects of biological aging and longevity.
The aging process is characterized by gradual cumulative damage to the structure and functions of stem cells that occurs throughout the life of the organism. This article discusses integrative studies of stem cell aging and the therapeutic effect of adult stem cells, including cord blood cells, and the underlying mechanisms of this complex process at various molecular levels, the ultimate goal of which is the practical application of stem cells in the therapy of elderly people to maintain their health. In addition, an integrative method is discussed – technologies of the "-omic" class, which can help us understand the complex biology of aging.
Aging can be considered as a process in which a pool of endogenous stem cells progressively loses its ability to replace damaged cells with age. For almost all living organisms, the time-dependent extinction of the regenerative potential of stem cells is responsible for an increased predisposition to aging and a number of age-related diseases. The reduced regenerative capacity of endogenous stem cells is partly explained by DNA damage, changes in stem cell niches and activation of the tumor suppressor gene. However, it is unclear to what extent these factors contribute to human aging, especially the aging of stem cells, and determine life expectancy. The complexity of the aging process causes the need for new approaches to clarify its multifactorial mechanisms.
2. "-omic" class technologies and stem cell aging
In recent years, new high-performance technologies known as "-omics", or OMICS, have been used to dive deeper into the biology of aging. They are used in the form of various approaches to study the molecular changes accompanying aging. "-omics" refers to technologies whose names contain the suffix "-omic". These technologies, including genomics, transcriptomics, proteomics, and metabolomics, are designed for qualitative and quantitative analysis of pools of molecules at different levels. Researchers use "-omics" in experiments aimed at identifying the relationship between molecular changes and aging. However, to date, research in this field is mainly based on the study of blood samples containing various types of cells, and usually use one of the "-omics", which makes it difficult to interpret the phenomenon being detected or leads to an erroneous interpretation of the complex aging process.
Another factor complicating the research is age-specific tissue-specific changes in gene expression, further complicating the interpretation of the process. Therefore, an alternative approach may be to study the aging of stem cells using "-omic".
Stem cells throughout the adult life of the body act as an endogenous source of cells that replace cells that die during homeostasis or damage. The regenerative ability of different tissues fades with aging and often ceases to meet the needs of developing tissues, which leads to the development of many age-related phenotypes or diseases. As a result, during the aging process, the accumulation of functional disorders can manifest itself in various macromolecules, ranging from DNA to metabolites, which are considered to be the closest to phenotypes. Damaged macromolecules, in turn, disrupt signaling pathways, which contributes to the occurrence of stem cell dysfunction accompanying aging and forms a vicious circle. In addition, the reduction of stem cell pools is most likely associated with the functional extinction of hematopoiesis, neurogenesis and myogenesis accompanying aging. Therefore, it can be assumed that the key to delaying the aging process or reversing it is to deepen our knowledge about adult stem cells.
Just like other factors of aging, the mechanisms that induce time-dependent extinction of stem cells are still poorly understood and therefore need integrative analysis, for which technologies of the "-omic" class can be applied. Understanding the molecular processes involved in stem cell dysfunction may shed light on the causes of aging, which will eventually lead to strategies to prevent the aging process from starting or reversing.
Maintaining the viability of stem cells or their rejuvenation has great therapeutic potential in relation to age-related disorders. For example, heterochronous parabiosis – the creation of a common circulatory or physiological system between a young and an old organism – has demonstrated its effectiveness in eliminating age-related phenotypes by improving the functioning of stem cells. One landmark study of parabiosis demonstrated that the entry of young blood cells into the bloodstream of old mice facilitates the manifestations of cognitive function disorders, improving the plasticity of brain synapses. The results of another experiment demonstrated that under the influence of the muscle tissue niche of young mice, the regeneration of damaged satellite cells occurred in old animals, which ensured the restoration of the regenerative potential of muscle tissue.
Recent data also confirm that the decline in regenerative capacity is reversible and that the aging process can be delayed by improving the functioning of stem cells, which contributes to the restoration of damaged tissues. This indicates that exposure to stem cells of different origins can ensure the restoration of age-associated defects by replacing damaged cells in aging tissues.
