Progeria and telomeres
Telomere lengthening reversed premature cell aging
Oleg Lischuk, N+1
American scientists have managed to reverse the premature aging of cells taken from patients with progeria by lengthening telomeres using RNA therapy. The results are published in the Journal of the American College of Cardiology.
Telomeres are "attachments" at the ends of chromosomes that provide replication (doubling) DNA during cell division. With each division, they shorten, which limits the ability of cells to reproduce (the maximum possible number of divisions is called the Hayflick limit). Shortening of telomeres with age is one of the factors of aging of the body. The enzyme telomerase is present in cells, capable of increasing the length of telomeres, but it is active only in cells that need to be constantly divided (stem, sexual, some epithelial and most malignant).
Hutchinson-Guilford progeria is a rare genetic disease caused by a mutation of the LMNA gene, which encodes the protein lamin A, which is part of the cell nucleus envelope. The defective form of this protein, called progerin, disrupts the architecture of the nucleus, DNA repair, and many other biochemical processes, and also dramatically accelerates the shortening of telomeres. All this leads to rapid aging of the body – the average life expectancy in progeria does not exceed 13 years.
The staff of the Houston Methodist Research Institute using monochrome multiplex quantitative PCR measured the length of telomeres in fibroblasts of 17 patients with progeria aged from 1 to 14 years, as well as similar cells of healthy newborns and adults. In 12 patients, this length corresponded to 69-year-old healthy people, in the remaining five it turned out to be normal.
After that, scientists introduced matrix RNA (mRNA) encoding human telomerase (hTERT) into some fibroblasts of patients with progeria, and into the rest – mRNA encoding a catalytically inert form of this enzyme (CI hTERT), which binds to telomeres, but does not lengthen them. The procedure was repeated three times with an interval of 48 hours, which led to stable mRNA expression for several days.
RNA therapy with conventional hTERT restored the proliferation of fibroblasts with shortened telomeres, reduced cell loss in culture and extended cell life. This was accompanied by signs of fibroblast rejuvenation, including an increase in telomerase activity and telomere length, a decrease in the secretion of inflammatory cytokines, and others (the authors intend to describe them in detail in subsequent publications). In general, the kinetics of cell growth approached normal, but immortalization (acquisition of the ability to unlimited reproduction and malignant degeneration) of cell culture was not observed.
The introduction of CI hTERT into defective fibroblasts and hTERT into fibroblasts with normal telomere length did not produce such effects, that is, it was the restoration of the length of shortened telomeres that was responsible for them.
"The results obtained indicate that the temporary expression of telomerase mRNA can serve as a fast and effective method of reversing cell aging in progeria. Although prolonged expression of telomerase may cause concerns related to immortalization, our approach did not lead to cell degeneration," the authors write. In the future, they intend to improve the methodology so as to adapt it to clinical use.
Previously, scientists managed to slow down the aging of mouse cells with an analog of progeria by temporarily "turning on" transcription factors that convert mature cells into stem cells. An organ-on-a-chip was also created to study the reaction of cells of patients with progeria to mechanical deformation.
Portal "Eternal youth" http://vechnayamolodost.ru 25.08.2017