New research in The FASEB Journal suggests that delivering modified mRNA encoding the protein telomerase reverse transcriptase (TERT) to cells extends their telomeres a finite but significant amount
Will extending telomeres lead to longer, healthier lives? Researchers have taken an important step toward answering this question by developing a new treatment used in the laboratory that extends telomeres.
One of the key aspects of aging is the shortening of telomeres over time. Telomeres, which serve as protective “end caps” for chromosomes, help keep DNA healthy and functioning as it replicates. Unfortunately, these protective end caps become shorter with each DNA replication, and eventually are no longer able to protect DNA from sustaining damage and mutations. In other words, we get older.
An important step toward lengthening telomeres has now been made, which not only allows scientists to increase cell numbers for testing drugs, but may also hold a key to longer and healthier lives. This research was published online in The FASEB Journal.
“In the near term, since biomedical research depends heavily on having large numbers of cells available for study, we hope that these findings will be broadly applicable in the search for treatments and cures for disease,” said Helen M. Blau, Ph.D., who led the research as Director of the Baxter Laboratory for Stem Cell Biology in the Department of Microbiology and Immunology at Stanford University School of Medicine in Stanford, California, and an Associate Editor of The FASEB Journal, the Bethesda, Maryland-based journal in which her report was published. “Ultimately, we hope that these findings will help prevent, delay or treat age-related conditions and diseases, as well as certain devastating genetic diseases of inadequate telomere maintenance.”
To make this discovery, Blau and colleagues delivered modified mRNA encoding TERT, the enzyme that increases the length of telomeres by adding DNA repeats, to four groups of cells. The first group received modified mRNA encoding TERT, and the other three groups were controls that received either mRNA encoding an inactive form of TERT, the solution in which TERT is delivered, or no treatment. The telomeres of the first group (telomere-extending treatment group) were rapidly lengthened over a period of a few days, whereas the telomeres of the three control groups were not extended. The first group was also able to undergo more cell divisions, whereas the controls were not. Importantly for the potential safety of this approach, the telomeres of the first group resumed shortening after they were extended, showing that due to the short, transient treatment, the cells were not immortalized.
Further, all of the cell populations treated eventually stopped dividing, indicating that they were not immortalized. This approach has been tested on cell types including fibroblasts and myoblasts and is now being tested on stem cells. Additionally, this research showed that cells could be treated several times with enhanced effects on the capacity for division. Since the increase in numbers is compounded with each treatment, a small sample of cells, for example from a small biopsy, can be amplified to very large numbers.
“We were surprised and pleased at how quickly modified TERT mRNA extends telomeres,” said John Ramunas, first author and postdoctoral fellow who pioneered this work in Blau’s Stanford University laboratory. “In fibroblasts, over a decade of telomere shortening was reversed in a few days, suggesting that a therapy might be brief and infrequent.”
“It might not be the Fountain of Youth to keep us young forever, but this discovery is a real shot in the arm. This work is a game-changer,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. He added, “in the short term it will help us to understand how aging affects the molecular machinery of cells. In the long-term, the sky’s the limit. Biologists have long guessed that the key to a longer lifespan is figuring out how to extend telomeres. Helen Blau and her colleagues have just done that.”
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FASEB is composed of 27 societies with more than 120,000 members, making it the largest coalition of biomedical research associations in the United States. Our mission is to advance health and welfare by promoting progress and education in biological and biomedical sciences through service to our member societies and collaborative advocacy.
Details: John Ramunas, Eduard Yakubov, Jennifer J. Brady, Stéphane Y. Corbel, Colin Holbrook, Moritz Brandt, Jonathan Stein, Juan G. Santiago, John P. Cooke, and Helen M. Blau. Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells. FASEB J. doi:10.1096/fj.14-259531; http://www.
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