With the expansion of the scope of application, metabolomics is now turning into a new approach to deciphering the mechanisms of metabolic regulation involved in aging. Metabolites are products of complex biological processes and can be considered as final reactions to internal states and external influences, which may be able to provide new unexpected data on how the extinction of stem cell functions affects human aging. It has been demonstrated that oxidative metabolism and maintenance of mitochondrial function are associated with aging of stem cells. In accordance with this, the metabolic states of stem cells play a key role in determining the fate of cells that can either proliferate or differentiate. Both conditions are predominantly associated with mechanisms regulating the balance between glycolysis and oxidative phosphorylation. In addition, clinical studies on the relationship between aging and metabolic profiles have demonstrated the existence of strong correlations between age-specific metabolites, some of which are associated with fatty acid oxidation, which indicates the importance of metabolomics for the interpretation of the aging process.
2.1. Analysis of neural stem cell transcriptome in the process of dopamine differentiation
In their study, the authors primarily analyzed changes in gene expression in neural stem cells during differentiation into dopaminergic neurons and as they were transplanted to a new passage in a proliferative state. Both of these states can be considered as aging: differentiation – as a component of "chronological aging", and an increase in passages – as "replicative aging".
During differentiation, neural stem cells demonstrated gene expression profiles specific to this stage of development, while specific genes participated in neurogenesis through the formation of a molecular co-expression network.
Under conditions of maintaining a proliferative state, stem cells induced the expression of genes whose protein products are involved in phosphorylation, cell proliferation, kinase cascade, stress response and signal transmission.
The entry into the differentiation phase is characterized by an increase in the expression of genes mainly involved in the mitotic cell cycle, mitosis and cell division. In the late stages of differentiation, there is an increase in the expression of genes responsible for the transmission of signals in synapses and the regulation of synaptic plasticity.
The results clearly demonstrated that different biological processes are involved in the aging of cells in the states of proliferation and differentiation, most likely leading to the synthesis of metabolites specific to different cellular states.
2.2. Analysis of the transcriptome under the influence of hypoxia on placental cells as passages increase (reseeding)
In addition, the authors studied the effect of hypoxia and normoxia on repeatedly transplanted placental cells based on transcriptome data. Ontological analysis of genes has shown that most of the genes characterized by increased expression in hypoxia are associated with cell proliferation, macromolecule synthesis, metabolic and signaling pathways, as well as cellular homeostasis. This was confirmed by the data obtained in vitro, according to which hypoxia conditions increase the proliferative capacity of cell culture. At the same time, a decrease in expression under hypoxia conditions was characteristic of genes associated with cell death/apoptosis and protein aggregation, which supports the hypothesis that protein homeostasis and the balance between proliferation and physiological aging are critical for stem cell aging.
These data indicate that under conditions of hypoxia, stem cells enter a state characterized by increased proliferation and survival and suppression of mechanisms of cell death and signaling pathways that contribute to aging. At the late stage of cell culture, many of the differentially expressed genes under hypoxia conditions were associated with nucleosome assembly and chromatin organization, which indicates the involvement of epigenetic regulation.
Finally, the authors compiled metabolic profiles of aging mice to which placental cells were transplanted. Most of the metabolites whose levels increased as a result of cell therapy were associated with lipid metabolism, which is probably associated with unique profiles of gene expression after cell transplantation and indicates the feasibility of further studies using integrated data obtained using "-omic".
The obtained results give weight to the opinion that the study of stem cell aging with the help of "-omic" is an effective approach to deciphering the biological foundations of the aging process.
These data prompted the authors to conduct an ongoing study in which old mice (older than 23 months) are transfused with human umbilical cord blood (the youngest available blood). In addition, a clinical study of the results of cord blood transfusion to old people is being conducted. Mesenchymal stem cells of the human placenta are also being studied as a potential anti-aging agent. Animal experiments have demonstrated an improvement in cognitive function 12 weeks after the introduction of such cells. To carry out further translational research, analytical studies are currently being conducted using technologies of the "-omic" class.
3. Conclusion
The physiological changes and individual differences characteristic of aging have always caused difficulties for researchers trying to understand the normal aging process, which indicates the need for new strategies that allow for an integrative study of molecular changes instead of using traditional experimental approaches. Technologies of the "-omic" class allow simultaneous assessment of dynamic molecular changes at different levels with the receipt of a large number of different types of data, which facilitates the identification of biomarkers of aging/rejuvenation and, accordingly, the prevention of age-related diseases.
Studies using "-omics" have allowed us to look from new perspectives at what molecular mechanisms determine a complex progressive process, despite the fact that there is still a lot to clarify. In particular, in combination with genomics, transcriptomics and proteomics, the study of the metabolic profile can provide unprecedented data on aging. In general, the integration and context-dependent interpretation of the multifaceted data provided by "omics" greatly facilitates the understanding of the complex aging process.
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22.08.2016