November 20, 2002
New Telomere Lengthening Technique Developed

Recall the recent post about how youthful stem cells from embryo livers outcomputed older adult stem cells in cows. It is not known what exactly about the youthful stem cells made them more competitive. One possibility is that their telomeres are longer and hence they can divide more times. A recent report of a group at Stanford provides a way to more easily lengthen telomeres:

Writing in the Nov. 18 Proceedings of the National Academy of Sciences (PNAS), Stanford researchers described how newly created circles of synthetic DNA - called "nanocircles" - could help researchers learn more about the aging process in cells.

"In the long run, we have this dream of making laboratory cells live longer," said Eric Kool, a professor of chemistry at Stanford and co-author of the PNAS study. "We thought of this pie-in-the-sky idea several years ago, and we've been working toward it ever since."

All cells carry chromosomes - large molecules of double-stranded DNA that are capped off by single-strand sequences called telomeres. In their study, the research team successfully used synthetic nanocircles to lengthen telomeres in the test tube.

"The telomere is the time clock that tells a cell how long it can divide before it dies," Kool noted. "The consensus is that the length of the telomere helps determine how long a cell population will live, so if you can make telomeres longer, you could have some real biological effect on the lifespan of the cell. These results suggest the possibility that, one day, we may be able to make cells live longer by this approach."

Cellular death Human telomeres consist of chemical clusters called "base pairs" that are strung together in a specific sequence known by the initials TTAGGG. This sequence is repeated several thousand times along the length of the telomere. But each time a cell divides during its normal lifecycle, its telomeres are shortened by about 100 base pairs until all cell division finally comes to a halt.

"Suddenly there's a switch in the cell that says, 'It's time to stop dividing,'" Kool explained. "It's still not completely clear how that works, but it is clear that once telomeres reach the critically short length of 3,000 to 5,000 base pairs, they enter senescence and die."

In nature, a chromosome can be lengthened by the enzyme telomerase, which adds new TTAGGG sequences to the end of the telomere. But because telomerase is difficult to produce in the lab, Kool and his co-workers decided to create synthetic nanocircles that mimic the natural enzyme.

Each nanocircle consists of DNA base pairs arranged in a sequence that is complementary to the telomere. When placed in a test tube, the nanocircles automatically lengthen the telomeres by repeatedly adding new TTAGGG sequences.

"Nanocircles are so simple they're amazing," Kool observed. "Each nanocircle acts like a template that says, 'Copy more of that sequence.' In the test tube, we start with very short telomeres and end up with long ones that are easy to see under the microscope with fluorescent labeling. This suggests the possibility that one day we may be able to make cells live indefinitely and divide indefinitely, so they essentially become refreshed, as if they were younger."

Aging and cancer Kool pointed out that most cells have a limited lifespan, which is part of the normal aging process.

"The link between organism aging and cell aging is less clear, but there very likely is a link," he noted. "On the other hand, it is pretty clear that telomere length governs how long an individual cell lives."

In some diseases, such as premature aging (progeria) and cirrhosis, patients have cells with unusually short telomeres, Kool said. Cancer is another disease closely associated with telomere size.

"In order for a cell to become cancerous, one of the things it has to do is switch on the telomerase gene which makes the telomeres longer," he said. "The body has decided that the best way to keep an organism alive is to keep telomerase turned off, because otherwise you can get mutations and cancer too easily."

Because researchers need to study cells that live a long time, many labs rely on tumor-derived cells, which continuously divide and therefore are immortal. Kool predicted that nanocircle technology could one day provide an alternative method that would allow researchers to use healthy cells in their experiments instead of cancerous ones.

This is a very useful technique for aging research. For example, to test why younger stem cells can outcompete adult stem cells one could take adult bone marrow blood-forming stem cells, lengthen their telomeres, and then test to see if they can do just as well as clone embryo liver stem cells to outcompete adult stem cells that have not had their telomeres lengthened.

Even if telomere lengthening makes adult stem cells more able to replicate and even if this results in better body repair that doesn't mean that telomere lengthening would become a generally good thing to do to all adult stem cells in a human body. It is possible that telomere lengthening will allow cells that have otherwise damaged DNA to survive and to become cancerous. It is theorized that telomere shortening is a safeguard mechanism to help prevent cells from turning into cancer cells.

Another part of the puzzle needed to make a safe and effective rejuvenation therapy is the ability to sort thru adult stem cells and separate out the ones that have the least amount of DNA damage. Then one could take the better less damaged cells and extend the telomeres and reimplant them into the body. These more carefully selected cells would present less risk of becoming cancerous. To further reduce the risk of cancer from stem cells that have had their telomeres lengthened it will some day be possible to apply gene therapies that would repair a small number of locations in the genome where mutations contribute to the conversion of cells into cancers.

To summarize the significance of this latest report: This new technique for telomere lengthening will initially be useful to investigate the relative contribution that telomere shortening makes to cellular senescence. In the longer run it may also be useful in adult stem cell rejuvenation therapies and as part of organ replacement growth methods.

