• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo

Telomerase Therapies and Cancer Risk


  • Please log in to reply
9 replies to this topic

#1 reason

  • Guardian Reason
  • 1,101 posts
  • 241
  • Location:US

Posted 24 April 2015 - 10:17 PM


To date progress in the development of stem cell treatments has been accompanied by a markedly lower risk of cancer than was expected at the outset. The characteristic decline in stem cell activity with age is believed to be an evolutionary adaptation that reduces cancer risk: there is a balance between on the one hand the risk of cancer due to over-active damaged cells, and on the other hand the failure of tissues and organs due to loss of maintenance activities on the part of stem cells. It is the responsibility of stem cells to deliver supplies of fresh, fit cells as needed to replace those that have become damaged, worn, or have reached the inherent limits imposed on replication of somatic cells. That supply tapers off in old age, however, as stem cells gather damage and spend ever more time quiescent rather than active.

Despite the comparative lack of cancer resulting from stem cell therapies, there is still every reason to expect that caution should attend the development of any therapy that spurs greater regeneration in old tissues. The cells in those tissues have a higher load of nuclear DNA damage, and thus a greater cancer risk attends their activity. Yet in practice it isn't working out to be as great a risk as expected, or at least not so far based on the date gathered to date. Why this is the case is an interesting question with no solid answer at this time.

The replication limits of somatic cells depend in part on telomere shortening. Telomeres are repeated lengths of DNA at the ends of chromosomes. A little of that length is lost with each cell division, and very short telomeres trigger cellular senescence or programmed cell death. In comparison stem cells retain long telomeres, and thus the ability to continually create new daughter somatic cells with long telomeres to deliver into the tissues they support. This maintenance of telomere length in stem cells is achieved through the activity of telomerase, an enzyme that adds repeated DNA sequences to the ends of chromosomes.

Based on all of the above, it is not unreasonable to expect that more telomerase activity in more cells would mean a greater risk of cancer. It would mean cells being more active, and older, more damaged cells being more active. In mice, however, this is not what happens. The risk of cancer actually falls, even as life span is lengthened: researchers believe there is increased stem cell activity and tissue maintenance, but not enough time in even the extended mouse life span for the other shoe to drop and cancer risk to catch up. A firm and comprehensive analysis of what exactly is going on inside these mice is probably still a few years away, however. Nonetheless, the picture painted above suggests that we should be cautious about extrapolating a beneficial balance of time and cellular activity in mice to indicate that telomerase treatments would be similarly great for humans. The span of time is different, our telomere biology is different, and the balance of aging and cell activity is different.

On the other hand, the medical community seems to be doing pretty well with stem cell treatments that are just another way of spurring increased cell activity and tissue maintenance in old, damaged tissues. Enhanced telomerase activity seems worthy of further investigation for all the same reasons that stem cell therapies were worthy of clinical development. I don't see telomerase therapies as a treatment for aging per se, however. The approach of increased telomerase activity doesn't address the underlying issues that cause stem cell decline, but instead forces damaged cells to get back to work by overriding the normal reactions of an aged biochemistry. In the view of aging as accumulated cellular damage, stem cell failure with age is an evolved reaction to an increasingly damaged tissue environment. The best way forward is to repair that environment, not override the signals. As first generation stem cell treatments have shown, however, it is possible to achieve beneficial results by taking this path, even while failing to address the root causes of aging. Benefits are good, but we shouldn't let them distract us from the end goal.

Telomerase does Not Cause Cancer

I am one of a growing minority of life extension scientists who believe that telomerase may be our most promising, near-term path to a major boost in the human life span. Notably, almost all the scientists who specialize in telomere biology have come to this opinion. But research investment in this strategy has been limited and the main obstacle has been fear of cancer. Back in 1990, a young Carol Greider was the first to float the idea that the reason that man and most other mammals have evolved with short telomeres is to help protect against cancer. Independently in 1991, senior geneticist Ruth Sager proposed the same hypothesis with more detail, citing circumstantial evidence. Inference of evolutionary purpose is of necessity indirect.

