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Main theme>Stem Cell Exhaustion and its effect on aging as prescribed in the Hallmarks of Aging[1]
Stem Cells are responsible for the creation and maintenance of the differentiated tissues of an organism. Stem cell exhaustion occurs over time when the stem cells accumulate defects with reproductiona nd lose the ability to proliferate.
Stem cells are undifferentiated cells, meaning that they do not have a specific function. Stem cells are important in maintaining tissue and organ function because as specific cells are damaged stem cells become specialized and replace the worn-out cells in the organism. Over time DNA damage, caused by mistakes, in the process of DNA replication, causes stem cells to become exhausted and cease replication. This inability to replicate and form new specialized cells causes damage to organs and tissues because there are no new cells to replace the damaged or worn down cells in the organism. This damage and wearing down of tissues and organs lead to aging in the organism.
Since 2013, when the "Hallmarks of Aging," there has been major research into exactly what stem cells effect and how the body, as a whole, responds. This research has focused on such topics as classic telomere length, shown in a 2015 study "Telomere Dysfunction Causes Alveolar Stem Cell Failure." Other studies have shed light onto processes that were previously thought to be unaffected such as looking at DNA methylation and different pathways that hadn't been explored. These studies include "Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging" and "Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice."[2] [3] These studies show a change in research conducted since the 2013 "Hallmarks of Aging" was published.
The article “Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging" published by Beerman is significant because this article tackles many different hypothesizes that were discussed in the 2013 article but not researched. One of the major findings from this article is that telomere length is independent of stem cell DNA methylation and age-related problems.[2] This is radically different than previous research that said there was a link between the two. This article also looked at global DNA methylation and debunked a theory that DNA methylation increased over time when, according to this study, DNA methylation was consistent throughout aging.[2]
Other studies that are more focused and not as wide-reaching have discovered specific pathways that affect the mechanisms in which stem cell lose their function and viability. One such study was "The Polycomb Group Gene Ezh2 Prevents Hematopoietic Stem Cell Exhaustion"[4] This study focused on the reasons for stem cell loss of function with regards to aging wild types. They discovered the Enhancer of zeste homolog 2 (Ezh2) which was found to be the most expressed transcript in hematopoietic cells. They then overexpressed Ezh2 and found that they could overcome cellular senescence and they conserved repopulating potential, of the stem cells, long after the wild-type cells had been exhausted. They concluded that this Ezh2 helped with stabilization that helped conserve the stem cells from stress related to aging.[4]
A study published in January 2017 was "Increased Arf/p53 activity in stem cells, aging and cancer" published in the journal Aging Cell.[5] This study focused on the Arf/p53 pathway and how it's role in cancer suppression is affected by quantity and age. They found that increasing p53 delays stem cell exhaustion and decline of homeostatic tissues. However, they also observed that if p53 is being constantly activated then the pathway accelerates the aging process of stem cells which reduces tissue regeneration and replicative regulation.[5]
A new study, "RNA Editing-Dependent Epitranscriptome Diversity In Cancer Stem Cells"[6] found that cancer stem cells (CSCs) can regenerate all the parts of the tumor and unless destroyed can regenerate all of the affected cells. This study aimed to examine what exactly contributed to CSCs ability to proliferate and their maintenance.[6] This study found that the more damage, caused by DNA methylation and incorrect RNA editing and splicing allowed for these CSCs to form and from them allowed all facets of the tumor to proliferate.[6]
- ^ López-Otín, Carlos; Blasco, Maria A.; Partridge, Linda; Serrano, Manuel; Kroemer, Guido (2013-06-06). "The Hallmarks of Aging". Cell. 153 (6): 1194–1217. doi:10.1016/j.cell.2013.05.039
- ^ a b c Beerman, I., Bock, C., Garrison, B. S., Smith, Z. D., Gu, H., Meissner, A., & Rossi, D. J. (2013). Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell stem cell, 12(4), 413-425.
- ^ Singh, K. P., Bennett, J. A., Casado, F. L., Walrath, J. L., Welle, S. L., & Gasiewicz, T. A. (2013). Loss of aryl hydrocarbon receptor promotes gene changes associated with premature hematopoietic stem cell exhaustion and development of a myeloproliferative disorder in aging mice. Stem cells and development, 23(2), 95-106.
- ^ a b Kamminga, Leonie M.; Bystrykh, Leonid V.; Boer, Aletta de; Houwer, Sita; Douma, José; Weersing, Ellen; Dontje, Bert; Haan, Gerald de (2006-03-01). "The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion". Blood. 107 (5): 2170–2179. doi:10.1182/blood-2005-09-3585. ISSN 0006-4971. PMC 1895717. PMID 16293602.
{{cite journal}}: CS1 maint: PMC format (link) - ^ a b Carrasco-Garcia, Estefania; Moreno, Manuel; Moreno-Cugnon, Leire; Matheu, Ander (2017-04-01). "Increased Arf/p53 activity in stem cells, aging and cancer". Aging Cell. 16 (2): 219–225. doi:10.1111/acel.12574. ISSN 1474-9726. PMC 5334536. PMID 28101907.
{{cite journal}}: CS1 maint: PMC format (link) - ^ a b c Jiang, Qingfei; Crews, Leslie A.; Holm, Frida; Jamieson, Catriona H. M. (2017-04-18). "RNA editing-dependent epitranscriptome diversity in cancer stem cells". Nature Reviews Cancer. advance online publication. doi:10.1038/nrc.2017.23. ISSN 1474-1768.