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A Novel Method of Telomere Extension

Telomeres are the protective caps of repeated DNA sequences found at the end of chromosomes. Telomere length is a part of the regulatory system that prevents cells from dividing indefinitely: a little length is lost with each cell division, and a cell destroys itself or otherwise ceases to divide when its telomeres become too short. In stem cell populations, responsible for delivering fresh batches of long-telomere daughter cells into tissues to replace those lost due to reaching the limits of replication, the enzyme telomerase is active to maintain lengthy telomeres by adding extra repeating sequences to the ends. Cancer cells also make use of telomerase or other methods of lengthening telomeres in order to maintain their ability to rapidly and continually divide, but this process isn't normally active in the majority of the cells in the body. Average telomere length in white blood cells tends to decrease with age and illness, and this is really a proxy measure that blurs some combination of cell division rates and stem cell activity.

Researchers have lengthened healthy life in mice by boosting the activity of telomerase via genetic engineering, though it is still the case that there is no definitive experiment to show which of the possible mechanisms causes this life extension. Is it a matter of more stem cell activity, some secondary effect of having long telomeres such as increased cell life span, or another aspect of telomerase, such as its influence on mitochondrial biology? There is considerable interest in the research community in continuing to explore what might happen when telomeres are lengthened, and so it is inevitable that better methods of lengthening will be developed:

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. 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. 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.

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.

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. "We were surprised and pleased that modified TERT mRNA worked, because TERT is highly regulated and must bind to another component of telomerase. 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."

Link: http://med.stanford.edu/news/all-news/2015/01/telomere-extension-turns-back-aging-clock-in-cultured-cells.html

Comments

Great news Telomere length is a key player in aging and causing the body to break down. Problem is testing in humans is likely to take decades to arrive.

Posted by: Steve H at January 23rd, 2015 9:22 AM

Pure layman speculation here, but couldn't future doctors use RNA interferance to knock down the gene(s) for telomerase in every cell of the body to prevent cancer, then target some modified mRNA unaffected by the RNAi to stem cells?

Actually it seems easier just to target and destroy cancer cells... but this does look like a much easier way of expanding cells in culture than using plasmids to try and express telomerase.

Posted by: Jim at January 23rd, 2015 4:06 PM

I have been waiting for news like this for a long time. This could be the first real step towards a non invasive anti aging treatment that actually works!

Posted by: Denzel at January 23rd, 2015 6:55 PM

@Jim: Because telomerase therapy extends life in mice while reducing incidence of cancer?

https://www.fightaging.org/archives/2012/05/telomerase-gene-therapy-extends-life-eliminates-cancer-in-adult-mice.php

Though in fairness that second point wasn't exactly expected as an outcome. Mice do have very different telomere dynamics, however, so it isn't the case that we should expect things to work the same way for people without more careful testing.

Even before that, however, people were on the telomere lengthening bandwagon and proposing telomere erosion as a causative process in aging. There were a couple of biotech companies launched a decade or so ago to try to make telomere lengthening work, neither of which went anywhere.

Posted by: Reason at January 23rd, 2015 7:25 PM

Denzel, don't think for a moment that any one thing discussed on this blog is going to yield results by itself. For functional anti-aging you need to replace neurons and replace bone marrow cells and restore youthful balances of signaling molecules and restore the blood-brain barrier and scrape out glucosepane and restore elastins and destroy 7KC and squeeze out tau and scrape off amyloids and restore thymal function and remove senescent cells and a great many other things I forgot to mention, some of which involve cancer and things we probably don't even know about yet because they only show up in 200-year-old humans.

Curing all aging-related degeneration is like curing all disease. It must be done a bite at a time.

Posted by: Slicer at January 23rd, 2015 9:01 PM

@ Jim: "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".
http://med.stanford.edu/news/all-news/2015/01/telomere-extension-turns-back-aging-clock-in-cultured-cells.html

Posted by: Barbara T. at January 23rd, 2015 10:09 PM

Jim wrote:

"Pure layman speculation here, but couldn't future doctors use RNA interferance to knock down the gene(s) for telomerase in every cell of the body to prevent cancer, then target some modified mRNA unaffected by the RNAi to stem cells?"

It's much more easier for cancer cells to evolve resistance to this therapy than to the therapy of completely eliminating the telomerase gene.

http://www.sens.org/research/introduction-to-sens-research/cancerous-cells

Posted by: Antonio at January 24th, 2015 2:27 AM

Sorry but wilt is one of the few sens approaches I find unfeasible. Increasing telomere length is likely to restore cells to a younger phenotype and some studies have shown it doesn't increase cancer risk. Blasco et al demonstrated this.