The idea that lengthening telomeres poses a danger of cancer took a life of its own, based on marginal experimental data and firm grounding in a theory that is fundamentally flawed. It is now taken for granted in publications, and only token documentation and no reasoning is provided when this view is asserted. I believe that this concern is misplaced, that activating telomerase will actually reduce net cancer risk, and that the fear of cancer is damping the enthusiasm that telomere science so richly deserves.

I have written a technical article on this subject. There are forces at work here in opposite directions:

(Bad #1) Once a cell becomes cancerous, it can only continue to grow if it has telomerase. So giving the cell telomerase removes one barrier to malignancy.

(Bad #2) Secondary to its role in growing telomeres, the telomerase component hTERT also functions as a kind of growth hormone, that can promote malignancy.

(Good #1) The body's primary defense against cancer is the immune system. As we get older, our blood stem cells slow down because their telomeres are too short. Telomerase rejuvenates the immune system, and helps the body fight cancer before it gets started.

(Good #2) When telomeres in a cell get too short, the cell goes into a "senescent" state, in which it spits out hormones (called "cytokines") that raise inflammation throughout the body and damage cells nearby. Telomerase protects against this.

(Good #3) When telomeres in a cell get too short, the cell's chromosomes can become fragmented and unstable, and this can lead to cancer. Telomerase protects against this.

I believe that the three "goods" far outweigh the risk from the two "bads". In animal experiments this seems to be the case, and I think that the "theoretical" reasons for concern are based on discredited theory. Of course, we won't know for sure until we have more experience with humans.

It's a modestly long post, and worth reading. Bear in mind the author is coming at this from a programmed aging point of view, however. In this perspective, aging is not an accumulation of cell and tissue damage that leads to dysfunction, but is rather an evolved program of dysfunction that causes cell and tissue damage. In the programmed aging view, the right approach to treating aging is to alter levels of proteins to make the cellular environment more youthful in appearance, at which point damage will be repaired. In the aging as damage viewpoint, tinkering with the cellular environment has only limited utility and the right approach is to repair damage. Given sufficiently good repair, the reactions to damage will cease and the tissue environment will become more youthful in operation and appearance.


View the full article at FightAging
  • like x 1
  • Disagree x 1

#2 corb

  • Guest
  • 507 posts
  • 213
  • Location:Bulgaria

Posted 25 April 2015 - 07:28 PM

 

(Bad #1) Once a cell becomes cancerous, it can only continue to grow if it has telomerase. So giving the cell telomerase removes one barrier to malignancy.

(Bad #2) Secondary to its role in growing telomeres, the telomerase component hTERT also functions as a kind of growth hormone, that can promote malignancy.

(Good #1) The body's primary defense against cancer is the immune system. As we get older, our blood stem cells slow down because their telomeres are too short. Telomerase rejuvenates the immune system, and helps the body fight cancer before it gets started.

(Good #2) When telomeres in a cell get too short, the cell goes into a "senescent" state, in which it spits out hormones (called "cytokines") that raise inflammation throughout the body and damage cells nearby. Telomerase protects against this.

(Good #3) When telomeres in a cell get too short, the cell's chromosomes can become fragmented and unstable, and this can lead to cancer. Telomerase protects against this.

 

What if we consider a more recent tumorogenesis theory?

http://www.ncbi.nlm....les/PMC3941741/

 

If the main reason for cancer isn't nDNA mutation but mtDNA mutation, telomerase would neither inhibit nor enable malignancy significantly.

So in that case with cancer almost completely out of the picture we are left with only Good#2 and Good#1. And maybe with a Good#4 in the form of long telomeres giving added defense against unwaranted epigenetic modification which seem to happen in the presence of short telomeres in later life.

 

Either way it's interesting what would happen if/when the telomeres of a middle aged human are lengthened. Actually if we consider the article I posted then we get back to a mainly mitochondrialy driven aging theory and in that case it really shouldn't do much, if anything. But it's still an interesting area for research.


Edited by corb, 25 April 2015 - 07:30 PM.

  • Informative x 2

Click HERE to rent this BIOSCIENCE adspot to support LongeCity (this will replace the google ad above).

