Extra-telomeric benefits of telomerase – good news for telomerase activators

I am concerned that the popular view of telomerase activation is too simplistic and misses many the main benefits.  The popular view is that exogenously-activated telomerase extends telomeres (the endcaps of chromosomes) thus allowing cells to reproduce beyond the normal “Hayflick” limit of 50-70 reproductions  Therefore, by activating telomerase it may be possible to extend the lives of cell lines, and therefore the lives of organs, and therefore also the lives of animals including people.  This story is the one that got me into anti-aging science 15 years ago, still may be valid, and still inspires me.  However, it completely misses characterizing other recently-discovered health and longevity-producing benefits of telomerase, benefits that could turn out in the long run to be as or more important than telomere extension.  I review some of those benefits here. 

1.   Telomerase expression does not always lengthen telomeres.  When a cell is under stress, telomerase (actually its catalytic subunit TERT) migrates into the mitochondria.  There TERT plays a DNA-protective role and improves mitochondrial functioning. 

“While TERT maintains telomere length under standard conditions, telomeres under increased stress shorten as fast as in cells without active telomerase. This is because TERT is reversibly excluded from the nucleus under stress in a dose- and time-dependent manner. Extranuclear telomerase colocalises with mitochondria. In TERT-overexpressing cells, mtDNA is protected, mitochondrial membrane potential is increased and mitochondrial superoxide production and cell peroxide levels are decreased, all indicating improved mitochondrial function and diminished retrograde response. We propose protection of mitochondria under mild stress as a novel function of TERT(ref).”  Several other recent research reports supports this finding.  For example, see the June 2009 publication Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage.  Here is a May 2009 review study on the same issue. 

2.   Over- expression of telomerase can extend the lives as well as proliferation capability of adult of stem cells . 

“We have recently demonstrated that overexpression of human telomerase reverse transcriptase (hTERT) in hMSC (human mesenchymal stem cells) reconstitutes telomerase activity and extends life span of the cells.” – “Thus, telomerization of hMSC (by hTERT overexpression maintains the stem cell phenotype of hMSC and it may be a useful tool for obtaining enough number of cells with a stable phenotype for mechanistic studies of cell differentiation and for tissue engineering protocols(ref).”  As I said in my treatise “Loss of adult stem cells via telomere attrition provides strong selection for senescent, cycle-arrested, abnormal and malignant somatic cells, producing vulnerability to the diseases of old age.”  So keeping up expression of  telomerase in adult stem cells via telomerase activation could be very important for longevity.

3.   Telomerase promotes the differentiation of stem cells through a mechanism independent of telomere extension. 

Again, TERT does the job independently of telomere extension.   “We show that TERT(ci) retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis(ref).   And I am continuing to get more hair on top of my head as a result of telomerase activation as previously mentioned in this blog. And I can’t help but mention the shaggy mouse story yet again.  I have no doubt that telomerase promotes the differentiation of other kinds of stem and progeniotor cells as well, but the research literature related to this is just starting to appear.   

One tantalizing study I just ran across says that transduction with human telomerase has opposite effects on healthy and cancerous nerve stem cells(ref).  On the one hand “Neural progenitor cells (NPCs) transduced with human telomerase reverse transcriptase (hTERT), the catalytic component of telomerase, have the potential both to proliferate indefinitely in vitro and to respond to differentiation signals necessary for generating appropriate cells for transplantation.”  And on the other hand,  for the cancerous NT2 cell line,  “– following hTERT transduction. RT-PCR and telomerase activity data demonstrated that persistent exogenous hTERT expression significantly inhibited the differentiation of neurons from NT2 cells. Following retinoic acid induced differentiation, hTERT-NT2 cells produced only one fourth of the neurons generated by parental and vector-control cells.”   

Not only does exogenous telomerase support the proliferation and differentiation of  healthy stem cells, but it also inhibits the differentiation of cancer stem cells.  NT2 is a neuronally committed human teratocarcinoma cell line.  I have to say this finding partially puts to rest a concern I have expressed in this blog – that telomerase activation may activate cancer stem cells.  We will have to see how telomerase activation works in the case of other cancer stem cell types.   

