Telomeres are protective caps at the ends of chromosomes, which protect DNA during replication. These are shortened and eventually lost over the course of a lifetime, making the cell age and become susceptible to disease. A team of researchers have successfully used altered mRNA to lengthen telomeres in human cells, allowing them to act younger and proliferate more than untreated cells. It is hoped that this could eventually be used to help patients with diseases associated with shortened telomeres, such as Duchenne muscular dystrophy. Helen Blau of Stanford University School of Medicine is senior author of the paper, which was published in the Journal of the Federation of American Societies for Experimental Biology.
At birth, telomeres are roughly 9,000 nucleotides long. Due to the inability of DNA polymerase to begin replication at the end of the chromosome, a bit gets nipped off each time. After a certain number of rounds of mitosis, known as the Hayflick limit, the cell is no longer able to divide. Cells that are required to multiply an incredible number of times, such as stem cells or germ cells in males, freely express a telomere-lengthening enzyme called telomerase in order to keep the cells acting young and healthy. However, it is not generally expressed in adult cells.
"Now we have found a way to lengthen human telomeres by as much as 1,000 nucleotides, turning back the internal clock in these cells by the equivalent of many years of human life," Blau said in a press release. "This greatly increases the number of cells available for studies such as drug testing or disease modeling.”
The idea of lengthening telomeres is nothing new and has been tried in many ways, though they typically come with various drawbacks. The key to the team’s success was manipulating mRNA to include directions for TERT, an active subunit of telomerase. The effects last for 48 hours, but this transient nature provides an advantage. If TERT became a permanent fixture, and the cell could replicate indefinitely, it increases the risk of developing cancer. Additionally, this method does not cause an immune response, as has been seen by other approaches in the past.
Upon getting treated with the TERT mRNA and receiving more than a 10% increase in telomere length, skin cells were able to replicate 28 more times than their untreated counterparts, while muscle cells replicated three additional times. Moving forward, Blau’s team will be treating other types of cells.
"We're working to understand more about the differences among cell types, and how we can overcome those differences to allow this approach to be more universally useful," Blau said. "One day it may be possible to target muscle stem cells in a patient with Duchenne muscular dystrophy, for example, to extend their telomeres. There are also implications for treating conditions of aging, such as diabetes and heart disease. This has really opened the doors to consider all types of potential uses of this therapy.”
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