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Telomere length predicts cancer risk

telomeres cancer

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#1 Hebbeh

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Posted 03 April 2017 - 11:11 PM


https://www.scienced...70403083123.htm

 

Telomere length predicts cancer risk

 

April 3, 2017

University of Pittsburgh Schools of the Health Sciences

 

Longer-than-expected telomeres -- which are composed of repeated sequences of DNA and are shortened every time a cell divides -- are associated with an increased cancer risk, according to research led by scientists from Pitt and Singapore.

"Telomeres and cancer clearly have a complex relationship," said Jian-Min Yuan, M.D., Ph.D., who holds the Arnold Palmer Endowed Chair in Cancer Prevention at UPCI and is lead or senior author on two studies being presented at AACR. "Our hope is that by understanding this relationship, we may be able to predict which people are most likely to develop certain cancers so they can take preventive measures and perhaps be screened more often, as well as develop therapies to help our DNA keep or return its telomeres to a healthy length."

 

The length of the 'caps' of DNA that protect the tips of chromosomes may predict cancer risk and be a potential target for future therapeutics. Longer-than-expected telomeres -- which are composed of repeated sequences of DNA and are shortened every time a cell divides -- are associated with an increased cancer risk.

The length of the telomere "caps" of DNA that protect the tips of chromosomes may predict cancer risk and be a potential target for future therapeutics, University of Pittsburgh Cancer Institute (UPCI) scientists will report today at the AACR Annual Meeting in Washington, D.C.

Yuan and his colleagues analyzed blood samples and health data on more than 28,000 Chinese people enrolled in the Singapore Chinese Health Study, which has followed the health outcomes of participants since 1993. As of the end of 2015, 4,060 participants had developed cancer.

Participants were divided into five groups, based on how much longer their telomeres were than expected. The group with the longest telomeres had 33 percent higher odds of developing any cancer than the group with the shortest telomeres, after taking into account the effect of age, sex, education and smoking habits. That group also had 66 percent higher odds of developing lung cancer, 39 percent higher odds of developing breast cancer, 55 percent higher odds of developing prostate cancer and 37 percent higher odds of developing colorectal cancer. Of all the cancers, pancreatic had the largest increase in incidence related to longer telomeres, with participants in the highest one-fifth for telomere length at nearly 2.6 times the odds of developing pancreatic cancer, compared to those in the lowest one-fifth for telomere length. Only the risk of liver cancer went down with longer telomeres.

 

For three cancers, the risk was greatest for both the groups with extreme short and extreme long telomeres -- creating a "U-shaped" risk curve. Participants in the group with the shortest telomere length had 63 percent higher odds of stomach cancer, 72 percent higher odds of bladder cancer and 115 percent higher odds of leukemia than the group in the middle of the curve. The group with the longest telomeres had 55 percent higher odds of stomach cancer, 117 percent higher odds of bladder cancer and 68 percent higher odds of leukemia.

 

Story Source:

Materialsprovided by University of Pittsburgh Schools of the Health Sciences.


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#2 Darryl

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Posted 30 July 2017 - 04:14 PM

More bad news. Longer telomeres don't just predict, but can be inferred as causal in cancer risk, in this Mendelian randomization study. On the other hand, they appear causally protective in coronary heart disease, abdominal aortic aneurysm, celiac disease, and especially protective in interstitial lung disease.

 

Burgess et al 2017.  Mendelian randomization study of the association between telomere length and risk of cancer and non-neoplastic diseasesJAMA Oncology https://doi.org/10.1...oncol.2016.5945

Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).

 

 


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#3 hav

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Posted 31 July 2017 - 01:52 AM

The basic logic of this study appears to be severely twisted.  They didn't study telomere length in isolation, but "after taking into account the effect of age, sex, education and smoking habits."  Telomere length is generally understood to be directly associated with age. So if they took age into account, would that zero out any observations due to telomere length differences?  If so, the rest of the study is toast. Haven't seen a telomere study relating length to gender... would expect longer telomeres in females based on longer life expectancy.  Education?  You got to be kidding me.  Maybe for meditation majors?  Smoking habits would be interesting to study to see if telomere elongation might be protective. Oxidative stress studies suggest that would be the case. 

 

Howard


Edited by hav, 31 July 2017 - 01:53 AM.

