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Telomere Length: Cause of Aging or Marker of Aging?


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#1 reason

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Posted 14 May 2013 - 10:23 PM


Telomeres are repeating sequences of nucleic acids that cap the ends of chromosomes in the cell nucleus and stop actual gene-coding DNA from being chopped off when a cell divides. The mechanisms of DNA replication require extra leg room at the ends of the strand, a trailing sequence that is not copied over to the new strand under assembly - and the primary role of telomeres is to be the part that is dropped on the floor. A little of their length is thus lost with every cell division. This shortening acts as a clock to count cell divisions, and cells with very short telomeres stop replicating - they either enter cellular senescence (which ideally then causes the immune system to destroy them) or destroy themselves directly via programmed cell death mechanisms.

Telomere length is more dynamic than this simple picture, however. In some cell populations, such as the various types of stem cell that maintain tissues and produce new cells to replace those lost or damaged, an enzyme called telomerase continually lengthens telomeres so as to allow a cell lineage to continue dividing indefinitely.

Ordinary, non-stem cell populations exhibit a range of telomere lengths, some short, some long. You might imagine that a population of cells replenished more frequently or recently by stem cells will have longer telomeres on average. A population that is receiving less support might have shorter telomeres. Researchers have shown that a higher proportion of short telomeres in white blood cells correlates well with ill health or stress, and somewhat correlates with age. Some more complex measures of telomere length, a step above just taking the average, have been shown to correlate well with age, however, and other techniques do a fair job of predicting future life expectancy in laboratory animals.

A few years back a brace of startup biotech companies were aiming to address aspects of aging by lengthening telomeres through the use of telomerase. None of that went anywhere, unfortunately, but it's possible that they were just too early - it is frequently the case that all of the first batch of companies in a new area of biotechnology fail. It's a tough business to be in. I was a skeptic at the time regarding their potential for success based on my expectation that telomere length will prove not to be a root cause of aging.

Nonetheless, researchers are demonstrating extension of life in mice through telomerase these days, but it is as yet unknown as to exactly why this works. Perhaps it makes stem cells work harder to maintain tissues, perhaps there is just one critically limiting type of stem cell or tissue that benefits from more telomerase, or perhaps it involves other effects causes by increased levels of telomerase that have nothing to do with telomere length. It is worth bearing in mind that there is a considerable difference between natural levels of telomerase and the resulting telomere dynamics in mice and people, however. Telomerase therapy is probably not something you'd want to just up and try without the research community first obtaining a much greater understanding of why it works to extend life in mice.

Why? Well, the risk of telomere lengthening in humans is cancer. Any mechanism that globally, or possibly even narrowly, extends telomere length in people will raise the risk of suffering cancer. The whole system of telomere dynamics and cellular senescence is intimately tied to the processes of cancer suppression, while all cancers evolve ways of lengthening their telomeres to allow unlimited cell division. Boosting your telomerase levels looks a lot more risky to me than, say, undergoing first generation stem cell transplants.

There continues to be a lot of activity in telomere research and development. The present brace of telomere-related biotech startups are commercializing ways to measure telomere length rather than extend it. The products are tests that will at first add another measure to inform patients on the state of their health, then possibly act as an effective biomarker of biological age, and perhaps later prove useful in further research if it turns out that telomerase-based therapies can be beneficial in humans.

How Long Will You Live?

A growing number of researchers say telomere length is a critically important indicator of how old we really are, and of how many healthy years we may have in front of us. A new industry is sprouting up around the science of longevity, offering telomere testing to the public - and Nobel laureate Elizabeth Blackburn is a notable part of it. Her company, Telome Health, is set to launch a telomere test later this year, joining a handful of others that already do. Like a cholesterol or blood-pressure test, telomere testing could one day become standard in doctors' offices.

And maybe in the future, we'll be able to slow or reverse the effects of aging -the vision of researchers searching for ways to boost telomerase, a goal already achieved in lab mice. Some are already marketing so-called "telomerase activators" to a public hungry for ways to stop the clock, although no such drugs have been approved. With so many companies rushing to come on board, "there's a lot of weird stuff going on out there," cautions Jerry W. Shay of the University of Texas Southwestern Medical Center, an expert on cell biology and telomere length.