The technique here is also transient so it's not constantly promoting telomerase and encouraging rampant cell division.It's effectively a top up therapy which is a valid rejuvenation approach.I think a restoration of telomere length could offer protection against damage and cancers as the cells would function at a younger state.

Telomeres are less important in mice and so their effects in humans who rely on the mechanism more could be more profound. Tests on human cells in labs have shown promise. It's definitely an avenue worth pursuing as a regenerative method.

Posted by: steve h at January 24th, 2015 4:03 AM

Also the whole Cancer promoting argument doesn't wash with me, if Telomerase and longer telomeres encouraged Cancer we would see it running rampant in the young which isn't the case. This would seem to suggest that optimal length Telomeres offer protective qualities as well as repairing damage.

Restoration of Telomeres could have a powerful rejuvenating effect on the body and its worth pursuing. Surely all these different labs could come together again and work on a joint project to ratify the effects?

Posted by: Steve H at January 24th, 2015 5:30 AM

@Steve:

The purpose of WILT is not increasing longevity through lengthening of telomeres. It's purpose is eliminating cancer.

"I think a restoration of telomere length could offer protection against damage and cancers as the cells would function at a younger state."

Even if you have longer telomeres, the (epi)mutations you accumulated in your life will still be there. Maybe this therapy will make the immune system stronger or whatever, and thus there will be some decrease in cancer risk, but it will not eliminate cancer, and you will have more and more mutations with each year. Sometime this will cause cancer.

"if Telomerase and longer telomeres encouraged Cancer we would see it running rampant in the young which isn't the case."

Non sequitur. The young haven't still accumulated much genetic damage.

Posted by: Antonio at January 24th, 2015 2:59 PM

Fair comment but wilt isn't the way to stop cancer imo. Telomere rejuvenation via a transient therapy offers great potential for damage repair, there is some evidence it repairs some DNA damage too according to some reports I have read.

There has to be a better method than wilt to combat cancer. The idea of removing all telomerase is just completely impractical. there are other approaches to treating cancer being developed such as t cell programing which offer alternative approaches among others. that said Sens offers good solutions to most damage forms aside from wilt.

Posted by: steve h at January 24th, 2015 4:33 PM

"wilt isn't the way to stop cancer imo"

Why?

"there are other approaches to treating cancer being developed such as t cell programing"

That will only reduce the incidence of cancer, not eliminate it.

Posted by: Antonio at January 25th, 2015 3:46 AM

There is no opposition between this technology and WILT. WILT does not mean average telomere length must be kept short; it only requires that cells be stripped of the capacity to indefinitely extend their own telomeres. This technology for delivering mRNA does not rely upon such a capacity.

Instead, it seems to me that this approach could possibly ease the implementation of WILT.

Posted by: José at January 25th, 2015 3:34 PM

This is great news! I could envision first uses might be for purely cosmetic purposes like greying hair.

Don't discount the cosmetic -- if enough of those techniques work, people will wonder, "hey, I look young and it's great. What about feeling young too?"

Posted by: John at January 26th, 2015 12:13 AM

Can we ask SENS what is their take on this?

This study is in line with other previous researches, right? pretty much validate some hypothesis by Michael Fossel, Bill Andrews, Ronald DePinho, TA Sciences/Geron, etc. that by increasing telomerase results longer telomeres, and in turn some rejuvenation pathways are activated.

@ John - cosmetics is a very good selling point and I do not understand why is not looking into more as will generate a lot of revenue that SENS and other are in need so much.

Seems like TA Sciences introduces a skin product a while ago.
While I do not take TA-65, I red some anecdotal comments about gray hair, skin, etc. - but until they run clinical studies, are just anectodal reports.

Maybe is time for some entity to step in a take the bull by the horns?

Posted by: Adrian at January 26th, 2015 6:44 AM

@Adrian: It doesn't validate any of those things. It is just a very useful way of using telomerase to lengthen telomeres, which should in turn speed up work on getting to answers on where this sits in the scheme of things.

TA-65 and any similar items are the standard "anti-aging" market scam - sell some herbs on the basis of exceedingly dubious or valid but unrelated research. They have nothing to do with any real science, and you're wasting your time looking at that sort of thing.

Posted by: Reason at January 26th, 2015 7:23 AM

Not being disrespectful to anyone's beliefs, but there seem to be a few older individuals out there who just want rejuvenation to be fairly straightforward, and possible fairly soon (for understandable reasons). So denying that telomerase is the answer causes an entirely reasonable emotional reaction.

The SENS take, as far as I understand it, would be that all seven classes of proposed damage would have to be repaired. Increasing telomere length does increase lifespan in mice (when they are also given extra cancer suppressing genes). But there are loads of cavets, including the fact that mice are often rubbish models of human biology.