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#4 Nate-2004

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Posted 03 August 2017 - 03:58 PM

Hrm, that cancer uses telomerase to lengthen telomeres for infinite cell divides does not mean longer telomeres or having more telomerase activity causes cancer.

 

Some theories do suggest that the Hayflick limit is there to prevent diseases like cancer and other maladaptive mutations, but maybe getting around that involves improving DNA repair (SIRT) activity along with telomerase activity.



#5 Darryl

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Posted 03 August 2017 - 06:03 PM

does not mean longer telomeres or having more telomerase activity causes cancer.

 

That's precisely what a Mendelian randomization study permits us to infer.

 

However, its worth noting that the cancers with the strongest inferred causation don't include many more common lethal cancers (colorectal, breast, prostate, leukemia, liver, Non-Hodgkin's lymphoma), and appears to be limited to tissues with lower rates of stem cell division. The main exception is adenocarcinoma of the lung, which is the most common lung cancer in never-smokers.

 

Given that there was a marked reduction in far more likely causes of death (coronary artery disease, abdominal aortic aneurysm), the net effect of longer telomeres may still be net positive on mortality.


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#6 Benko

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Posted 06 August 2017 - 02:23 AM

Not my area of expertise but looks like it is addressed here by Josh Mitteldorf (aging matters) (spoiler does not cause cancer):

 

https://joshmitteldo...f-a-good-thing/


Edited by Benko, 06 August 2017 - 02:36 AM.

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#7 OP2040

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Posted 26 April 2018 - 08:35 PM

Would like to revive this thread.  I've debated whether to take cycloastragenol for a long time but I am concerned about the cancer risk.

 

A lot of people including myself, have referenced a couple studies that showed lots of longevity increase in mice, with no additional cancer burden.  Well, the problem with these studies is that they are using a specific methodology that may not translate to supplementation with cycloastragenal, for example. 

 

They use AAV transfection of hTERT in mature mice.  There are a number of reasons why this matters, according to the study itself.  First, the good news.  Many of the previous studies showed an increase in cancer because they were expressing hTERT from birth in the germline.  This is so far from what we want to do that we can basically toss those studies out.  However, here is the bad news, which I will quote:

 

 

Importantly, AAV9-mTERT treated mice do notdevelop more cancer, illustrating the safety of this type of strategy. This is likely to be related to the fact that AAV vectors are non-integrative, and therefore mTERT over-expression will be lost in highly proliferating cells. In addition, AAV preferentially targets post-mitotic cells from peripheral tissues,which are considered more resistant to cancer than the highly proliferative ones, and could explain the tissue contribution for healthspan amelioration. Indeed, the limited gene transfer tosome tissues (such as the brain) could account some of the modest effects observed.

 

This small snippet changes A LOT when it comes to using cycloastragenol or any supplementary strategy.  We don't know a lot of the details about when/how/where it activates telomarase.  I do remember reading something about cyclo or some other substance that did preferentially increase shorter telomeres.  But many of the non-TERT studies don't measure much more than LTL, which makes the situation of ignorance even worse.  Now I'm wondering if they even tested other tissues aside from leukocytes when they were developing it.

 

I'm still 80% leaning toward taking it but it will definitely be a temporary intervention.

Thoughts?



#8 QuestforLife

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Posted 30 April 2018 - 08:40 AM

Well cycloastragenol is only a supplement not a gene therapy; it's highly unlikely to have an effect on telomeres once you stop taking it.

 

There are basically two things that lead to rising cancer rates as we age: 1. Failing immune system, 2. Accumulation of DNA mutations. Shortening telomeres in proliferating somatic cells are supposed to take care of 2. But they also contribute to 1. So having the ability to lengthen telomeres across the body will boost the immune system but could potentially let somatic cells accumulate more errors (if they never get replaced).

 

On balance I think 1 probably trumps 2, as the immune system can clear out cancerous or pre-cancerous arrested cells. But evolution is very worried about any rise in cancer in the young so it will always err on the side of keeping cancer rates low in the young, but let it (along with all other maladies) rise in the old.

 

 


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#9 QuestforLife

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Posted 08 May 2018 - 08:13 PM

Someone posted a recent paper about smoking and both long and short telomere length being risk factors - can't find the thread now, but it was reported here:

http://www.oncothera...tor-lung-cancer

Anyway I made several quite lame attempts to explain it, but I've now finally cracked it!