I have mentioned the role of telomerase in promoting stem cell differentiation before, both in my treatise and in blog posts, though it seems not to have been taken up in other anti-aging blogs.  It is important because longevity of organisms, people in particular may in fact more depend more on continuing differentiation of adult stem cells than on the number of times mature adult somatic cells reproduce.  See the 14th theory of aging in my treatise Decline in Adult Stem Cell Differentiation.   

To editorialize a bit I feel strongly that it if we want to understand aging we have to go beyond looking at it only through the filter of a single theory like Telomere Shortening and Damage.  “There are more things in heaven and earth, Horatio, than are dreamt of in your philosophy.”  (words of Shakespeare spoken by Hamlet).  The Decline in Adult Stem Cell Differentiation theory provides a new and refreshing view of aging, one synergistic with the Telomere Shortening and Damage theory. 

4.   When considering telomeres. Not only lengths but absence of DNA damage is important for healthy cell reproduction and avoidance of cellular senescence. 

Cellular senescence can be triggered by either too-short telomeres or by unrepaired nuclear DNA damage .  Mitochondrial health and telomeric health seem to be bound up with each other.  “Firstly, it has been established that telomere shortening, which is the major contributor to telomere uncapping, is stress dependent and largely caused by a telomere-specific DNA single-strand break repair inefficiency. Secondly, mitochondrial DNA (mtDNA) damage is closely interrelated with mitochondrial ROS production, and this might also play a causal role for cellular senescence.” – “Together, these data suggest a self-amplifying cycle between mitochondrial and telomeric DNA damage during cellular senescence(ref).”  Going back to the first point above, TERT that has migrated to the mitochondria under conditions of cellular stress can protect the DNA there averting signaling that results in telomere shortening. Activated telomerase works indirectly to keep telomeres from shortening under conditions of stress.  This demonstrates an inter- relationship between four of the theories of aging in my treatise Oxidative Damage, Cell DNA Damage, Mitochondrial Damage , and Telomere Shortening and Damage. 

In the light of the above, I am not excessively concerned about whether telomere lengthening is happening in me as a result of my taking the astragaloside IV telomerase activator.  The other benefits are likely to be worthwhile by themselves.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com. Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.
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3 Responses to Extra-telomeric benefits of telomerase – good news for telomerase activators

  1. Mike says:

    As usual great work Vince, I love reading your posts and I find them very imformative.
    I am however confused by this paragraph and hope you would explain it in greater detail.
    “Not only does exogenous telomerase support the proliferation and differentiation of healthy stem cells, but it also inhibits the differentiation of cancer stem cells. NT2 is a neuronally committed human teratocarcinoma cell line. I have to say this finding partially puts to rest a concern I have expressed in this blog – that telomerase activation may activate cancer stem cells. We will have to see how telomerase activation works in the case of other cancer stem cell types.”
    Thanks Mike

  2. admin says:

    Hi Mike

    ““Not only does exogenous telomerase support the proliferation and differentiation of healthy stem cells, but it also inhibits the differentiation of cancer stem cells.” Differentiation of normal stem cells is important for health and declines with age. My 14th theory of aging in my treatise is DECLINE IN ADULT STEM CELL DIFFERENTIATION, so promotion of such differentiation for aging people may be critical for longevity. The research cited in the post shows that the telomerase component TERT also inhibits the differentiation of NT2.
    “NT2 is a neuronally committed human teratocarcinoma cell line.” says that NT2 is a cancer found only in human neurons.
    “I have to say this finding partially puts to rest a concern I have expressed in this blog – that telomerase activation may activate cancer stem cells. We will have to see how telomerase activation.” In my blog post last week called Telomerase activation – upside and downside, I expressed a concern that my taking a telomerase activator may have contributed to an occurence of a skin cancer found a few weeks ago, because the telomerase activator may have triggered differentiation of cancer skin stem cells. The research cited in the current post shows that, at least for the NT2 cancer, telomerase activation produces the opposite effect – decreases differentiation of the cancer stem cells. Further research will be needed to prove out that this is also the case for other cancer lines,

  3. Mike says:


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