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A Novel Method of Telomere Extension


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#1 reason

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Posted 23 January 2015 - 12:39 PM


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....ured-cells.html


View the full article at FightAging

#2 johnross47

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Posted 23 January 2015 - 08:07 PM

would repeated treatment produce more lengthening? Could my 68 year old cells be given telomeres like a teenager in other words?



#3 SearchingForAnswers

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Posted 24 January 2015 - 06:47 AM

I don't think they know yet, but in the study they did repeat it several times to increase overall length by about 10%.


Edited by SearchingForAnswers, 24 January 2015 - 07:17 AM.


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#4 corb

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Posted 24 January 2015 - 02:15 PM

would repeated treatment produce more lengthening? Could my 68 year old cells be given telomeres like a teenager in other words?

 

I don't think they know yet, but in the study they did repeat it several times to increase overall length by about 10%.

 

mRNAs are genetic commands - it goes to the ribosomes and tells them to synthesize a protein - in this case TERT - a component of telomerase.

More simply put mRNAs are like a shopping list, and your ribosomes are like a grocery store, every time you go with this list, you'll get out of the shop with the ingredients you had in the list. So this mRNA will always have the same result when supplied to a cell - make the ribosomes synthesize TERT.

 

The 48 hours thing is good, in the sense that it won't induce an uncontrolled production of telomerase and make it too easy for cells to become cancerous.

It still carries the risk to an extent. But it's significantly safer than all the methods tried earlier.

 



#5 niner

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Posted 24 January 2015 - 08:39 PM

This is an exciting development.  My main questions involve delivery methods-- How do you get the mRNA into the cell, and how do you get it into the right cells in particular?



#6 corb

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Posted 24 January 2015 - 09:03 PM

This is an exciting development.  My main questions involve delivery methods-- How do you get the mRNA into the cell, and how do you get it into the right cells in particular?

 

Good question.
Right now they're only doing it in vitro.

Which is what the article is about.

In vivo is a whole different story, our bodies typically kill any mRNAs on sight. But the article said there's prospects of future in vivo therapies so probably they're working on it.



#7 niner

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Posted 24 January 2015 - 10:42 PM

 

This is an exciting development.  My main questions involve delivery methods-- How do you get the mRNA into the cell, and how do you get it into the right cells in particular?

 

Good question.
Right now they're only doing it in vitro.

Which is what the article is about.

In vivo is a whole different story, our bodies typically kill any mRNAs on sight. But the article said there's prospects of future in vivo therapies so probably they're working on it.

 

Yeah, as I was reading it, I was saying "ok, this will be a nice tool to create long-lived cell lines, but it doesn't sound like something that could be done in vivo.  Then I saw the line about "treatments", so either they have a plan or maybe they are naive.  Hard to say.  I'd like to know how they plan to do it...



#8 pone11

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Posted 20 February 2015 - 02:25 AM

So the procedure described works in vitro, but how could it ever scale?   If you gave it to an organism orally or intravenously, is there any way that the same effect could take place, on any scale?

 

A very practical problem here is how could you ever get funding for this in a human study?   There are non trivial risks, and there is no "disease" you are treating.   An ethics or review board is likely to look at this as a vanity problem simply not worth the liability.   I am NOT agreeing with that position!  I am pointing out the kinds of obstacles that might stand in the way of doing something like this in vivo.



#9 corb

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Posted 20 February 2015 - 03:44 AM

So the procedure described works in vitro, but how could it ever scale?   If you gave it to an organism orally or intravenously, is there any way that the same effect could take place, on any scale?

 

Here is a paper describing a the difficulties of using mrna in vivo and introducing a new approach.

 

 

Messenger RNA (mRNA) has a high potential to produce proteins or peptides for therapeutic purposes in a safe manner without any risk of random integration into the genome. Although pioneering studies to transfect mRNA into cells using a nonviral method were reported in the 1980s [1], [2], the interest in the clinical use of mRNA has been limited for a long time. There are two major problems associated with mRNA introduction: mRNA is considered to be unstable to obtain sufficient protein expression in clinical settings [3] and mRNA induces strong immune reactions through recognition by Toll-like receptors (TLRs) [4], [5], hampering repeated mRNA administration. Thus, efforts for clinical applications of mRNA have been limited, mainly in cancer immunotherapy by ex vivo transfection toward dendritic cells [6], [7], [8], [9]. In contrast, there are only a few studies reporting the trials of in vivo mRNA administration [10], [11].