Certainly you should be looking askance at any group that's selling herbal "telomerase activators" - it's the standard garbage from the supplement marketplace, and sadly that's the place that formerly funded companies doing original research often end up. It's hard to make money doing something useful in medical research, but depressingly easy to make money doing something useless in the supplement business. The traditional model here is to grab a little research that's somewhat relevant, scare up a bunch of Chinese herb extracts, and then hope that if you market the thing hard enough it'll overcome the obvious ineffectiveness and pointlessness. If you can buy out the shell of a company formerly doing research to try to profit from its one-time reputation, then all the better. Caveat emptor is the watchword, as ever.

So where do telomeres fit in the taxonomy of cause versus secondary effect in aging? Because of the dynamic nature of telomere length I'm given to think that it's a secondary effect: get sick and average telomere length in white blood cells shortens; get well and it lengthens again. This sounds very much like a system responding to circumstances, and those circumstances most likely include the general level of cellular damage, inflammation, and metabolic waste products - all of which grow with age. As for so many other similar questions about aging, the fastest and cheapest way to answer this question about telomere length is to implement the Strategies for Engineered Negligible Senescence (SENS): build the biotechnologies to repair these forms of damage and then see what happens to telomere length once its done. That is a good deal easier at this point than obtaining a full understanding of the aging of human biology.

None of the above precludes short telomeres from causing further damage or changes of their own, of course. Aging proceeds as a cascade of harmful effects as damage causes further damage and flailing biological systems cope badly with the new circumstances they find themselves in. Here is a recent article on how telomere length can impact gene expression and thus the operation of metabolism in a previously unsuspected way, for example:

Telomeres Affect Gene Expression

DUX4, a gene responsible for the genetic disease facioscapulohumeral muscular dystrophy (FSHD), is normally silenced because it sits next to a telomere - a protective DNA sequence that caps the ends of chromosomes, according to [a recent study]. But as telomeres shorten, as they do with age, DUX4 expression climbs, which may explain the late onset of FSHD. Another gene, called FRG2, which sits 100 kilobases away from the telomere, is also affected by telomere length.

"This was completely unexpected. We think that DUX4 and FRG2 are the tip of an iceberg." Due to shrinking telomeres, many genes might gradually become more active as we get older, which may be important for several diseases of old age. "This represents a very significant general advance in our understanding of how telomere shortening may affect human biology."


<br> <br>View the full article
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#2 Mind

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Posted 09 June 2013 - 11:13 AM

Another (blog) article about the usefulness of telomeres for measuring aging and whether or not the two are related.

The Hayflick limit may represent an organism’s maximal lifespan, but what is it that actually kills us in the end? To test the Hayflick limit’s ability to predict our mortality we can take cell samples from young and old people and grow them in the lab. If the Hayflick limit is the culprit, a 60-year-old person’s cells should divide far fewer times than a 20-year-old’s cells.
But this experiment fails time after time. The 60-year-old’s skin cells still divide approximately 50 times – just as many as the young person’s cells. But what about the telomeres: aren’t they the inbuilt biological clock? Well, it’s
complicated.


Edited by Mind, 09 June 2013 - 11:14 AM.


#3 niner

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Posted 09 June 2013 - 01:53 PM

Nice find! There are an awful lot of people who are attached to the idea that telomere attrition is the number one key to aging. This idea is attractive- it's easy to understand and makes a good "story". There's even a Nobel prize attached to it. It's certainly promoted by people who sell telomerase activators, or random unproven substances purported to be that. People don't like complicated messy stories with some pages missing, but that's what we're really dealing with.

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#4 xEva

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Posted 10 October 2013 - 10:28 PM

Nice find!


Not really. I found this error: " Most importantly, trusty lab mice have telomeres that are five times longer than ours but their lives are 40 times shorter. That is why the relationship between telomere length and lifespan is unclear."

A paper a was published about a year ago that showed that mice telomeres shorten 100 times faster than human http://www.cell.com/...1247(12)00263-X

If we take the data cited in this paper, telomere length is "50 kb in young ..mice, compared with15 kb in young humans", then a very crude calculation will show :

m = h(50kb/15kb)/100 = 0.033h

where m and h stand for mouse and human lifespan respectively

or that the average mouse lifespan should be 0.033 of the human. If we take human life for 80 years, then a mouse should live for 2.6 years, which seems to match the data. It appears telomeres do matter, no?

