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Study menemukan, Ekstensi telomer membalik jam penuaan di kultur sel manusia
Sebuah prosedur baru dapat dengan cepat dan efisien meningkatkan panjang telomer manusia , protective caps pada ujung kromosom yang terkait dengan penuaan dan penyakit , menurut para ilmuwan ....read more
Telomere
extension turns back aging clock in cultured human cells, study finds
Date:
January 23, 2015
Source:
Stanford University
Medical Center
Summary:
A new procedure can
quickly and efficiently increase the length of human telomeres, the protective caps
on the ends of chromosomes that are linked to aging and disease, according to
scientists.
.............
A new procedure can
quickly and efficiently increase the length of human telomeres, the protective
caps on the ends of chromosomes that are linked to aging and disease, according
to scientists at the Stanford University School of Medicine.
Treated cells behave as if they are much younger than untreated cells,
multiplying with abandon in the laboratory dish rather than stagnating or
dying.
The procedure, which involves the use of a modified type of RNA, will
improve the ability of researchers to generate large numbers of cells for study
or drug development, the scientists say. Skin cells with telomeres lengthened
by the procedure were able to divide up to 40 more times than untreated cells.
The research may point to new ways to treat diseases caused by shortened
telomeres.
Telomeres are the protective caps on the ends of the strands of DNA called
chromosomes, which house our genomes. In young humans, telomeres are about
8,000-10,000 nucleotides long. They shorten with each cell division, however,
and when they reach a critical length the cell stops dividing or dies. This
internal "clock" makes it difficult to keep most cells growing in a
laboratory for more than a few cell doublings.
'Turning back the internal clock'
"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," said Helen Blau, PhD, professor
of microbiology and immunology at Stanford and director of the university's
Baxter Laboratory for Stem Cell Biology. "This greatly increases the
number of cells available for studies such as drug testing or disease modeling."
A paper describing the research was published today in the FASEB
Journal. Blau, who also holds the Donald E. and Delia B. Baxter
Professorship, is the senior author. Postdoctoral scholar John Ramunas, PhD, of
Stanford shares lead authorship with Eduard Yakubov, PhD, of the Houston
Methodist Research Institute.
The researchers used modified messenger RNA to extend the telomeres. RNA
carries instructions from genes in the DNA to the cell's protein-making
factories. The RNA used in this experiment contained the coding sequence for
TERT, the active component of a naturally occurring enzyme called telomerase.
Telomerase is expressed by stem cells, including those that give rise to sperm
and egg cells, to ensure that the telomeres of these cells stay in tip-top
shape for the next generation. Most other types of cells, however, express very
low levels of telomerase.
Transient effect an advantage
The newly developed technique has an important advantage over other
potential methods: It's temporary. 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.
The transient effect is somewhat like tapping the gas pedal in one of a
fleet of cars coasting slowly to a stop. The car with the extra surge of energy
will go farther than its peers, but it will still come to an eventual halt when
its forward momentum is spent. On a biological level, this means the treated
cells don't go on to divide indefinitely, which would make them too dangerous
to use as a potential therapy in humans because of the risk of cancer.
The researchers found that as few as three applications of the modified RNA
over a period of a few days could significantly increase the length of the
telomeres in cultured human muscle and skin cells. A 1,000-nucleotide addition
represents a more than 10 percent increase in the length of the telomeres.
These 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 Ramunas. "Previous attempts to deliver
mRNA-encoding TERT caused an immune response against telomerase, which could be
deleterious. In contrast, our technique is nonimmunogenic. 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. This suggests that a treatment using our method could be brief
and infrequent."
Potential uses for therapy
"This new approach paves the way toward preventing or treating
diseases of aging," said Blau. "There are also highly debilitating
genetic diseases associated with telomere shortening that could benefit from
such a potential treatment."
Blau and her colleagues became interested in telomeres when previous work
in her lab showed that the muscle stem cells of boys with Duchenne muscular
dystrophy had telomeres that were much shorter than those of boys without the
disease. This finding not only has implications for understanding how the cells
function -- or don't function -- in making new muscle, but it also helps
explain the limited ability to grow affected cells in the laboratory for study.
The researchers are now testing their new technique in other types of
cells.
"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, MD, PhD. Cooke, a co-author
of the study, formerly was a professor of cardiovascular medicine at Stanford.
He is now chair of cardiovascular sciences at the Houston Methodist Research
Institute.
"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," said Blau, who also is a member of the Stanford
Institute for Stem Cell Biology and Regenerative Medicine.
"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."
Story Source:
The above story is based on materials provided by Stanford University Medical Center. The original article was written by
Krista Conger. Note: Materials may be edited for content and length.
Journal Reference:
1. J. Ramunas, E. Yakubov, J. J. Brady, S.
Y. Corbel, C. Holbrook, M. Brandt, J. Stein, J. G. Santiago, J. P. Cooke, H. M.
Blau. Transient delivery of modified mRNA encoding TERT rapidly extends
telomeres in human cells. The FASEB Journal, 2015; DOI: 10.1096/fj.14-259531
