Stem Cells Aging
The stem cell theory of aging claims that the aging process is the result of the inability of various types of resident tissue stem cells to continue to replenish the tissues of an organism with functional differentiated cells, capable of maintaining that tissue’s original function. Therefore, stem cell aging, a subcategory of cellular theories of aging, is defined as a deficit of stem cells to replace the harmed tissue cells due to the decrease in the totality of tissue resident stem cells and/or their regenerative potential.
Aging is a complex biological process accompanied by a progressive decrease in the organism’s capacity to maintain physiological organ homeostasis, culminating in disease and death (Kirkwood 2005). At a cellular level, aging can be defined as the progressive decline in the number and ability of tissue’s cells to cope with stress and injury due to the accumulated action of different types of pathologies caused by genomic vulnerability, telomere erosion, mitochondrial dysfunction, epigenetic modifications, and stem cell weariness (Lopez-Otın et al. 2013).
Stem cells are cells that serve as an internal repair system to replenish other cells in the tissues. Stem cells are distinguished from other cell types by two important characteristics. First, they are unspecialized (undifferentiated) cells capable of renewing themselves through cell division, sometimes after long periods of inactivity. Second, under certain physiological or experimental conditions, they can be induced to differentiate and become organ-specific cells with special functions (Weissman 2000). Stem cells differentiate through many commitment steps, controlled and guided by unique growth factors and therefore characterized as multipotent, pluripotent, or restricted progenitors inducing the different cell phenotypes of the three germ layers: endoderm, mesoderm, and ectoderm (Kiecker et al. 2016). There are many different types of stem cells that come from different places in the body or are formed at different times in our lives. These include embryonic stem cells that exist only at the earliest stages of development and various types of tissue-specific (or adult) stem cells such as bone marrow, which appear during fetal development and remain in our bodies throughout life. In the 3- to 5-day-old embryo, called blastocyst, the inner cells give rise to the entire body of the organism, including all of the many specialized cell types and organs such as the heart, lung, skin, sperm, eggs, etc. In some adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease. Given their unique regenerative abilities, stem cells offer new potential for therapies to treat disease, which is also referred to as regenerative or reparative medicine (Arien-Zakay et al. 2010; Stabler et al. 2015). Indeed, clinical trials using unique stem cells hold promise for the treatment of various human diseases (Trounson and McDonald 2015). A growing number of preclinical studies suggest that the effects generated by stem cell transplants are not associated with cell replacement but mainly with stem cells secretion, known as a “secretome.” The major components of a secretome are “exosomes” – naturally occurring nanoparticles that mediate intercellular communication by delivering molecules such as mRNA into recipient cells. They promise to be a new and valuable therapeutic strategy in regenerative medicine compared with transplanted stem cells (Altanerova et al. 2017). In addition, the secretome contains a vast array of growth factors, cytokines, chemokines, metabolites, and bioactive lipids. This secretome, released by stem cells in an autocrine and/or paracrine manner, has the capacity to change the injured tissue’s fate and to modulate specific microenvironments (Drago et al. 2013).
Stem cell aging theory claims that failure of stem cells to replace the damaged cells is the result of the decrease in their physiological properties, regenerative potential, and/or in the count of tissue resident stem cells (Charville and Rando 2011; Fulle et al. 2012; Font de Mora and Díez Juan 2013; Moehrle and Geiger 2016; Schultz and Sinclair 2016). Adult stem cells are found in most mammalian tissues where they are involved in tissue homeostasis and repair (Li and Clevers 2010). As a repair system, stem cells act continually to replenish damaged tissues with healthy ones. Based on the accumulating evidence in advancing aging, these supportive sources of tissue regeneration undergo age-related changes in their replicative self-renewal capacity and differentiation potential (Rossi et al. 2005). Moreover, their exosomes have also been found to participate in the processes of cellular senescence and aging (Xu and Tahara 2013).