#5 hav

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Posted 11 October 2013 - 09:16 PM

Don't know that the study speaks to cause and effect... just correlation markers. But a bunch of flags all moving in the same direction usually indicate which way the wind is blowing:

telomeres.jpg

Short of proving that telomerase activation actually increases longevity, I'd settle for it controlling those other markers. In which case, a small change in telomere length looks like it could exert a big influence on muscle, lung, and reaction time performance.

The TwinsUK registry tracks a number of the biomarkers mentioned and makes its data available to researchers . If the chart above held up when comparing identical twins with contrasting telomere lengths... that would do it for me.

Howard

#6 olaf.larsson

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Posted 03 December 2013 - 08:24 PM

Not really. I found this error: " Most importantly, trusty lab mice have telomeres that are five times longer than ours but their lives are 40 times shorter. That is why the relationship between telomere length and lifespan is unclear."


It was not an error. Mouse have longer telomeres but they get shorter faster appearently.

Now if it really would be so that telomere length would be central for aging it should be possible to make a genetically modified mice with inducible telomerase promotor so that midlife mice could be rejuvenated by feeding/injecting them with the promotor inducer and thus lengthening the telomeres. An experiment like this is totally doable, genetically modified mice have been around for ages.



The Hayflick limit may represent an organism’s maximal lifespan, but what is it that actually kills us in the end? To test the Hayflick limit’s ability to predict our mortality we can take cell samples from young and old people and grow them in the lab. If the Hayflick limit is the culprit, a 60-year-old person’s cells should divide far fewer times than a 20-year-old’s cells.
But this experiment fails time after time. The 60-year-old’s skin cells still divide approximately 50 times – just as many as the young person’s cells. But what about the telomeres: aren’t they the inbuilt biological clock? Well, it’s
complicated.


They should take a closer look at the stemcells that the fibroblast come from rather then the fibroblasts themselves.

Edited by olaf.larsson, 03 December 2013 - 08:42 PM.


#7 xEva

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Posted 04 December 2013 - 05:50 AM

Not really. I found this error: " Most importantly, trusty lab mice have telomeres that are five times longer than ours but their lives are 40 times shorter. That is why the relationship between telomere length and lifespan is unclear."


It was not an error. Mouse have longer telomeres but they get shorter faster apparently.

Now if it really would be so that telomere length would be central for aging it should be possible to make a genetically modified mice with inducible telomerase promotor so that midlife mice could be rejuvenated by feeding/injecting them with the promotor inducer and thus lengthening the telomeres. An experiment like this is totally doable, genetically modified mice have been around for ages.


What I meant was that he wrote the article on telomeres and yet did not know this very crucial info about mouse telomeres shortening 100 times faster than human (even though he wrote it almost a year after that paper was published). He reiterates the well-known fact that mice telomeres are much longer and yet their lifespan is just a small fraction of ours -- in support of the old idea that telomeres did not matter much. That's where he is wrong.

My understanding is this is that researchers currently believe that telomeres do matter, a lot. Driven by inertia, general public still goes by the previous, outdated take on this. My simple calculation implies that lifespan = initial telomere length X attrition rate.


Re inducible telomerase promoter in mice, I believe there was a study about this -? could be Maria Blasco again.

Edited by xEva, 04 December 2013 - 05:51 AM.


#8 hav

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Posted 04 December 2013 - 05:03 PM

What I meant was that he wrote the article on telomeres and yet did not know this very crucial info about mouse telomeres shortening 100 times faster than human (even though he wrote it almost a year after that paper was published). He reiterates the well-known fact that mice telomeres are much longer and yet their lifespan is just a small fraction of ours -- in support of the old idea that telomeres did not matter much. That's where he is wrong.

My understanding is this is that researchers currently believe that telomeres do matter, a lot. Driven by inertia, general public still goes by the previous, outdated take on this. My simple calculation implies that lifespan = initial telomere length X attrition rate.