This is probably just a technology that will enable telomerase's relationship with the seven classes of damage to be better teased out.

Posted by: Jim at January 26th, 2015 9:59 AM

I'm 57 right now, I am ready to gamble. Death is not an option. Like Dirk Pearson said just find something that will expand my life 20 years so that the next technology can be here to expand it yet again. It would be sad if some of the answers to expanding life were available but all you hear is the prevailing "but". I know experimenting on our cousin apes sounds so terribly cruel to some, but why not try telomerase therapy on apes who are aged and suffering already and see what happens? To conduct the experiment they don't all have to be in the same place either. The fallacy of the controlled study is that sometimes to observe a true result, an organism has to be exposed to varying conditions' to observe an outcome.

Posted by: Richard at January 26th, 2015 10:44 AM

@ Reason -

while I have no relationship with TA-65 I did read couple things. So please look at them and tell me if you see things differently, but I do apply a validation logic in all my research.

1. as far as I know/read, TA-65 is based on initial work done by Geron. And actually I did search the patent and that patent do exists. When I find the time I can copy and paste the links.

2. Here are couple studies done by Maria Blasco @ Spanish National Cancer
Research Centre (CNIO). In some of the studies the work refer directly to TA-65. If TA Sciences is paying her and her team, and the whole research is rigged, then that is beyond me. But I like to believe that the research is honest and correct. If you read these studies and you come to a different conclusion, I would like to ask what kind of logic are you using, because is beyond my understanding. With all due respect, I do like SENS, I do want them to succeed (and as fast as possible!), and I do donate to them, but if something doesn't go in the line with what SENS preaches, we do have to look at that thing and ask questions. Same thing with them, they should be very flexible, dynamic and integrate new sound research.

It sounds harsh, but sometimes I have the feeling that people here on this blog are ready to start a new religion and whatever falls aside form SENS approach should be attacked. I think it's much better if we keep our minds open and free and wonder at new discoveries while trying to integrate them in the large scheme of things in order to solve faster the reverse aging process.

Anyway, here are the studies I read, please let me know what is your take on them:

"The telomerase activator TA-65 elongates short
telomeres and increases health span of adult
old mice without increasing cancer incidence"

http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2011.00700.x/pdf

"A Natural Product Telomerase Activator As Part
of a Health Maintenance Program"

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3045570/pdf/rej.2010.1085.pdf

"Telomerase at the intersection of cancer and aging"

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896987/pdf/emss-56319.pdf

"The telomerase activator TA-65 elongates short telomeres
and increases health span of adult/old mice without increasing cancer incidence"

http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9726.2011.00700.x/full

Again, could be that these studies might be manipulated, but if that is the case is beyond me.
And I do keep my position that the last study by Prof. Helen Blau is a “continuation” in the same
line of thought and “validates” previous things. I welcome a sound logic to counteract these remarks.

Posted by: Adrian at January 26th, 2015 11:41 AM

@Adrian: Thanks for those links; I clearly haven't been keeping up with TA-65 since the initial standard dubious outset.

So I'll revise my statement to say that it is disappointing that researchers are directed and funded and feel the need to waste their time on this. It is the same sort of thing as work on calorie restriction mimetics: ultimately pointless as the upside in life span in longer-lived species is so very small in the grand scheme of things and the work need to build and validate treatments is so very large.

I advocate for SENS and SENS-like repair strategy work because the expense should be similar over the long term, yet the outcome at the end of the day should be thousands of times better. From this perspective it is a terrible thing that most of the research and development community are spending time on mining the natural world for things like TA-65 rather than working on the basis for repair strategies. Even direct manipulation of metabolism such as the work quoted in this post is a league better as a research activity in comparison to the standard drug discovery approach of shuffling through naturally occurring compounds in search of marginal outcomes.

Posted by: Reason at January 26th, 2015 2:38 PM

@Richard:

"The fallacy of the controlled study is that sometimes to observe a true result, an organism has to be exposed to varying conditions' to observe an outcome."

It's not a fallacy. There are many things that influence longevity. If you don't control them, your experiments about telomeres will be meaningless.

Posted by: Antonio at January 27th, 2015 2:04 PM

I'm glad that more people are focusing on known likely pathways to prevent/slow aging (which is a disease). I think Telomerase is only part of the story. There is a whole other side to the story in energy balance (sirtuins/NAD, mTOR) and there may be also a neuronal control. I may be off the rocker here, but one may need to target all of them simultaneously. If not done correctly, this may also produce considerable side-effects since you are simultaneously manipulating several important pathways. Right now everyone is touting the lead that they discovered, but so far I haven't seen anyone trying to combine all these principles in an animal study at various doses.

Posted by: George at April 21st, 2015 7:15 PM

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