It's no surprise short telomeres can cause cancer as chromosomal fusions, rearrangements etc., which are a hallmark of cancer, are caused by critically short telomeres. But the independent association with long telomeres, smoking, and lung cancer (Plus some of the rarer cancers and long telomeres, which is discussed both elsewhere and in this thread) has been a real puzzle. But here is my solution.

A pre malignant cell will grow, ignoring instructions from its neighbours and is able to overcome p53 arrest, probably due to a mutation in that gene or one of its downstream critical targets. But it still hits replicative senescence. This is only a temporary obstacle for cancer, but it's a chance for the immune system to zero in on the inflammatory signals and destroy the cells. But as we grow older replicative senescence amongst other things means that immune surveillance is failing. So cancer cells start growing again, run out of telomeres completely, and chromosomes start fusing, breaking, rearranging via transposons, etc. Basically all hell breaks loose and pretty much all the cells die. But something like 1 in 3 million cells will manage to re-elongate telomeres, probably due to just the right chromosomal rearrangement activating HTERT, or maybe ALT. Then you have a real cancer that most likely will become clinical and you will need treatment or die. So where do long telomeres come in?

It's easy to win the lottery if you buy enough tickets!

It's all about the number of cells a pre-malignant, misbehaving, but still mortal cell can generate. Say a youngish fibroblast can double another 30 times (that's conservative, they can probably double 50 times if they're brand new) so that's 2^30 = 10^9 cells! An old cell with only 10 doublings left can only make 2^10 = 1000 cells (approx). That's a massive difference when you think about the 1 in 3 million chance of immortalisation each cell has. With only a 1000 bad cells, you're still probably okay (1 in 300k chance of immortalisation). But with a mass of a billion cells in chromosomal crisis, your days are surely numbered.

So now we see the two perils evolution must steer between: death by cancer versus death by senescence. The proliferative potential of young cells means that telomeres must be strictly limited to reduce the chance an out of control cell can 'win the lottery' and immortalise. (Even if only immune cells had very long telomeres, and all other cancers were destroyed by it, we'd just get blood cancer.) But limit telomeres too much and we all die young from senescence.

Now obviously lung cancer is mainly caused by (the mutation/s caused by) smoking, not long telomeres. But it goes to show that in this case longer is not always better; we want telomeres long enough that the cells are healthy, can divide normally and perform all their normal functions. But no longer!

Edited by QuestforLife, 08 May 2018 - 08:22 PM.

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#10 Kentavr

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Posted 09 May 2018 - 12:41 AM

There are methods by which, we can dramatically reduce the possibility of cancer.
 
1. We have long telomeres at the beginning of life, and we do not have cancer.
 
Immunity inhibits cancer.
 
Prevention:
 
drugs that regenerate the immune system (eg, thymus).
 
Example:
  • Endoluten (medium danger - also extends telomeres, but also regenerates the immune system),
  • high doses of melatonin (very risky, high risk),
  • Vladonix (low danger),
2. In adolescence, we have a low number of DNA damage.
 
Prevention:
 
drugs that contribute to the healing of DNA damage.
 
Example:
  • nicotinamide ribozide (NR) or nicotinamide + ribose (low hazard),
  • NMN (low hazard)
  • SkQ1 (low hazard)
3. After 40-50 years we have a large epigenetic age
 
Prevention:
 
The rollback of epigenetic age (it is very difficult to do until we find the substances that help to do this).
 
Example:
  • fasting or FMD diet (danger from low to medium),
  • exercises on power loads to stimulate the release of calcium for recoil epigenetic markers (low danger)
  • metformin - read that slightly slows down the epigenetic clock (low danger),
 
4. After 40 years the number of own stem cells decreases sharply
 
Prevention:
 
Stimulation of the production of own stem cells
 
Example:
  • starvation or FMD diet (danger from low to medium) - decrease in the factor of IGF-1 and in the recovery period after fasting - an increase in FOXO1. Activation FOXO1 stimulates the multiplication of stem cells
  • exercise (low risk),
  • sartans - perhaps slow the epigenetic clock (assumption, average danger).
  • VESUGEN - Stem cell stimulator of the vessel and bone marrow
  • BONOMARLOT - activation of the bone marrow reserve
Thus, applying clause 4, we try to replace aging cells with young ones.
 
Apparently, this is something. There is a base for work. :) 

Edited by Kentavr, 09 May 2018 - 12:47 AM.

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