The human body and its cells have several different mechanisms for protecting its essential parts and expressing all the indicators that shape every individual in unique ways. Telomeres play a lead role in that process, ensuring our genetic blueprints remain intact, but even they have a limit. With the rise of genetic engineering, researchers have found a way to extend the lifespan of telomeres and delay senescence and onset of disease.
Genetic material gathered in a DNA molecule is crucial for the expression of proteins that finally combine every reaction and mechanism in a seemingly perfect construct. But perfection does not exist, certainly not in our body and cells. Like a mother gives a part of her heart to her child, a cell also gives up a part of its telomere length with every division. And this leads to the shortening of telomeres over time due to incomplete chromosomal end replication and also due to other factors that include oxidative damage. Cell division consequently reaches the point where there are no telomere parts left that could protect the chromosome from deterioration. This process leads to disease development and ageing.
But what if we could find a way to lengthen telomeres in chromosomes? It would have a massive impact on finding a way to reduce progressive diseases linked to cell senescence. And that is exactly what researchers from the Stanford University School of Medicine, CA, say they found. A mechanism that could be the ultimate game changer.
In the study, they presented telomere extension as a means to improve ways in treating diseases and as new ways in tissue engineering. They reported that a key component of the research is modified mRNA encoding TERT. Telomerase is a ribonucleoprotein that extends telomeres. It’s two essential parts are TERT (protein component), which complexes with TERC (RNA component). Now we know, that we have a “builder” of telomeres in many cell types including stem and progenitor cells. But telomeres still shorten over the lifetime in most tissues.
This research is based on the delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts. Technique reportedly increases telomerase activity transiently and extends telomeres. In the research, they presented different cell populations as an example of potential differences between versions of TERT insertion.
Firstly they treated fibroblasts and myoblasts with modified mRNA encoding TERT. In this case, the telomerase activity was detected in the cell population. Contrary in the case of cells treated with modified mRNA encoding CI TERT (catalytically inactive), there were no effects on proliferative capacity compared to untreated controls even at the highest dose. They figured that the telomerase activity is dose-dependent and it peaked at 24h and then returned to baseline levels in 48h. As for the length of telomeres, they discovered that the average lengthening between the start and the end of the treatment was 0.13 +/- 0.02 kb/PD.
Nevertheless, in comparison of immortalized cells with treated cell population shows, the latter exhibited an increase in cell numbers but eventually reached a plateau in their growth. With that cells expressed senescence markers to the same extent as untreated cells.
Researchers concluded that the delivery of TERT mRNA temporarily increases telomerase activity, proliferative capacity, and telomere length without making cell culture immortal. It can extend telomeres in fibroblasts by 50% – 90% in a few days (in human lifetime fibroblast telomeres shorten approximately 1-2kb). The advantage of this method is the rapid extension of telomeres without the risk of insertional mutagenesis. Additionally, the telomere shortening mechanism remains intact.
This method of delivering mRNA TERT to tissues in vivo has been achieved, but it still represents a challenge for most tissues. But researchers in this study made a big step towards figuring out a way to rapidly extend telomeres and with that delay senescence. And their findings may have a significant impact on biologic research and medicine in the future.
Ramunas, J., Yakubov, E., Brady, J. J., Corbel, S. Y., Holbrook, C., Brandt, M., … Blau, H. M. (2015). Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells. The FASEB Journal, 29(5), 1930–1939.doi:10.1096/fj.14-259531
By Neža Kirn