#3 xEva

  • Guest
  • 1,594 posts
  • 24
  • Location:USA
  • NO

Posted 27 April 2015 - 01:05 PM

What if we consider a more recent tumorogenesis theory?


It's not recent, but a reiteration of "Warburg effect", which this group keeps on publishing, with minor variations, through the years. I find it strange that they don't even bother to bring up and discuss the common objections to this old idea, the first of which is that cancer cells often have perfectly normal mitochondria, but use glycolysis, because that's a normal metabolic pathway for the tissues undergoing rapid growth (i.e. they need not as much ATP as they need building materials to sustain their growth, and somehow --I myself don't know how :)-- glycolysis allows for that while cellular respiration does not).

the good thing is they keep criticizing the prevalent theory of cancer origins though

#4 corb

  • Guest
  • 507 posts
  • 213
  • Location:Bulgaria

Posted 27 April 2015 - 01:56 PM

 

What if we consider a more recent tumorogenesis theory?


It's not recent, but a reiteration of "Warburg effect", which this group keeps on publishing, with minor variations, through the years. I find it strange that they don't even bother to bring up and discuss the common objections to this old idea, the first of which is that cancer cells often have perfectly normal mitochondria, but use glycolysis, because that's a normal metabolic pathway for the tissues undergoing rapid growth (i.e. they need not as much ATP as they need building materials to sustain their growth, and somehow --I myself don't know how :)-- glycolysis allows for that while cellular respiration does not).

the good thing is they keep criticizing the prevalent theory of cancer origins though

 

 

 

 

Mitochondrial structure is intimately connected to mitochondrial function. This fact cannot be overemphasized. We have reviewed substantial evidence of morphological, proteomic, and lipidomic abnormalities in mitochondria of numerous types of cancer cells (17,85,91). Tumor cells can have abnormalities in both the content and composition of their mitochondria. The work of Arismendi-Morillo and Oudard et al. showed that the ultrastructure of tumor tissue mitochondria differs markedly from the ultrastructure of normal tissue mitochondria (17,92–94). In contrast to normal mitochondria, which contain numerous cristae, mitochondria from tumor tissue samples showed swelling with partial or total cristolysis (Figure 2). Cristae contain the proteins of the respiratory complexes and play an essential structural role in facilitating energy production through OxPhos (95). The structural defects in human glioma mitochondria are also consistent with lipid biochemical defects in murine gliomas (96,97).



#5 xEva

  • Guest
  • 1,594 posts
  • 24
  • Location:USA
  • NO

Posted 28 April 2015 - 12:17 AM

What if we consider a more recent tumorogenesis theory?


It's not recent, but a reiteration of "Warburg effect", which this group keeps on publishing, with minor variations, through the years. I find it strange that they don't even bother to bring up and discuss the common objections to this old idea, the first of which is that cancer cells often have perfectly normal mitochondria, but use glycolysis, because that's a normal metabolic pathway for the tissues undergoing rapid growth (i.e. they need not as much ATP as they need building materials to sustain their growth, and somehow --I myself don't know how :)-- glycolysis allows for that while cellular respiration does not).

the good thing is they keep criticizing the prevalent theory of cancer origins though

 
 

Mitochondrial structure is intimately connected to mitochondrial function. This fact cannot be overemphasized. We have reviewed substantial evidence of morphological, proteomic, and lipidomic abnormalities in mitochondria of numerous types of cancer cells (17,85,91). Tumor cells can have abnormalities in both the content and composition of their mitochondria. The work of Arismendi-Morillo and Oudard et al. showed that the ultrastructure of tumor tissue mitochondria differs markedly from the ultrastructure of normal tissue mitochondria (17,92–94). In contrast to normal mitochondria, which contain numerous cristae, mitochondria from tumor tissue samples showed swelling with partial or total cristolysis (Figure 2). Cristae contain the proteins of the respiratory complexes and play an essential structural role in facilitating energy production through OxPhos (95). The structural defects in human glioma mitochondria are also consistent with lipid biochemical defects in murine gliomas (96,97).



-?? and how this quote addresses the question I brought up?

