6 replies to this topic

[kurt9]

Another paper on telomere shortening:

http://the-scientist...-axis-of-aging/

http://f1000.com/897...78ntc705nlzkbp5

The problem is you have to pay $32 for the actual paper.

Once you have the paper, the question becomes, "What is the mechanism that actually causes telomere shortening and how does it work for tissues of different turn over (cell replication periods) rates?".

Its also the chicken and the egg. Does telomere shortening cause mitochondrial dysfunction? Or does mitochondrial dysfunction cause telomere shortening (like I think)?

It is the failure to answer these questions that make telomere shortening theory as a cause aging dubious to me.

My questions for you guys are:

1) Can any of you get this paper for free?

2) Can you answer my questions above?

[1101]

Another paper on telomere shortening:

http://the-scientist...-axis-of-aging/

http://f1000.com/897...78ntc705nlzkbp5

The problem is you have to pay $32 for the actual paper.

Once you have the paper, the question becomes, "What is the mechanism that actually causes telomere shortening and how does it work for tissues of different turn over (cell replication periods) rates?".

Its also the chicken and the egg. Does telomere shortening cause mitochondrial dysfunction? Or does mitochondrial dysfunction cause telomere shortening (like I think)?

It is the failure to answer these questions that make telomere shortening theory as a cause aging dubious to me.

My questions for you guys are:

1) Can any of you get this paper for free?

2) Can you answer my questions above?

I couldn't find the paper but I can answer your questions. The mechanism of telomere shortening is VERY well understood. It has to do with DNA replication. If you look at a basic diagram of the double helix being replicated (http://www.accessexc...llaboration.jpg) you can see that there are two strands, the leading and the lagging strand. You see the DNA polymerase that makes DNA can only synthesize new nucleotides in the 5' to 3' direction of DNA. The leading strand is replicated completely because it is complementary to the direction that DNA polymerase synthesizes in. However the lagging strand is not complementary. In order to compensate for this the DNA is synthesized in short chunks called Okasaki fragments. Basically an RNA primer is laid out next to each Okasaki fragment, DNA polymerase then binds to this primer and replicates the Okasaki fragment. HOWEVER, because the primer must be placed before each fragment it is impossible to place one at the ends of the DNA because there isn't anymore DNA to place RNA primers on. This means every time DNA is replicated we lose a bit of our DNA. Luckily the ends of the DNA are filled with repeating telomeres rather than vital information. However we still lose telomeres every time our DNA is replicated. Now the rate of telomere loss in a cell is proportional to how often that cell divides since DNA is only replicated during cell division. So we lose telomeres faster in tissue types that divide often (ie skin) and more slowly in tissue types that seldom divide (ie nerves).

Now your second question about mitochondrial dysfunction. Telomere shortening DOES NOT cause mitochondrial dysfunction. You see mitochondria actually have their own set of DNA. Unlike chromosomal DNA this DNA is circular and not linear. Because it is circular it is possible to completely replicate it when the mitochondria divides. Therefore mitochondria don't even need telomeres since they aren't losing DNA when they divide. However it is possible that changes in the chromosomal DNA could effect the bodies mitochondria and that these changes could be brought on by telomere shortening, but I don't know for sure. I think it's far more likely that mutations in mitochondrial DNA are the main cause of problems associated with them. Oh and mitochondrial dysfunction certainly DOES NOT cause telomere shortening (as explained in the answer to your first question this is caused by the replicated of chromosomal DNA). So it really isn't a case of the chicken or the egg since the two aren't related.

Edited by 1101, 25 June 2011 - 07:43 PM.

[AgeVivo]

Yes from a dna-strand point of view. But from what I understand, at a more macro level (cell, or rather tissue), there is a question. With some sorts of stresses telomeres shorten faster. And telomerase activation may happen depending on the type of cells and conditions. Etc.

Are short telomeres a trouble for normal ageing? That's a real question

[niner]

Another paper on telomere shortening:

http://the-scientist...-axis-of-aging/

http://f1000.com/897...78ntc705nlzkbp5

The problem is you have to pay $32 for the actual paper.

Once you have the paper, the question becomes, "What is the mechanism that actually causes telomere shortening and how does it work for tissues of different turn over (cell replication periods) rates?".

Its also the chicken and the egg. Does telomere shortening cause mitochondrial dysfunction? Or does mitochondrial dysfunction cause telomere shortening (like I think)?

It is the failure to answer these questions that make telomere shortening theory as a cause aging dubious to me.

My questions for you guys are:

1) Can any of you get this paper for free?

2) Can you answer my questions above?

