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Exploring the Effects of Longer Telomeres without Telomerase Gene Therapy

Researchers investigating telomeres, telomerase, and aging are now trying to isolate effects of telomere length from effects of telomerase by employing a novel method of breeding mice with very long telomeres. Telomeres are repeated DNA sequences at the ends of chromosomes that form a part of the limiting mechanism for cell division. Telomere length falls with each cell division, cells self-destruct or become senescent when telomere length is short, and stem cells employ telomerase to lengthen their telomeres to retain their ability to generate new daughter cells with long telomeres. Average telomere length in tissues then derives from some combination of cell division rates and cell replacement rates, and tends to fall over the course of aging. Work on lengthening telomeres in mice over the past decade has focused on the use of telomerase, such as via gene therapy. This has been shown to extend life and improve health, an outcome likely to derive from increased stem cell activity.

But is the telomere length or is it the telomerase? Telomerase lengthens telomeres, yes, but that isn't its only activity. Like all proteins, it plays a role in many mechanisms, not all of which are fully mapped at this point. A sizable fraction of the research community see reduction in average telomere length as an outcome of the state of age and damage - a marker of aging, and not a cause of aging. In this context, finding a way to extend telomere length without the use of telomerase is a good choice for further exploration of the mechanisms, and that is the achievement made by the research team in this case. The results of this study, demonstrating a slowing of some measures of aging purely based on longer telomeres, present a challenge to the view of telomere length as a marker only, though we can still argue over whether it is a primary or secondary mechanism of aging, especially when measured in immune cells. Possible mechanisms of enhanced health that could derive from telomere length only might include lower levels of cellular senescence, for example, and it would be interesting to see that measured.

Researchers have succeeded in creating mice in the laboratory with hyper-long telomeres and with reduced molecular ageing, avoiding the use of what to date has been the standard method: genetic manipulation. This new technique based on epigenetic changes avoids the manipulation of genes in order to delay molecular ageing. In 2009 researchers described that the in vitro culture of induced pluripotent stem cells caused the progressive lengthening of telomeres, to the point of generating what the authors called "hyper-long telomeres". Sometime later, in 2011, it was found 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, and 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? Researchers now prove that this is the case.

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 show that pluripotent stem cells that 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". The next step that the researchers are already working on 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. 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?"

Link: https://www.cnio.es/ing/publicaciones/mice-with-hyper-long-telomeres-without-altering-the-genes

Comments

Reason,

Does this nudge your opinion of the role of telomere length at all?

Posted by: bmack500 at June 2nd, 2016 8:53 AM

@bmack500: I'm still thinking on this. Unfortunately we're probably going to be waiting a few years for more rigorous determination of the mechanisms involved. I'd think that reduced numbers of senescent cells is a likely one, but the results also imply greater stem cell activity, which is interesting and a concept that needs more unpacking as to the differences between telomerase and no telomerase. Mice and humans have very different telomere length situations - mice have very long telomeres - and that may be even more of a problem for this approach than for telomerase therapies when it comes to making inferences on how it will turn out in humans. I'd want to see this tried in other primates or dogs or pigs - a mammal with closer to human telomere dynamics.

Posted by: Reason at June 2nd, 2016 1:18 PM

"Mice and humans have very different telomere length situations - mice have very long telomeres..."

Yes, but mice also lose their telomeres 100 times faster than humans.

Posted by: Annonymous at June 2nd, 2016 7:23 PM

"Mice and humans have very different telomere length situations - mice have very long telomeres..."

I am sorry but that is just not right. Mice have longer telomeres yes but as Michael Fossel and Blasco have clearly shown, the starting length is irrelevant it is the loss from that starting point that is important. That is what dictates changes in gene expression and phenotype not simply how long they are.

If the mouse strain is created with super long telomeres then it will very likely live longer because its gene expression profile will change more slowly. The majority of super long lived animals are all able to maintain very stable gene expression via this method.

I have not changed my opinion on telomeres and telomerase and this just adds more fuel to the fire as far as I am concerned. I am waiting for Blasco to publish her data for Fibrosis which she is working on now, if she can reverse fibrosis I think this speaks volumes. We shall see soon enough.

Posted by: Steve Hill at June 3rd, 2016 9:27 AM

The purpose of telomere lengthening is not to make the telomeres longer, but to trigger a gene expression change.

Posted by: John at June 3rd, 2016 12:51 PM

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