Sounds good in principle but what I see in the report's charts looks like it tells a slightly different story.

http://www.cell.com/...imageType=large

In Chart A the trans-genetic (TgTert) mice that over express telomerase shows them doing just fine with extra-long telomeres and hardly any critically short up till about 140 weeks of age. Then they go over a cliff. Their telomeres seem like they fall off and they drop dead... pretty much simultaneously. Clearly, up until that moment, no measure of telomere length will predict what is about to happen to them. The normal-gene (WT) mice show more gradual falloff and a similar but little less steep plunge which is 5 to 10 weeks earlier but mostly seem to be heading towards the same maximum age limit as the trans-genetic mice.

I think the strongest thing this research illustrates is that increased telomerase expression alone might increase average lifespans but have a very small effect, if any, on maximums. Delayed but more sudden death.

Howard

Edited by hav, 04 December 2013 - 05:03 PM.


#9 xEva

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Posted 04 December 2013 - 09:23 PM

Sounds good in principle but what I see in the report's charts looks like it tells a slightly different story.

http://www.cell.com/...imageType=large

In Chart A the trans-genetic (TgTert) mice that over express telomerase shows them doing just fine with extra-long telomeres and hardly any critically short up till about 140 weeks of age. Then they go over a cliff. Their telomeres seem like they fall off and they drop dead... pretty much simultaneously. Clearly, up until that moment, no measure of telomere length will predict what is about to happen to them. The normal-gene (WT) mice show more gradual falloff and a similar but little less steep plunge which is 5 to 10 weeks earlier but mostly seem to be heading towards the same maximum age limit as the trans-genetic mice.

I think the strongest thing this research illustrates is that increased telomerase expression alone might increase average lifespans but have a very small effect, if any, on maximums. Delayed but more sudden death.



Not sure what you mean by that. They conclude:

"Collectively, these findings demonstrate that the rate of increase in the percentage of short telomeres during an individual’s lifetime... determines longevity in mice. These results bring into question the prevailing viewpoint that telomere shortening does not influence replicative aging ... "


Re Increasing max lifespan, they only "used a total of 38 mice (20 WT and 18 TgTERT). Two mice from each cohort were sacrificed after the last telomere length measurement point for experimentation, and were excluded from the survival curves and other correlations", which leaves 18 and 16 mice in each group, 34 total. Max numbers could be different with larger cohorts.

They also stress that the causes of death were the same for all groups and subgroups (quartiles) -- even though it came at vastly different times.

Essentially, they demonstrated that once the bulk of cells run out of telomeres life is over and it is the prevalence of cells with short telomeres that determines this (i.e. that there may still be cells with long telomeres becomes irrelevant).

Edited by xEva, 04 December 2013 - 10:08 PM.


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#10 Hebbeh

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Posted 04 December 2013 - 10:40 PM

It's still the chicken or the egg dilemma. Did shortening telomeres cause death or were shortening telomeres a side effect of diminishing health (old age) and impending death? Did shortening telomeres cause aging or did aging cause shortening telomeres? That question has never been answered by the research and is qualified on how you wish to interpret the data. Presently it's still the chicken and the egg quandary and i doubt a scientist will commit presently one way or the other.

Edited by Hebbeh, 04 December 2013 - 10:42 PM.


#11 hav

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Posted 04 December 2013 - 11:40 PM

Sounds good in principle but what I see in the report's charts looks like it tells a slightly different story.

http://www.cell.com/...imageType=large

I think the strongest thing this research illustrates is that increased telomerase expression alone might increase average lifespans but have a very small effect, if any, on maximums. Delayed but more sudden death.



Not sure what you mean by that. They conclude:

"Collectively, these findings demonstrate that the rate of increase in the percentage of short telomeres during an individual’s lifetime... determines longevity in mice. These results bring into question the prevailing viewpoint that telomere shortening does not influence replicative aging ... "


Re Increasing max lifespan, they only "used a total of 38 mice (20 WT and 18 TgTERT). Two mice from each cohort were sacrificed after the last telomere length measurement point for experimentation, and were excluded from the survival curves and other correlations", which leaves 18 and 16 mice in each group, 34 total. Max numbers could be different with larger cohorts.

They also stress that the causes of death were the same for all groups and subgroups (quartiles) -- even though it came at vastly different times.

