Telomere extension turns back aging clock in cultured human cells, study finds

January 23, 2015, Stanford University Medical Center
Human chromosomes (grey) capped by telomeres (white). Credit: PD-NASA; PD-USGOV-NASA

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 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 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 , 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 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 , 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 . 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 : about 28 more times for the skin cells, and about three more times for the .

"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 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 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."

Explore further: Researchers target the cell's 'biological clock' in promising new therapy to kill cancer cells

More information: 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 www.fasebj.org/content/early/2 … j.14-259531.abstract

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ayesdi_fdesay
2 / 5 (2) Jan 23, 2015
Is "turning back the aging clock" the same thing as "cells dividing many more times"? Or is it just one aspect of aging? Would we, for example, see someone's skin return to its younger state if we could simply allow the skin cells to divide many more times?
El_Nose
not rated yet Jan 23, 2015
the skin is made of many many different types of cells ---
buzzkolbush
5 / 5 (1) Jan 23, 2015
Fascinating! I will turn 50 this year. With these increasing discoveries in DNA research and medicine, perhaps I can live to be 120.
dedereu
2 / 5 (1) Jan 23, 2015
Function and information content of DNA methylation are quite complex as explained in Nature 15 january 2015 page 321 vol 517
So no hope for every one to live to 124 years like Jeanne Calment !!
EnricM
3 / 5 (3) Jan 25, 2015
Fascinating! I will turn 50 this year. With these increasing discoveries in DNA research and medicine, perhaps I can live to be 120.


I would love it too, but we need to consider the implications of several billions of very long living individuals... What will be the price tag on such treatments? Will it be only available for a rich minority? Will there be selection for that so that only healthy individuals can opt to it or will unhealthy ones taxing our environment and the rest of the population even more?
MRBlizzard
1 / 5 (2) Jan 25, 2015
Over the years, I've come to think that the very long lived should live off planet. They can come back to visit their greatly grandchildren for a limit of, say, six months.
Mazarin07
not rated yet Jan 29, 2015
OK, but if you work until the end of your live, that's another story.
Centuries ago there were no pensions and old care centers, all people worked untill they fell.

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