Key Research Findings
Genomic stability is essential for stem cell maintenance and longevity. This concept is supported by human diseases associated with premature aging and animal models of DNA damage which lead to abnormalities of stem cell survival. Furthermore, stem cell survival can be assessed in the face of DNA repair defects, and results from these investigations support the general conclusion that chemotherapy and other forms of DNA damage lead to stem cell failure syndromes and malignant transformation (Gerson et al. 2006).
Neurogenesis is a complex process involved in high order cognitive functions. Converging evidences from animal and in vitro studies points to nutrient sensing and energy metabolism as major physiological determinants of neural stem cell fate as modulators of the whole neurogenic process. While the cellular and molecular circuitries underlying metabolic regulation of brain neurogenesis are still not completely understood, the key role of mitochondrial activity and the importance of autophagy have begun to be fully appreciated. Moreover, nutrient-sensitive pathways and transducers such as the insulin-like growth factor 1 (IGF 1) signaling pathway, the 5′ adenosine monophosphate-activated protein kinase (AMPK)/the mammalian target of rapamycin (mTOR) axis, and the transcription regulators cAMP-responsive element binding protein 1 (CREB 1) and sirtuin (Sirt-1, silent mating type information regulation 2 homolog) have been characterized, beside more established “developmental” signals like the canonical Notch and Wnt signaling pathways. These systems participate in the molecular networks that dictate neural-stem-cell self-renewal, migration, and differentiation in response to local and systemic inputs. Many of these nutrient-related cascades are deregulated in the contest of neural stem cells aging, and may contribute to impaired neurogenesis and thus to cognition defects observed in neurodegeneration and brain senescence (Fidaleo et al. 2017).
Senescence of blood vessels’ endothelial progenitor cells, mesenchymal stromal cells, and cardiac progenitor cells, observed over normal aging, appear to be accelerated by cell extrinsic and intrinsic factors in age-related diseases enhancing the risk of a defective vascular phenotype and/or developing heart diseases (Angelini et al. 2017). Aging is a major risk factor contributing to vascular dysfunction and the progression of vascular diseases. Extrinsic factors reflect systemic or environmental changes which alter endothelial and vascular smooth muscle progenitor physiology, contributing to vascular pathology, while intrinsic factors modulate vascular cells toward cellular senescence. Replenishing or rejuvenating the aged/dysfunctional vascular or heart stem cells is critical to the effective restoration of the impaired cardiovascular function, to oppose cardiovascular aging, and prolong lifespan (Mistriotis and Andreadis 2017).
Stem cells have special mechanisms to minimize the risk of damage accumulation. These include the suppression of metabolic activity to reduce the intracellular production of toxic metabolites, and the maintenance of a state of quiescence to reduce replication-associated DNA damage (Behrens et al. 2014). Minimizing the risk of DNA damage is important, as DNA repair systems generally are not more active in stem cells than in somatic cells, but by contrast, DNA repair can be even more error prone in the G0/G1 phases of the cell cycle in which many stem cells reside. Stem cell quiescence and the associated reduction in transcription and translation processes contribute to the maintenance of a healthy proteome, as the folding and refolding, and the removal of misfolded and damaged proteins are highly energy-consuming processes that limit the energy available to other regulatory cellular pathways. Stem cells employ various damage removal systems, including autophagy (which can remove damaged proteins and organelles), but it is unclear whether these systems are more efficient in stem cells than in somatic cells or whether stem cells rely on reducing damage load by maintaining a quiescent state, as in the case of DNA damage (Ho et al. 2017). Despite the protective measures in place, stem cells accumulate molecular damage and lose functionality with aging which involves cell-intrinsic processes as well as aging-associated alterations in the stem cell microenvironment (niche) and in the blood circulation (Ermolaeva et al. 2018).
Several intrinsic processes have been proposed as possibilities to control stem cell aging, particularly those residing in tissues with higher turnover which experience multiple rounds of replication leading to senescence. Intrinsic molecular and cellular processes contributing to stem cells ageing are: telomere attrition and/or DNA damage or mutations, chromosomal rearrangement, epigenetic alterations, mitochondrial damage, and increase in oxidative redox potential, defects in cellular polarity, and proteasome activity, etc. (Schultz and Sinclair 2016).