Essentially, they demonstrated that once the bulk of cells run out of telomeres life is over and it is the prevalence of cells with short telomeres that determines this (i.e. that there may still be cells with long telomeres becomes irrelevant).


Yes, that's my point. That their data doesn't demonstrate exactly what they say it does. Because so many of the mice genetically altered for enhanced telomerase expression died in such close proximity to having literally spectacular telomere length readings. I think a more fair description of their data would be that genetic predisposition towards increased telomere length first slows down aging, and then accelerates it.

That's not a totally bad outcome, in my opinion. It might enhance quality of life for more years than otherwise. And maybe enhancing telomerase expression with supplements might have different behavior... be less of a roller coaster ride. Particularly if telomere health is not the sole strategy.

Howard

#12 xEva

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Posted 05 December 2013 - 03:46 AM

... their data doesn't demonstrate exactly what they say it does. Because so many of the mice genetically altered for enhanced telomerase expression died in such close proximity to having literally spectacular telomere length readings.


Where did you get this? They measured telomeres only 4 times, last time at 25 months, which was not far past the midpoint of life for the transgenic mice. I understood that transgenic mice, despite the overexpression of telomerase, had the number of cells with short telomeres growing just like WT mice, albeit at a slower rate.

I think a more fair description of their data would be that genetic predisposition towards increased telomere length first slows down aging, and then accelerates it.


Again, imo you're reading more into it that they state. Where did you get the accelerated aging part? But they did speak of delayed aging in the trangenic mice group.



It's still the chicken or the egg dilemma. Did shortening telomeres cause death or were shortening telomeres a side effect of diminishing health (old age) and impending death? Did shortening telomeres cause aging or did aging cause shortening telomeres? That question has never been answered by the research and is qualified on how you wish to interpret the data. Presently it's still the chicken and the egg quandary and i doubt a scientist will commit presently one way or the other.


I do not see it that way. To me it looks like they state clearly that longer telomeres correlate with better health and longer lifespan across various species. I understand that you want to stress that correlation is not causation -- still, my understanding is that most scientists today would agree that short telomeres cause cell cycle arrest -> emergence of senescent phenotype -> organ disfunction -> disease and death.

#13 olaf.larsson

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Posted 05 December 2013 - 03:54 AM

Re inducible telomerase promoter in mice, I believe there was a study about this -? could be Maria Blasco again.

Thank you. I suspected it had been done by someone allready. Until recently I have been doing programing for some years so I am not updated about new papers.

My understanding is this is that researchers currently believe that telomeres do matter, a lot. Driven by inertia, general public still goes by the previous, outdated take on this. My simple calculation implies that lifespan = initial telomere length X attrition rate.


It would beautiful to make a graph for different species with percent total telomere attrition/time unit on one axis and lifespan on the other.

#14 Hebbeh

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Posted 05 December 2013 - 04:52 AM

It's still the chicken or the egg dilemma. Did shortening telomeres cause death or were shortening telomeres a side effect of diminishing health (old age) and impending death? Did shortening telomeres cause aging or did aging cause shortening telomeres? That question has never been answered by the research and is qualified on how you wish to interpret the data. Presently it's still the chicken and the egg quandary and i doubt a scientist will commit presently one way or the other.


I do not see it that way. To me it looks like they state clearly that longer telomeres correlate with better health and longer lifespan across various species. I understand that you want to stress that correlation is not causation -- still, my understanding is that most scientists today would agree that short telomeres cause cell cycle arrest -> emergence of senescent phenotype -> organ disfunction -> disease and death.


Or is it the other way around? That instead of short telomeres causing poor health that poor health is the cause of short telomeres. No science has demonstrated that short telomeres occurs before the onset of poor health and therefore is the cause of said poor health. The poor health occurs first and short telomeres are merely a marker of said poor health. And therefore, restoring telomere length after the fact is not going to restore health. This has never been demonstrated.

And most scientists do not buy into your theory. The few (very few) scientists promoting the telomere aging theory have vested financial interests and are attempting to make the story fit.

