Telomeric Theory - Those Damn Mice

Excelife excelife at earthlink.net
Mon Sep 7 16:37:47 EST 1998


In article <35F44466.20BB at netcom.ca>, tmatth at netcom.ca says...
>
>Excelife wrote:
>
>> Those cells that normally require telomerase, like the germ cells, in Dr.
>> Greider's knock out mice, are affected by the absence of the gene coding 
for
>> telomerase.  After around six generations the telomeres in the germ cells 
are
>> too short to support additional replications and the mice are sterile.  
But
>> the cells not requiring telomerase had their telomeres replenished during
>> embryonic development of each generation by the genes described above.
>> 
>> The answer to the first question, why the mice and their cells die with 
such
>> long telomeres, was also amazingly simple.  It seems that some mice
>> chromosomes have significantly shorter telomeres than the other 
chromosomes.
>> Their length is such that they could cause a cell to enter senescence 
after
>> approx. 10 population doublings, which is exactly what is observed in the
>> studies of the mice.  Yeast studies have shown that the loss of a single
>> telomere can result in cell-cycle arrest and chromosome loss.
>
>I see a potential contradiction between these two paragraphs. While I
>appreciate that the mechanism of germline DNA generation does not
>operate with intact chomosomes, even so would it not be likely that
>these short telomere ends on *some* chromosomes, which you are using to
>explain the short mouse lifespan, would also differently affect the
>germline chromosomes.


Under normal circumstances the germ cells have active telomerase to maintain 
telomeric length on all the chromosomes.  The artificial device used to knock 
out the telomerase gene in Greider's mice allowed the telomeres in the germ 
cells to shorten with each replication.  I haven't seen any data on the 
telomeric length of each of the germ lines chromosomes but given that they 
were sufficient to survive six generations I would presume the telomeres on 
every chromosome were of sufficient length to achieve these results.

Analysis of mouse embryonic cells did show loss of telomeres and Robertsonian 
fusions in the later generations but the cells were still viable.  This 
suggests that only certain chromosomes have the genes necessary for cellular 
viability and until one of these vital chromosomes are lost the effects are 
not catastrophic.

In the normal replicating cells the chromosome with the short telomeres 
appear to contain genes vital to cellular viability or at least to avoidance 
of senescence and the loss of telomeres on that chromosome is likely 
determinant of cellular reproductive capacity and potentially the life span 
of the mouse itself.

 

>It appears to me that you are simply applying each argument in the best
>possible way to "explain" your "desired" solution and at the same time
>ignoring other equally reasonable explanations which don't fit your
>"desired" paradigm.


In these articles I am trying to detail how the telomeric theory of aging 
addresses the research findings.  In that context I do try to present the 
best arguments supporting the telomeric theory of aging.

That there are other plausible explanations for some of the research findings 
is not being questioned.  You will see in some later posts how other theories 
of aging interact with this theory and how they compliment and enhance each 
other.

The basis of my posts are to describe the telomeric theory of aging, how it 
explains the research findings to date, where the research is headed and 
probably most important to all theories, what predictions can be made from 
the theory. 



Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.
http://home.earthlink.net/~excelife/index.html





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