Extrinsic factors include all environmental influences from the stem cell’s surroundings that could directly affect cell function and maintenance. Indeed, stem cell functions are dynamically regulated at several levels from their local microenvironment, namely tissue niche, where stem cells dynamically interact with other cells (Voog and Jones 2010). Moreover, they are also influenced by the global milieu of the organism (Scadden 2006). The microenvironment has an essential role in activation of stem cells for causing tissue regeneration; therefore, any changes in the physicochemical properties of the surrounding environment could apply an important rejuvenation effect on aging stem cells (Conboy et al. 2005). It is important to emphasize that embryonic stem cells could also be affected by environmental factors during fetal development. For example, there is considerable evidence available on prenatal exposure of environmental toxicants (Hodjat et al. 2015) and their effects on the offspring (Baldacci et al. 2018). During embryogenesis, which is a period of rapid cellular division, stem cells are highly susceptible to the toxicity of environmental chemicals (Hodjat et al. 2015) that could lead to an adverse effect on embryonic and fetal development (Pellizzer et al. 2005). Although the link between environmental toxicants and embryonic stem cell aging has not been defined directly in humans, there are in vitro studies that confirm the aggravation effect of these toxicants on embryonic stem cells and their contribution to an accelerated aging process. Oxidative stress is a major risk factor for development of several age-related diseases and has been implicated as an important molecular contributor to cellular damage following exposure to environmental agents (Fig. 1).
- (iii)There also exists evidence against the theory of stem cell aging. Diseases such as Alzheimer’s disease, renal failure, and heart diseases are caused by different mechanisms that are not related to stem cells. Also, some diseases related to the hematopoietic system, such as aplastic anemia and complete bone marrow failure, are not considered as age-dependent. A comparison of the engraftment properties of young and old bone marrow in a mammal model failed to show any decrement in stem cell function with age (Zaucha et al. 2001). However, a lot of information is mounting in favor of age-related changes that affect stem cell properties, in particular in the hematopoietic system. To the extent that many tumors are stem cell derived, cancer may provide some of the strongest evidence supporting the concept of stem cell aging.
Examples of Application
Neural stem cells (NSCs) are multipotent and self-renewing cells and are located primarily in the nervous system. In response to many signaling pathways, NSCs differentiate into various specific cell types locally in the central nervous system (CNS), like neurons, astrocytes, and oligodendrocytes. NSCs in humans are responsible for brain homeostasis and replenishment of new neurons, which are important for cognitive functions. Therefore, NSCs possess huge therapeutic potential for neurodegenerative diseases (Gincberg et al. 2012). However, there is now strong evidence for the aging-associated cognitive deficits, such as spatial memory deficits and neurodegenerative disorders which are caused by deterioration of brain endogenous NSCs proliferation and differentiation and enhanced NSCs senescence as a consequence of aging (Ming and Song 2011).
Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into cells of mesenchyme tissues, including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells), and adipocytes (fat cells). MSCs can be isolated from almost every organ including fat, liver, spleen, pancreas, kidney, lung, bone, muscle, and brain and have also been isolated from umbilical cord tissue, cord blood, and placenta. However, the major sources of MSCs are the bone marrow, the adipose tissue, and placenta. To date, the majority of clinical trials for therapy of different diseases are performed with different types of MSCs. Aging also affects MSCs in humans and in animal models as indicated by the decrease in the bone marrow MSC pool and also shifts their lineage differentiation from one that usually favors osteoblastic differentiation to one that prefers adipogenic differentiation (Liu et al. 2015), which is largely responsible for the gradual and aging-associated shift of hematopoietic (red) marrows to fatty (yellow) marrows, and which also contributes significantly to the etiology of senile osteoporosis. It is also evident that with increasing donor age, MSCs from both bone marrow and adipose tissues have been shown to have reduced capacity to handle oxidative stress (Sethe et al. 2006). During the aging process, oxidative stress leads to hyperactivity of several signaling pathways, such as Insulin/IGF-1 and mTOR pathways, and the subsequent accumulation of toxic components ultimately leads to cell death. In addition, in some nonskeletal tissues, particularly the hematopoietic system, MSCs are a key niche component for hematopoietic cells. Aging of MSCs has been shown to be detrimental with respect to this important function.