Share |      Randall Parker, 2002 November 20 10:45 AM  Aging Reversal

Jay Hicks said at September 1, 2003 7:53 PM:

How can I sign up to become a guinie pig for telomere lengthening?

Matthew Hudson said at September 20, 2003 1:17 PM:

Yes me too Please!!!

Connie Dee Scott said at September 22, 2003 6:16 AM:

Put me up next, I want to stick around for a while too!

greg said at April 8, 2006 2:30 PM:

i hope to test this out myself right after i finally clone some mice so that they have normal life spans

Robert Dinse said at November 17, 2007 1:17 AM:

"The body has decided that the best way to keep an organism alive is to keep telomerase turned off, because otherwise you can get mutations and cancer too easily."

This is a commonly held belief but there is much evidence to suggest that it is wrong.

Sharks have telomerese expressed in every cell and their telomeres do not shorten, yet cancer is extraordinarily rare among sharks and their genetic mutation rate very low. Similarly, young humans with long telomeres have much shorter rates than old humans with short telomeres but they have much lower cancer rates. Children with progeria, born with shorter telomeres, have high cancer rates as well as other normally age related diseases. The same is true of people with Werner's syndrome.

Most human cells have telomerese turned off; the exception to this is germ cell stem cells and stem cells responsible for making blood cells which have to reproduce rapidly because of the short lifespan of blood cells. Yet, leukemia is a much less common cancer than lung, stomach, co-rectal, liver, kidney, bladder, esophagal, and oral cancers involving normal somatic cells.

There is another reason I believe that telomerese is turned off in mammals, and I elaborate on it here: The reason in a nutshell is that it gave a survival advantage to groups in a rapidly changing environment at the expensive of individuals.

Randall Parker said at November 17, 2007 8:52 AM:

Robert Dinse,

Thanks very much for your comments. Some observations, I hope you'll react:

1) I've read that mutation to activate telomerase is one of the mutations needed for cancers to grow far enough to kill a person. True or false?

2) I've read that a large fraction of cancers actually come from stem cells mutating. If so the point about leukemia does not sound quite as convincing.

3) I've also read that stem cells make telomerase. True or false?

4) I've also read that one of the reasons cancer becomes more prevalent with age is accumulation of mutations. Long telomeres among the young then are less risk than long telomeres among the old.

5) I've also read that immune system decay as we age increases the risk of cancer. Some interesting research out of Zheng Cui's lab at Wake Forest suggests this. So, again, long telomeres would seem less risky among the young.

Jason Striggs said at March 8, 2010 9:25 PM:

Has anything happened in this field recently?

Jason Striggs said at April 3, 2010 4:20 PM:

Some interesting potential for a new telomere lengthening supplement at Regenorex. Looks like it is supposed to work by activating telomerase, but it seems the product is not shipping yet. The studies on the site are interesting, though.

Jessica R said at September 23, 2010 12:53 PM:

Hello everybody,
I would love for this telomere lengthening supplement to be released. Many people may think this immortality option is wrong but I say its time for those king of people to shut the f-ck up, those who want this should be able to get it no matter what, I personally have wanted immortality my whole life Iíve always wanted it and still do and plan to, and if there is a way I would love to be a part of what ever it is to get it, there may be these theories about disease are more easier to get and all that but blah blah I think immortality holds a lot more to it than meets the eye. I have a feeling in my gut that says once your immortal nothing could touch you, which I do have to relate to vampirism which I think is possible although we may be able to live without having to have blood though. This can be nice. But I do have a strong faith in scientist for doing this miracle, I think they need to pay all there attention toward immortality screw everything else. Even though the religious people in the world and politicians may get angry about the scientist doing this well f-ck them as Iíve always noticed and said its time for everybody thatís standing in scienceís way to step aside, they need to let science take over I find even though this may be greedy but its true if you all just look at everything science has done Iím sure youíll find information on how people and culture have gotten in there way and I am very pist off about this and I hope a lot of you can agree with the way I feel. And If you do then we can believe in scientist and theyíll see and be boosted with confidence to give up and help us with what we want. Cause of all things in this world and even beyond this world I wish to have that one wish which I would choose immortality and Iím not even that old Iím only 18 now which I turned not to long ago which like I said Iíve always wanted this and nothing and no one will change my mind and please if there is someone that agrees with me and believes in the same thing as I do please contact me here please I hope Iím not alone. I will sacrifice everything whenever to get this immortality and forever stay the way I am I have the fear of death as many and I donít think immortality as a crutch to take away the fear cause that is complete bull-sh-t. So please anybody please believe the same. Cause together we shall all be stronger.

Sincerely: Jessica Rousseau of Colorado on September 23, 2010

Nick G said at September 23, 2010 3:21 PM:

Go Jessica!

Dale M. II said at April 19, 2011 11:05 AM:

Is there any logical thought in the idea of lengthening and or reactivating telomere for new cell production in order to reestablish a connection between the nerve endings of freshly dead tissue and the brain?

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