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Telomerase Expression Reduces Senescence and Cancer Risk

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A joint study by researchers at the National Institutes of Health (NIH) and the University of Maryland (UMD) has revealed a previously undocumented protective function of the telomerase enzyme.

Telomerase is used by somatic cells too

It was thought for a long time that telomerase is only active in certain cell types, such as stem cells, immune cells, and embryonic cells, in order to protect them from aging. Aside from a few cell types and, of course, cancer cells, which are able to hijack the telomerase enzyme in order to replicate uncontrollably, researchers believed that the enzyme is switched off in other types of cells.

However, a new study published in Proceedings of the National Academy of Sciences (PNAS) has shown that telomerase can be reactivated in healthy adult cells during the course of cell aging. The researchers think that this is a protective mechanism to reduce the chance of DNA damage, which would increase cancer risk due to genomic instability, one of the primary hallmarks of aging. This new discovery significantly changes our understanding of telomerase and how it relates to aging.

This research shows that there is a role for the reactivation of telomerase in adult cells that goes beyond the formation of cancer cells, as the transient activation of telomerase in this manner serves to mediate cellular senescence and reduce the risk of cancer.

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Each of the chromosomes that stores our genetic information has a protective cap at each end known as a telomere, a specific DNA sequence that is repeated thousands of times. The sequence has two purposes: firstly, it protects the coding regions of the chromosomes and prevents them from being damaged, and secondly, it acts as a clock that controls the number of replications that a cell can make. Each time a cell divides, the telomeres become shorter; this telomere attrition is the basis of replicative senescence and is another primary hallmark of aging.

In regular adult cells, once the cell reaches its replicative limit triggered by the telomeres reaching a critical length, the cell stops dividing and dies via a self-destruct mechanism called apoptosis. However, sometimes the cell experiences DNA damage, fails to enter apoptosis, and lingers, sometimes becoming a pro-inflammatory senescent cell or, less often, a cancer cell.

In some special types of cells, such as stem and progenitor cells, telomerase remains active, which means that these cells keep topping up their telomeres as they divide, preventing them from reaching a critical length. This is why stem cells can live for many decades compared to the shorter-lived regular cells that make up the majority of the cells in our body.

The telomerase enzyme itself is made up of two parts: the template RNA (TR, telomerase RNA), and the reverse-transcriptase catalytic subunit (TERT, telomerase reverse transcriptase). Previous studies have shown that in mouse strains bred to lack the telomerase gene (telomerase knockout mice), the subsequent generations of mice born tended to have shorter lifespans and increased cancer risk, and the total length of their telomeres was also shorter than regular mice.

A new role for telomerase in aging and transformation

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It has also been shown that mice lacking telomerase can have the negative effects of this reversed by reactivating TERT; this led these researchers to wonder if telomerase may also play an additional role in somatic cells with short telomeres that went beyond the formation of cancerous tumors.

In order to investigate this, the researchers compared the skin cells of related wild-type and telomerase-deficient mice and found that the white blood cell lines from both had similarly short telomeres. However, the cells from the telomerase-deficient mice ceased dividing sooner and had a higher rate of cancer formation than the cells from the wild-type mice.

The researchers observed that in the wild-type mice, the skin cells were able to transiently activate telomerase when the telomeres approached critical length, which re-lengthened the telomeres, slowing down the rate of aging and reducing the risk of DNA damage and the resulting increased risk of cancer. The researchers suggest that this final burst of telomerase towards the end of the cell’s lifespan was designed to reduce the impact of this aging process and create a more gradual descent into apoptosis as well as being protective against cancer formation.

The researchers also demonstrated that reactivation of telomerase in telomerase-deficient cells was able to rescue the cells from death, allowed them to keep dividing, and reduced the chance of DNA damage occurring. This is consistent with a number of other previous studies that have shown similar results from the transient activation of telomerase.

Finally, they also showed that this happens in normal human skin cells, which also activate a burst of telomerase as they approach critical telomere length. The researchers then disabled telomerase expression in normal human skin cells and noted that the cells displayed a decline in activity of the genes associated with DNA damage response as they approached replicative senescence.

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The next step for the research team will be to explore how this transient telomerase expression is activated in cells approaching replicative senescence and discern the underlying mechanisms through which telomerase provides a cushioning effect on the journey of cells to senescence.

Telomerase is an enzymatic ribonucleoprotein complex that acts as a reverse transcriptase in the elongation of telomeres. Telomerase activity is well documented in embryonic stem cells and the vast majority of tumor cells, but its role in somatic cells remains to be understood. Here, we report an unexpected function of telomerase during cellular senescence and tumorigenesis. We crossed Tert heterozygous knockout mice (mTert+/−) for 26 generations, during which time there was progressive shortening of telomeres, and obtained primary skin fibroblasts from mTert+/+ and mTert−/− progeny of the 26th cross. As a consequence of insufficient telomerase activities in prior generations, both mTert+/+ and mTert−/− fibroblasts showed comparable and extremely short telomere length. However, mTert−/− cells approached cellular senescence faster and exhibited a significantly higher rate of malignant transformation than mTert+/+ cells. Furthermore, an evident up-regulation of telomerase reverse-transcriptase (TERT) expression was detected in mTert+/+ cells at the presenescence stage. Moreover, removal or down-regulation of TERT expression in mTert+/+ and human primary fibroblast cells via CRISPR/Cas9 or shRNA recapitulated mTert−/− phenotypes of accelerated senescence and transformation, and overexpression of TERT in mTert−/− cells rescued these phenotypes. Taking these data together, this study suggests that TERT has a previously underappreciated, protective role in buffering senescence stresses due to short, dysfunctional telomeres, and preventing malignant transformation.

Conclusion

This is an interesting twist in the telomerase story and shakes up what was previously known about how cells use it. These researchers show that telomerase is expressed by mouse and human cells as they approach replicative senescence, almost like a cushioning mechanism to ease the cell into apoptosis easier. In mouse and human cells engineered to not express telomerase, the cells experience senescence sooner and become cancerous more frequently. These results support the proposal that the transient expression of telomerase in cells approaching the end of their lives is important in cellular senescence, transformation, and genomic stability.

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About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.