Instability is an inherent limitation of mRNA. Many in vitro transfection studies have revealed that although mRNA enabled even higher efficiency of protein expression than plasmid DNA (pDNA) within several hours after mRNA introduction into cells, the duration of expression was apt to be very short [12], [13]. For example, several groups recently induced pluripotent stem cells (iPSCs) by transfection of mRNA encoding Yamanaka factors [14], [15], [16]. Their success strongly suggests the feasibility of using mRNA for therapeutic purposes in the future; however, they generally performed repeat transfections with intervals of a few days, suggesting that the instability of mRNA hampered the durable protein expression after mRNA transfection.

Thus, the requirement of an effective mRNA delivery system to overcome the instability of mRNA should be further explored to realise in vivo mRNA administration. Although some strategies have been reported for nonviral in vivo mRNA administration, including injection of naked mRNA [17], [18] in combination with physical pressure such as electroporation or gene gun [1], [19] and the usage of synthetic carriers based on cationic lipids and polymers [20], [21], [22], low efficiency and short duration of protein expression remain significant problems to be solved. At present, there is only one phase 1 study clinical trial to treat metastatic melanoma by subcutaneous injection of naked or protamine-stabilised mRNAs [9]; however, a more efficient system for in vivo mRNA administration would be strongly required to expand the application to many other clinical fields.

In addition to the stability issue, the problem of mRNA immunogenicity also remains unsolved. Based on findings that mRNA containing modified nucleosides effectively suppresses recognition by TLRs [23], [24], mRNA modification was proposed as an effective method to reduce immunogenicity. Several protocols for mRNA modification have been reported to effectively regulate the induction of inflammatory cytokines after mRNA administration, for example, replacement of uridine with pseudouridine [11], [25] or replacement of 25% uridine and cytidine with 2-thiouridine and 5-methyl-cytidine [10]. However, cytokine induction was not completely eliminated even when using modified mRNA. Moreover, the modified forms of pseudouridine and thiouridine are rarely found in endogenous mRNA [26], leaving their clinical safety and availability unclear.

 

http://journals.plos...al.pone.0056220



#10 pone11

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Posted 20 February 2015 - 04:41 AM

 

So the procedure described works in vitro, but how could it ever scale?   If you gave it to an organism orally or intravenously, is there any way that the same effect could take place, on any scale?

 

Here is a paper describing a the difficulties of using mrna in vivo and introducing a new approach.

 

 

Messenger RNA (mRNA) has a high potential to produce proteins or peptides for therapeutic purposes in a safe manner without any risk of random integration into the genome. Although pioneering studies to transfect mRNA into cells using a nonviral method were reported in the 1980s [1], [2], the interest in the clinical use of mRNA has been limited for a long time. There are two major problems associated with mRNA introduction: mRNA is considered to be unstable to obtain sufficient protein expression in clinical settings [3] and mRNA induces strong immune reactions through recognition by Toll-like receptors (TLRs) [4], [5], hampering repeated mRNA administration. Thus, efforts for clinical applications of mRNA have been limited, mainly in cancer immunotherapy by ex vivo transfection toward dendritic cells [6], [7], [8], [9]. In contrast, there are only a few studies reporting the trials of in vivo mRNA administration [10], [11].

Instability is an inherent limitation of mRNA. Many in vitro transfection studies have revealed that although mRNA enabled even higher efficiency of protein expression than plasmid DNA (pDNA) within several hours after mRNA introduction into cells, the duration of expression was apt to be very short [12], [13]. For example, several groups recently induced pluripotent stem cells (iPSCs) by transfection of mRNA encoding Yamanaka factors [14], [15], [16]. Their success strongly suggests the feasibility of using mRNA for therapeutic purposes in the future; however, they generally performed repeat transfections with intervals of a few days, suggesting that the instability of mRNA hampered the durable protein expression after mRNA transfection.

