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January 23, 2015

More Manageable Telomere Extension, Thanks to Modified mRNA

  • A new means of lengthening telomeres works transiently, instigating a rapid surge in telomerase activity that ultimately peters out. The effect is rather like a tapping on the gas pedal of a car: first a brief acceleration, then a gentle deceleration. No worries about the gas pedal becoming stuck, causing the car to careen out of control.

    This surging/slowing pattern could benefit cells that undergo telomere lengthening because it is less likely to result in excessive, heedless cell division. This pattern might be suitable for regenerative medicine, where cells could undergo telomere lengthening without too much risk of running wild and causing cancer.

    The most immediate applications, however, are likely to be in improving cell culture, suggested Helen Blau, PH.D., a Stanford University scientist who led work on the new technique. “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,” said Dr. Blau, PhD. "This greatly increases the number of cells available for studies such as drug testing or disease modeling.”

    Dr. Blau and colleagues described their work January 22 in the FASEB Journal, in an article entitled, “Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells.”

    “Delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increases telomerase activity transiently (24–48 h) and rapidly extends telomeres, after which telomeres resume shortening,” wrote the authors. “Notably, unlike immortalized cells, all treated cell populations eventually stopped increasing in number and expressed senescence markers to the same extent as untreated cells.”

    The researchers found that as few as three applications of the modified RNA, which contained the coding sequence for the active component of telomerase, could significantly increase the length of the telomeres in cultured human muscle and skin cells. These applications, which occurred over a few days, were followed by a telomere extension of 1,000 nucleotides, which represents a more than 10% increase in telomere length. Treated cells divided many more times in the culture dish than did untreated cells: about 28 more times for the skin cells, and about three more times for the muscle cells.

    “We were surprised and pleased that modified TERT mRNA worked, because TERT is highly regulated and must bind to another component of telomerase,” said John Ramunas, Ph.D., one of the paper’s lead authors. "Previous attempts to deliver mRNA-encoding TERT caused an immune response against telomerase, which could be deleterious. In contrast, our technique is nonimmunogenic.”

    The authors indicated that the modified RNA is designed to reduce the cell's immune response to the treatment and allow the TERT-encoding message to stick around a bit longer than an unmodified message would. But it dissipates and is gone within about 48 hours. After that time, the newly lengthened telomeres begin to progressively shorten again with each cell division.

    “Existing transient methods of extending telomeres act slowly, whereas our method acts over just a few days to reverse telomere shortening that occurs over more than a decade of normal aging,” added Dr. Ramunas. “This suggests that a treatment using our method could be brief and infrequent."

    "This study is a first step toward the development of telomere extension to improve cell therapies and to possibly treat disorders of accelerated aging in humans," said John Cooke, M.D., Ph.D., a co-author of the study. This statement echoes the conclusion of the FASEB Journal article, which read as follows: “This rapid method of extending telomeres and increasing cell proliferative capacity without risk of insertional mutagenesis should have broad utility in disease modeling, drug screening, and regenerative medicine.”

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