Their focusing on cancers with damaged mitochondria says nothing about the cancers in which mitochondria are fine. It is these cancers that tend to survive both fasting and various forms of chemo. And the point is, they survive precisely because of their functioning mitochondria. You can just search pubmed on mitochondria and chemo-resistant cancers.

#6 niner

  • Guest
  • 16,276 posts
  • 2,000
  • Location:Philadelphia

Posted 28 April 2015 - 01:16 AM

I searched chemoresistance and mitochondria, and while I didn't see anything obviously stating that chemoresistant cells had perfectly normal mitochondria, I did run across this, which says that dysfunctional mitochondria can cause chemoresistance.
 

Biochem Pharmacol. 2014 Nov 1;92(1):62-72. doi: 10.1016/j.bcp.2014.07.027. Epub 2014 Aug 12.
Mitochondrial dysfunction in cancer chemoresistance.
Guaragnella N1, Giannattasio S2, Moro L1.

Mitochondrial dysfunction has been associated with cancer development and progression. Recent evidences suggest that pathogenic mutations or depletion of the mitochondrial genome can contribute to development of chemoresistance in malignant tumors. In this review we will describe the current knowledge on the role of mitochondrial dysfunction in the development of chemoresistance in cancer. We will also discuss the significance of this research topic in the context of development of more effective, targeted therapeutic modalities and diagnostic strategies for cancer patients, with a particular focus on the potential use of PARP inhibitors in cancer patients displaying mitochondrial DNA mutations. We will discuss recent studies highlighting the importance of the cross-talk between the tumor microenvironment and mitochondrial functionality in determining selective response to certain chemotherapeutic drugs. Finally, owing to the similarities between cancer and yeast cell metabolism, we will point out the use of yeast as a model system to study cancer-related genes and for anti-cancer drugs screening.

PMID: 25107705


  • Informative x 1

Click HERE to rent this BIOSCIENCE adspot to support LongeCity (this will replace the google ad above).

#7 xEva

  • Guest
  • 1,594 posts
  • 24
  • Location:USA
  • NO

Posted 28 April 2015 - 03:16 AM

You picked a wrong paper. This one focuses specifically on "mitochondrial dysfunction and its role in the development of chemoresistance". When I looked (after reading about a 4yo paper by the same group), the question I pursued was how cancers could survive nutrient deprivation and ketosis of starvation --with dysfunctional mitochondria!-- since, according to this Warburg hypothesis, they should not. But of course, I found out, they do just fine. To my surprise (and consequent disappointment in this idea) the studies I read stated matter-of-factly that cancers survive chemo, low levels of glucose and drugs blocking glycolysis by upregulating their mitochondrial function.

See, if cancer was simply a matter of mitochondrial dysfunction, as this paper suggests, then simply forcing cancerous cells to switch to cellular respiration would be enough of a treatment, right? But while such methods exist and are not without some merit, they are hardly a panacea.

And then I came across studies that stated exactly what I said in my first post above, i.e. cancer cells prefer glycolysis, because this is the right metabolic pathway for cells undergoing quick expansion. This naturally casts doubts on validity of 'Warburg effect' -- apparently not all cancers use glycolysis because they can't respire. Apparently, some can, but prefer not to.

Edited by xEva, 28 April 2015 - 03:36 AM.

  • Informative x 1
  • like x 1

#8 xEva

  • Guest
  • 1,594 posts
  • 24
  • Location:USA
  • NO

Posted 28 April 2015 - 06:28 AM

Ah sorry, I read more of this paper, and they do address some of the criticisms this time:
 

Much of the evidence arguing against Warburg’s central theory that respiratory insufficiency is the origin of the aerobic fermentation seen in cancer cells (Warburg effect) was derived from investigations of tumor cells grown in vitro (64,78,79,108–110). ... The presence of mitochondria and robust oxygen consumption rates in tumor cells grown in vitro suggested to some that mitochondria are normal in tumor cells and that Warburg’s central theory was incorrect (64,81,109).