Adult skeletal muscle stem cells (satellite cells) have a remarkable capacity to regenerate. Similarly, their regeneration capacity declines with age, although it is not clear whether this is due to extrinsic changes in the environment and/or to cell-intrinsic mechanisms associated to aging or both. This impaired regenerative capacity of skeletal muscle during aging is due to progressive deterioration of tissue structure and function, manifesting after injury or in response to the depletion of memory B cells and naive T cells in the hematopoietic system in the elderly. Hematopoietic stem cells (HSCs) are the blood-forming stem cells through the process of hematopoiesis. They are located in the red bone marrow within marrow cavity of most bones. HSCs also produce immune cells of the body. Since blood cells are responsible for constant maintenance and immune protection of every cell type of the body, the constant production of new blood cells by HSCs is very important for human life. HSC-derived monocytes can give rise to osteoclasts, macrophage, and granulocyte. Osteoclasts are giant cells with numerous nuclei that work in synergy with osteoblasts through complicated bone coupling mechanisms to maintain bone homeostasis. All these activities of HSCs are carefully modulated by a complex interplay between cell-intrinsic and extrinsic factors produced by the microenvironment. The aging process altered this fine-tuned regulatory network, leading to aberrant HSC cell cycle regulation, degraded HSC function, and hematological malignancy (Ahmed et al. 2017).
Future Directions of Research
Coming studies that combine proteomics, epigenomics, transcriptomics, and mutational analyses with the functional readout of individual aged stem cells will be necessary to dissect and fully understand the process of stem cells aging. Further identification of intrinsic and extrinsic factors and their effects on stem cells survival and aging will help to identify therapeutic tools for controlling the aging process and age-related diseases. This includes the development of in vivo and in vitro approaches that permit the functional evaluation of stem cell activity in more native settings, as opposed to the transplantation-based approaches that currently prevail. Although such approaches to a large extent have been hindered by technical limitations, the times are exciting with recent and rapid developments in proteomics, DNA sequencing-based approaches, genome editing, and iPSC technologies. Furthermore, the knowledge of the factors influencing cellular aging has a significant implication for stem cell-based therapies. Accordingly, we anticipate advances at an accelerated pace in this relatively young field of stem cell aging research, with the final goal of making therapies available to achieve healthier late stages of life.
From the various advances in stem cell research, it is clear that we grow old partly because our stem cells grow old with us. The reduction of stem cells could best be described as a continuous positive feedback loop as aging progresses, error increases, thus, disease progresses. Ethical, practical, and logistical approaches for slowing down the process of aging may be implemented to stave off erroneous driven disease states. The functions of aged stem cells become impaired as the result of cell-intrinsic pathways and surrounding environmental extrinsic effects (Fig. 1). The theory of stem cell aging has gained great attention in the field of gerontology and regenerative medicine. Stem cells are the foundation of embryonic generation and adult tissue regeneration that are divided into embryonic and adult stem cells. They have the capacity of self-renewal and differentiation into different cell types. In the theory of stem cell aging, failure to replace the damaged cells as a result of the decrease in the number or regenerative potential of stem cells is the main concern associated with the aging of organisms. As stem cells are among the longest living cells within an organism, stem cell aging is highly relevant as a driver of organismal aging, health, and longevity. Although phenotypes and mechanisms vary widely in different types and niches of stem cell populations, it appears they all decline in function with age. Stem cell therapy may allow hopeful passage for alleviating the harmful effects of disease and aging. With a greater understanding of stem cell aging and its reversal, it may be possible in the future to rejuvenate tissues and their physiological function in middle age and in the older adults, thereby increasing human fertility, health span, and even lifespan.
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