#15 xEva

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Posted 05 December 2013 - 07:36 AM

Or is it the other way around? That instead of short telomeres causing poor health that poor health is the cause of short telomeres. No science has demonstrated that short telomeres occurs before the onset of poor health and therefore is the cause of said poor health. The poor health occurs first and short telomeres are merely a marker of said poor health. And therefore, restoring telomere length after the fact is not going to restore health. This has never been demonstrated.

And most scientists do not buy into your theory. The few (very few) scientists promoting the telomere aging theory have vested financial interests and are attempting to make the story fit.


My theory? Short telomeres and defective telomerase has long been demonstrated to be the cause of poor health and early mortality. Take a look at this table from nature genetics discussing short telomeres syndromes. Even wiki on telomerase says "A variety of premature aging syndromes are associated with short telomeres." And here Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, in other words, making them younger. I believe that's what olaf.larsson wanted to see.

#16 hav

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Posted 05 December 2013 - 05:15 PM

... their data doesn't demonstrate exactly what they say it does. Because so many of the mice genetically altered for enhanced telomerase expression died in such close proximity to having literally spectacular telomere length readings.


Where did you get this? They measured telomeres only 4 times, last time at 25 months, which was not far past the midpoint of life for the transgenic mice. I understood that transgenic mice, despite the overexpression of telomerase, had the number of cells with short telomeres growing just like WT mice, albeit at a slower rate.


I think you're right... I misinterpreted Chart A as depicting telomere length on the x-axis. My mistake. Charts B & C show a steady decline in telomere length and increase in proportion of shortest telomeres. But a problem still remains. Only 2 out of 16 transgenetic mice seem to have died during the entire 25 months of their telomere measurements. Which still suggests that telomere length measurements for the test group were not very relevant during that period of measurement.

I think a more fair description of their data would be that genetic predisposition towards increased telomere length first slows down aging, and then accelerates it.


Again, imo you're reading more into it that they state. Where did you get the accelerated aging part? But they did speak of delayed aging in the trangenic mice group.


The data in Chart A speaks for itself. Acceleration is an increase in rate and is depicted in chart A by changes in the steepness of the death-rate slope. The transgenetic, telomerase overexpressing mice show more shallow death-rate slope than the normal WT mice up until around week 140. Up to this point the more shallow death-rate slope for TG mice indicates delayed death and presumably better quality of life.

At roughly week 140 the death-rate slope gets much steeper for the TG mice to the point where their net survival rate actually falls below that of the normal WT mice just past week 150... that period of accelerated death-rate is what I equate to accelerated aging.

TG_mice.jpg

Unfortunately, they didn't do any measurements (red arrows mark the spots) right before week 140 or 150 for the test mice when the the vast majority, about 75%, died. For some odd reason their last measurement was right before week 120 which only caught a snapshot of the controls right before their descent into death. There's no corresponding week 140 snapshot for the test group's pre-descent plunge. This makes any conclusions based on that measurement resemble those of an uncontrolled study without any test subjects.

Measurements before and during the critical time period of the plunges might reveal actual markers for impending death and my guess is its not any telomere length statistic but more likely a collapse of some other independent system that both shortens telomeres and kills. My guess is based on the fact that the entire TG curve doesn't shift to the right over time but gives back most of its gains like a negative rebound effect. I would guess that a catastrophic failure of anti-oxidant/ROS defenses might be happening. Which would chew up telomeres along with the rest of a cell. And that perhaps those defenses are supported by a part of the body and/or cell whose health is not strictly telomere-length related. In any event there seems to be some other superior clock in control.

Howard

Edited by hav, 05 December 2013 - 05:20 PM.


#17 xEva

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Posted 05 December 2013 - 09:16 PM

hav, they explain why they tested telomeres only 4 times and why they did not do it past week 25: the procedure of drawing blood for the test is very stressful for old mice and can hasten their demise. Besides, it is not the average or mean telomere length which is important predictor of longevity but the number of cells with critically short telomeres. This is what appears to drive aging via progressive organ dysfunction.

And regarding the shape of the curve, I believe that is due to the small number of animals. A mouse dying a day or two earlier or later, while not statistically significant, can have a dramatic impact on how the curve looks. imo you read too much into it.

But I think what you and hebbeh are driving at is that telomeres is not the whole story of aging -- and if so I agree. My take is that telomeres attrition is one of the major mechanisms. I think, at this point it is not disputed that short telomeres drive aging by promoting senescent phenotype. What is still unclear is why senescent cells are not taken out by the immune sys .. and many other questions implicating the influence of the milieu on the fate of a cell.