Though this is an academic debate and any layman is free to pick either side to cheer or boo, to me this group sounds like sore losers:

First they argue that functional mitochondria may be a feature of cancer cells grown in vitro only (which fails to explain why cancers survive starvation in vivo). Then look how they address the 'Crabtree effect', which "involves a glucose-induced suppression of respiration leading to lactate production whether or not mitochondria are damaged":
 

"The Crabtree effect differs from the Warburg effect, which involves lactate production arising from insufficient respiration. In other words, the aerobic lactate produced under the Crabtree effect arises from a suppressed respiration rather than from insufficient respiration as occurs in the Warburg effect. [lol] It can be difficult to determine with certainty, however, whether the aerobic fermentation (aerobic glycolysis) observed in cultured cells arises from a Crabtree effect, a Warburg effect or some combination of these effects."


Finally, they say that "human tumor cells when grown as xenografts" on immune-deficient mouse "can alter their gene expression patterns and growth behavior" thus rendering it invalid model either. etc. etc.

I have a nagging suspicion that this group is affiliated with a cancer clinic where fasting is combined with "non-toxic agents affecting metabolism", and insistence on the idea that cancer as a metabolic disease of dysfunctional mitochondria with papers like this is their way to promote it.


@niner, for you:
 

http://www.ncbi.nlm....pubmed/15475456

Imatinib (STI571)-mediated changes in glucose metabolism in human leukemia BCR-ABL-positive cells.

Gottschalk S1, Anderson N, Hainz C, Eckhardt SG, Serkova NJ.

Abstract
The therapeutic efficacy of imatinib mesylate (Gleevec) is based on its specific inhibition of the BCR-ABL oncogene protein, a widely expressed tyrosine kinase in chronic myelogenous leukemia (CML) cells. The goal of this study was to evaluate glucose metabolism in BCR-ABL-positive cells that are sensitive to imatinib exposure. ... In BCR-ABL-positive cells, the relevant therapeutic concentrations of imatinib (0.1-1.0 micromol/L) decreased glucose uptake from the media by suppressing glycolytic cell activity ... Additionally, the activity of the mitochondrial Krebs cycle was increased ... The improvement in mitochondrial glucose metabolism resulted in an increased energy state ... Unlike standard chemotherapeutics, imatinib, without cytocidal activity, reverses the Warburg effect in BCR-ABL-positive cells by switching from glycolysis to mitochondrial glucose metabolism, resulting in decreased glucose uptake and higher energy state.


Edited by xEva, 28 April 2015 - 06:38 AM.

  • Informative x 1

#9 corb

  • Guest
  • 507 posts
  • 213
  • Location:Bulgaria

Posted 28 April 2015 - 12:17 PM

I was more interested in their conclusion as to what starts the cancers not so much the metabolic properties the cancer exhibits after. Or the possibility to treat it with a diet, or metabolism modifying agents - which is done either way and shows some results but not enough to warrant any significant attention either way.

 

What I was saying is this - It's suspicious if telomeres have a significant cancer protective property if the cancer is initiated by damaged mitochondria in vivo, or more precisely instead of looking at cancer as wear and tear of nDNA, we should consider it could be wear and tear to mtDNA or proteostasis which then leads to a sudden insult to nDNA, grave enough to create a cancer cell - the cancer is still a result of nDNA mutation, but it's not a mutation that can conceivably happen in a slow process, there are too many safeguards (on the nuclear side at least) for that to be a possibility.

Of course we could argue telomeres are one of those safeguards but the fact is, cancer can proliferate without telomerase also. A safeguard against fast proliferation which can be so easily jumped over is more or less useless in the grand scale of things. And the notion cancers could be stopped if they suffer insult to their DNA is suspicious in itself, typically that is when cancers strive the most.

 

Either way it's too complex of a topic for even the scientific community to ponder over without empirical experimentation. Which is why they should experiment, it's faster.



Click HERE to rent this BIOSCIENCE adspot to support LongeCity (this will replace the google ad above).

#10 corb

  • Guest
  • 507 posts
  • 213
  • Location:Bulgaria

Posted 28 April 2015 - 05:21 PM

As a little addendum:

What I consider important in the working of the mitochondria isn't their ability to respirate.

It's the ability to initiate apoptosis and their misfolded protein response.


Edited by corb, 28 April 2015 - 05:22 PM.





0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users