Thus, the requirement of an effective mRNA delivery system to overcome the instability of mRNA should be further explored to realise in vivo mRNA administration. Although some strategies have been reported for nonviral in vivo mRNA administration, including injection of naked mRNA [17], [18] in combination with physical pressure such as electroporation or gene gun [1], [19] and the usage of synthetic carriers based on cationic lipids and polymers [20], [21], [22], low efficiency and short duration of protein expression remain significant problems to be solved. At present, there is only one phase 1 study clinical trial to treat metastatic melanoma by subcutaneous injection of naked or protamine-stabilised mRNAs [9]; however, a more efficient system for in vivo mRNA administration would be strongly required to expand the application to many other clinical fields.

In addition to the stability issue, the problem of mRNA immunogenicity also remains unsolved. Based on findings that mRNA containing modified nucleosides effectively suppresses recognition by TLRs [23], [24], mRNA modification was proposed as an effective method to reduce immunogenicity. Several protocols for mRNA modification have been reported to effectively regulate the induction of inflammatory cytokines after mRNA administration, for example, replacement of uridine with pseudouridine [11], [25] or replacement of 25% uridine and cytidine with 2-thiouridine and 5-methyl-cytidine [10]. However, cytokine induction was not completely eliminated even when using modified mRNA. Moreover, the modified forms of pseudouridine and thiouridine are rarely found in endogenous mRNA [26], leaving their clinical safety and availability unclear.

 

http://journals.plos...al.pone.0056220

 

 

It almost might as well be a trip to Mars.  It's going to be many years before we see that commercially available to humans, too late for most of us.

 

I'm much more enthusiastic about the potential of antioxidants like C60 for these reasons:

1) There is an easy way to introduce it in vivo today

2) C60 is a commodity that is now very cheap, so no commercial interest can kill progress through greed

3) It is nearly impossible for the FDA to control given how wide spread it is and the ease with which a liposomal delivery system can be created

 

Those are the kinds of elements that are all missing for telomere extension solutions like mRNA, today....

 

I have read the opinions of some researchers that mice are more subject to oxidative stress than humans, because humans have so many more antioxidants.   So, unfortunately, C60 may end up doing more for the lifespans of mice than humans.   But the jury is still out and we can hope!


Edited by pone11, 20 February 2015 - 04:42 AM.


#11 apmark

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Posted 26 January 2017 - 04:12 AM

would repeated treatment produce more lengthening? Could my 68 year old cells be given telomeres like a teenager in other words?

Apparently ta65 has some competition now, have read that there is remarkable increases with baseline telomere length with a drug normally used for conditions like endometriosis called dazanol 

http://www.revgeneti...meres-recommend also an interesting read on 

http://www.medpageto...eriatrics/58010

It is more expensive then ta65 but for short term use intermittently. It would be good if there were some more trials



#12 Never_Ending

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Posted 26 January 2017 - 04:28 PM

I don't think researchers are going to get confused with the meaning of   in vitro or in vivo.   It makes sense for them to focus on in vitro FIRST,  it's not going to start by them giving unknown substances for people to take. They're working on a novel method for substantial increase in telomerase, this effort is 100% meaningful and deserves people's support. It's the type of thing that really moves the needle(if successful in body).  Yes there's obstacles from going vitro to in vivo but it's likely a delivery method can be figured out. They likely need to work on targeting methods for getting the substance to the needed cells in the body, while perhaps less so to certain other cells.

 

Overall very interesting article!

 

As a side note their research might shed more light on the telomerase process, the extent of which it affects aging, and perhaps other novel compounds(not RNA based) for triggering telomerase production.


Edited by Never_Ending, 26 January 2017 - 04:32 PM.


#13 PeaceAndProsperity

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Posted 02 February 2017 - 12:29 PM

I'm much more enthusiastic about the potential of antioxidants like C60 for these reasons:

1) There is an easy way to introduce it in vivo today

2) C60 is a commodity that is now very cheap, so no commercial interest can kill progress through greed

3) It is nearly impossible for the FDA to control given how wide spread it is and the ease with which a liposomal delivery system can be created

As far as I've understood, c60 has never made anyone younger though some claim insignificant effects like better skin. Of course it's the same with astragalus compounds.


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