Hyper-long Telomeres Created In Unaltered Genes

Avoiding the use of what to date has been the standard method for lengthening telomeres, genetic manipulation, scientists at the Spanish National Cancer Research Centre (CNIO) have created mice in the laboratory with hyper-long telomeres, and with reduced molecular ageing.

The new technique is based on epigenetic changes and avoids the manipulation of genes in order to delay molecular ageing. The study also underlines the importance of this new strategy in generating embryonic stem cells and iPS cells with long telomeres for use in regenerative medicine.

Telomeres are the protective structures located at the ends of chromosomes. They are vital to the stability of our genetic material and to maintain the “youthful state” of our cells and of our bodies.

However, telomeres get shorter as we age.

Once they reach a critical length, cells enter a state of senescence or die. This is one of the molecular causes of cellular ageing and of the emergence of ageing-related diseases.

On the other hand, when telomeres are extra-long, they exert a protective role against ageing and ageing-related diseases.

In Vitro Expansion Of Pluripotent Cells

In 2009, a paper, published by the CNIO Telomeres and Telomerase Group in the journal Cell Stem Cell, described that the in vitro culture of iPS cells caused the progressive lengthening of telomeres, to the point of generating what the authors called “hyper-long telomeres”.

Later, in 2011, Elisa Varela (first author of the above-mentioned paper) and her colleagues at the CNIO, published a paper in the Proceedings of the National Academy of Sciences stating that this phenomenon also occurs spontaneously in embryonic stem cells when cultured in vitro.

“The in vitro expansion of the embryonic stem cells results in the elongation of the telomeres up to twice their normal length” explained the authors.

A lengthening occurs thanks to the active natural mechanisms without alterations in the telomerase gene.

However, would these cells be capable of developing into a mouse with telomeres that are much longer than normal and that would age more slowly? In the current paper, Elisa Varela and her colleagues prove that this is the case.

Less DNA Damage

The cells with hyper-long telomeres in these mice appear to be perfectly functional.

When the tissues were analysed at various moments (0, 1, 6 and 12 months of life), these cells maintained the additional length scale (they shortened over time but at a normal rhythm), accumulated less DNA damage and had a greater capacity to repair any damage. In addition, the animals presented a lower tumour incidence than normal mice.

These results demonstrate that pluripotent stem cells which carry hyper-long telomeres can give rise to organisms with telomeres that remain young at the molecular level for longer. According to the authors, this “proof of concept means that it is possible to generate adult tissue with longer telomeres in the absence of genetic modifications”.

Explains Blasco:

“Our work also demonstrates that it is possible to generate iPS cells with longer telomeres that would turn into differentiated cells also with longer telomeres and that would, therefore, be better protected against damage”.

This would be of benefit to the field of regenerative medicine; teams are now studying how to use iPS cells to generate adult cell types for cell therapy.

The next step will be to generate a new species of mice in which the telomeres of all the cells are twice as long as those in normal mice, explain Blasco and Varela.

“Then, we will be able to address some of the important questions that remain unanswered: would a mouse species with telomeres that are double in length live longer? Is this the mechanism that is used by nature to determine different longevities in genetically similar species? Would this new species present a higher or lower incidence of cancer?”

Elisa Varela, Miguel A. Muñoz-Lorente, Agueda M. Tejera, Sagrario Ortega & Maria A. Blasco
Generation of mice with longer and better preserved telomeres in the absence of genetic manipulations
Nature Communications 7, Article number: 11739 doi:10.1038/ncomms11739

Image: Spanish National Cancer Research Centre (CNIO)