#18 hav

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Posted 06 December 2013 - 07:45 PM

hav, they explain why they tested telomeres only 4 times and why they did not do it past week 25: the procedure of drawing blood for the test is very stressful for old mice and can hasten their demise. Besides, it is not the average or mean telomere length which is important predictor of longevity but the number of cells with critically short telomeres. This is what appears to drive aging via progressive organ dysfunction.


Sounds like we're being hamstrung by Heisenberg from nailing down exactly what the critical ratio is. Even if its intuitively obvious that there must be some ratio above which the percentage of cells going into apoptosis and not being replaced will become life threatening.

Howard

#19 GetMaxed

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Posted 12 December 2013 - 08:36 AM

So where do telomeres fit in the taxonomy of cause versus secondary effect in aging? Because of the dynamic nature of telomere length I'm given to think that it's a secondary effect: get sick and average telomere length in white blood cells shortens; get well and it lengthens again. This sounds very much like a system responding to circumstances, and those circumstances most likely include the general level of cellular damage, inflammation, and metabolic waste products - all of which grow with age.


I was doing a bit of research into redox/GSH lately to see what supporting evidence there is of redox dysregulation as a key cause of aging and came across this one: Glutathione regulates telomerase activity in 3T3 fibroblasts. “Telomerase activity is maximal under reduced conditions i.e. when the reduced/oxidized glutathione ratio is high. Consequently glutathione concentration parallels telomerase activity.”

Also very recently is this article on ScienceDaily http://www.scienceda...31205142127.htm

Most of the stressors -- from temperature and pH changes to various drugs and chemicals -- had no effect on telomere length. But a low concentration of caffeine, similar to the amount found in a shot of espresso, shortened telomeres, and exposure to a 5-to-7 percent ethanol solution lengthened telomeres.
...
In total, some 400 genes interact to maintain telomere length, the TAU researchers note, underscoring the importance of this gene network in maintaining the stability of the genome. Strikingly, most of these yeast genes are also present in the human genome.
...
More laboratory work is needed to prove a causal relationship, not a mere correlation, between telomere length and aging or cancer, the researchers say.


More reason to have that glass of wine a day? :)

Edited by GetMaxed, 12 December 2013 - 08:43 AM.


#20 olaf.larsson

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Posted 12 December 2013 - 01:59 PM

I was doing a bit of research into redox/GSH lately to see what supporting evidence there is of redox dysregulation as a key cause of aging and came across this one: Glutathione regulates telomerase activity in 3T3 fibroblasts. “Telomerase activity is maximal under reduced conditions i.e. when the reduced/oxidized glutathione ratio is high. Consequently glutathione concentration parallels telomerase activity.”


Some days ago I read an article stating that telomere length in yeast is regulated by the amount of dna damage in the cell. This fits into the picture that a stressfull environment that results in much free radicals, ROS etc. will also result in short telomeres.

#21 Proconsul

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Posted 25 December 2013 - 07:28 PM

The subject is indeed very complex and requires a lot of reading and research. But, according to my understanding, a possible mechanism could be the following: cell damage, especially DNA damage, would induce telomere shortening, which in turn would trigger cell scenescence. I.e., as answer to damage, telomere shortening would act as a signal to slow down the cell, hinder or block its division, and ultimately even shut it down entirely causing apoptosis. This would be a defense mechanism evolved to prevent the cell from becoming cancerous - and perhaps to avoid other bad things to happen as well. Lenghtening the telomere could well slow down or even invert cell scenescence, but at the price of increased cancer risk (and perhaps other ailments). IMO the OP is correct in stating that it would be better to focus on repairing the original damage that likely causes telomere shortening, rather than try and elongate the telomeres per se.

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#22 hav

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Posted 28 December 2013 - 03:22 AM

I think there are at least 2 reasons telomeres shorten. One is by damage. The other is that telomeres come out a little shorter after each cell division, regardless of damage. I think the theory is that anti-oxidants and pro-oxidants affect damage-related shortening. And that telomerase expression affects telomere length change during cell division.

Howard

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