I couldn't find the paper but I can answer your questions. The mechanism of telomere shortening is VERY well understood. It has to do with DNA replication. If you look at a basic diagram of the double helix being replicated (http://www.accessexc...llaboration.jpg) you can see that there are two strands, the leading and the lagging strand. You see the DNA polymerase that makes DNA can only synthesize new nucleotides in the 5' to 3' direction of DNA. The leading strand is replicated completely because it is complementary to the direction that DNA polymerase synthesizes in. However the lagging strand is not complementary. In order to compensate for this the DNA is synthesized in short chunks called Okasaki fragments. Basically an RNA primer is laid out next to each Okasaki fragment, DNA polymerase then binds to this primer and replicates the Okasaki fragment. HOWEVER, because the primer must be placed before each fragment it is impossible to place one at the ends of the DNA because there isn't anymore DNA to place RNA primers on. This means every time DNA is replicated we lose a bit of our DNA. Luckily the ends of the DNA are filled with repeating telomeres rather than vital information. However we still lose telomeres every time our DNA is replicated. Now the rate of telomere loss in a cell is proportional to how often that cell divides since DNA is only replicated during cell division. So we lose telomeres faster in tissue types that divide often (ie skin) and more slowly in tissue types that seldom divide (ie nerves).

Now your second question about mitochondrial dysfunction. Telomere shortening DOES NOT cause mitochondrial dysfunction. You see mitochondria actually have their own set of DNA. Unlike chromosomal DNA this DNA is circular and not linear. Because it is circular it is possible to completely replicate it when the mitochondria divides. Therefore mitochondria don't even need telomeres since they aren't losing DNA when they divide. However it is possible that changes in the chromosomal DNA could effect the bodies mitochondria and that these changes could be brought on by telomere shortening, but I don't know for sure. I think it's far more likely that mutations in mitochondrial DNA are the main cause of problems associated with them. Oh and mitochondrial dysfunction certainly DOES NOT cause telomere shortening (as explained in the answer to your first question this is caused by the replicated of chromosomal DNA). So it really isn't a case of the chicken or the egg since the two aren't related.

Actually, telomere shortening does lead to mitochondrial dysfunction; that's what the Sahin et al. paper was about. At the F1000 link above, Kevin Conley provides a pretty good explanation of Sahin:

Tying together the loose ends of aging: a common thread ties telomere deterioration to growth arrest and metabolic failure in old cells. Aging involves a wide range of cellular changes such as telomere shortening, growth arrest, DNA damage and mitochondrial dysfunction. A new paper by Sahin et al. summarizes work that links these loose ends into a common thread. In proliferating tissue, this thread starts with telomere shortening and runs through the growth suppressor and apoptotic regulator, p53, and ends with aging and degeneration.

The new insight for less proliferative tissues such as heart, liver and skeletal muscle is that p53 not only arrests growth but suppresses the 'master switch' activating mitochondrial function and biogenesis, peroxisome proliferator-activated receptor gamma, coactivator 1 (PGC-1). The result is a failure to activate and support metabolism, which facilitates the physiological decline, reactive oxygen species (ROS) generation and mitochondrial dysfunction characteristic of the aging cell. Thus, telomere dysfunction not only connects via p53 to cell-growth arrest but also to downregulation of metabolism to set the stage for cell death. A promising place to halt this unraveling of the cell with age may start by preventing the fraying of the telomere to maintain cell activity and avoid the metabolic failure of a dying cell.

[1101]

@niner
Well that's why I said that telomere shortening of chromosomal DNA could play a role in mitochondrial dysfunction. I guess I was thinking in terms of the mitochondria losing telomeres being a cause (which it can't since mitochondria don't have telomeres).

@Agevivo
As I said the rate of telomere loss is proportional to how often a cell divides (and thus replicates its DNA). Tissue that is subject to constant damage (ie the lungs due to smoking) is going to have to divide more often in order to repair itself and is thus going to lose telomeres faster.

Now you seem to be asking for evidence that telomere shortening is a cause of aging rather than a mere correlation. This page on the sierra sciences website list several proof of concept experiments:

http://www.sierrasci...roof/index.html

Also certain forms of progeria (a disease that for lack of better terms causes people to age more quickly) are associated with having less telometric repeats:

http://www.bookrags....rogeria-gen-01/

And a while back it was discovered that Ashkenazi Jews have a greater than average life expectancy which is believed to be caused by their possession of a "hyperactive" (see link) version of telomerase, which as you may know is the enzyme that rebuilds telometric repeats:

http://www.livescien...living-100.html

[Cremedelacreme]

Hi Kurt9,


Paper on: Human telomerase acting as a hTR-independent reverse transcriptase in mitochondria.
http://nar.oxfordjou...text-lowres.pdf


Paper on: Telomere dysfunction inducing metabolic and mitochondrial compromise.
http://basicmed.med...._img/1007-1.pdf

Paper on: The role of cell attachment in the regulation of telomerase during keratinocyte differentiation.
https://qmro.qmul.ac....pdf?sequence=1


Hope these will help to answer some of your questions on telomere shortening

[ihatesnow]

Edited by ihatesnow, 05 November 2012 - 10:47 AM.