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Cellular Immortalization and the Prevention of Aging
Lake Forest College
Telomerase activity influences the length of telomeres in aging cells. Hornsby (2007) reviews previous studies regarding telomerase and aging with the hopes of assessing the significance of this enzyme and its implications in cancer development, as well as for immortalizing cells. The studies that Hornsby reviews suggest that increasing telomerase activity and telomere length could prevent aging and could create healthy immortal cells. On the other hand, research has also shown that increased telomerase activity and telomere length could be related to increased cancer growth. However, a 2018 study offers an alternative solution to cellular immortalization with the discovery of two specific genes that also influence telomere length and aging.
Telomeres are repetitive DNA sequences at the end of chromosomes. Telomerase is a ribonucleoprotein DNA polymerase complex that maintains telomere length (reviewed in Hornsby). The complex is made of a protein called telomerase reverse transcriptase (TERT, hTERT in humans) and a catalytic RNA (TERC). If there is no telomerase activity or reduced telomere activity in a cell, telomeres in the cell shorten overtime. Most human somatic cells do not have telomerase activity because they do not express TERT (reviewed in Hornsby). Telomere shortening limits the growth of cells by senescence or crisis. Cells reach crisis and stop growing permanently if their telomeres become very short. However, if TERT is expressed in cells that do not usually have telomerase activity, they can avoid senescence and crisis and become immortalized.
Figure 1: A graph of telomere length over the number of cell divisions. Green strands are telomerase DNA segments. Telomerase activity can be restored to cells that do not express hTERT by hTERT gene transduction. The absence of telomerase limits cancer growth and telomerase activity can be reactivated (via hTERT up-regulation or reactivation) in cancerous cells (Shay and Wright, 2007).
Telomere length and telomerase activity may affect aging rates between individuals of certain species, including humans and other mammals. The review by Hornsby (2007) presents that cells of older humans have been found to have short telomeres and decreased telomerase activity. Older humans also more often have anemia, impaired wound healing, and certain other impaired functions related to aging. The study tries to find whether it is telomere shortening and decreasing telomerase activity that causes these functional impairments and affects health and life span. The review by Hornsby (2007) provides some evidence that short telomeres and decreased telomerase activity are related to aging and functional impairment; however, it is not clear whether telomerase activity and telomere length cause these phenomena or whether they are only associated with them.
Although not much is known about how telomerase and telomeres affect aging rates, there is evidence to support the idea that that TERT expression prevents cell death. Overcoming functional impairment related to aging and achieving cellular immortalization could be possible; however, finding more information is important to make an accurate conclusion and to find treatments for aging that do not cause increased cancer incidence.
A 2018 study of bats suggests that telomere length could be maintained without telomerase (Foley et al.). Many species of bats live for a very long time relative to their body size, and bats from the Myotis genus live the longest. To identify the molecular basis behind their long life spans, scientists conducted tests to determine whether telomeres in Myotis bat cells shorten over time. While the study found similar telomere lengths in older and younger bats, it did not detect expression of telomerase in Myotis bat blood cells or fibroblasts. The study suggests that DNA repair genes ATM and SETX may help to maintain telomere length in Myotis bats (Foley et al., 2018). ATM and SETX expression could be helpful alternatives to telomerase in cell therapy and cellular immortalization because cancer incidence in bats is low. Furthermore, the researchers note that increased ATM and SETX expression may also not result in increased cancer incidence in human patients, which is a prominent issue with reactivating or upregulating telomerase to prevent aging.
Foley et al. (2018) suggests that ATM, SETX, and some other DNA repair genes expressed in Myotis bats may maintain alternative lengthening of telomeres (ALT), mechanisms that have not been studied before. The study found that ATM, SETX, and other DNA repair genes are significantly differently expressed in different types of tissues in Myotis bats compared to those in other mammals. This differential expression may be one of many factors that influence how bats are able to maintain telomere length without telomerase. Further studies of the expression of these genes in bats may help scientists to better understand these ALT mechanisms and allow scientists to find ways to modify or use ATM, SETX, or other genes like those expressed in bats in human patients to prevent aging.
Foley, N. M., Hughes, G. M., Huang, Z., Clarke, M., Jebb, D., Whelan, C. V., … Teeling, E. C. (2018). Growing old, yet staying young: The role of telomeres in bats’ exceptional longevity. Science Advances,4(2). doi:10.1126/sciadv.aao0926
Hornsby, P. J. (2007). Telomerase and the aging process. Experimental Gerontology,42(7), 575-581. Retrieved January 13, 2019, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933587/
Shay, J. W., & Wright, W. E. (2007). Hallmarks of telomeres in ageing research. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland, 211(2), 114-123.
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