Telomeric Theory of Aging

Excelife excelife at earthlink.net
Wed Aug 19 17:40:08 EST 1998


In article <jstrout-ya02408000R1908981330050001 at news.ucsd.edu>, 
jstrout at ucsd.edu says...
>
>In article <35daf0c8.354067837 at nntp.ix.netcom.com>, ufotruth at ix.netcom.com
>wrote:
>
>>I have a question. I have heard lately of the creation of telomerase
>>"Knock Out Mice" that have the gene for telomerase removed from them.
>>Do you think it is possible that mice could be created or genetically
>>engineered that had the telomerase gene in every single one of their
>>cells? 

The gene for telomerase is already encoded in the DNA but when most cells 
terminally differentiate that gene is no longer expressed.  As noted below, 
by Joseph Strout, mice, particularly mus musculus, may not be the best 
candidate to test this experiment. Telomeric length in these mice are not 
only regulated by telomerase but also by an unrelated genetic component on 
chromosome 2.(Proc Natl Acad Sci U S A 1998 Jul 21;95(15):8648-8653 "Telomere 
length regulation in mice is linked to a novel chromosome locus.")

Many other mammals more closely compare to the human model of telomeric 
shortening leading to cellular senescence and presumed aging of the organism. 
Our knowledge of how to intervene in age related expression of specific genes 
is extremely limited so methods to re-activate the telomerase gene are not 
currently available.  

However, extra-nucleic expression of factors that can maintain telomeric 
length have been demonstrated. First by utlizing the RNA components 
associated with telomerase, (Nat Genet 1997 Dec;17(4):498-502 "Reconstitution 
of human telomerase with the template RNA component hTR and the catalytic 
protein subunit hTRT".)  Secondly, dispersed DNA coding for the T2AG3 
telomeric repeats has been found in immortal cells not expressing 
telomerase,(Biochem Biophys Res Commun 1998 Jul 20;248(2):223-227 "Release of 
telomeric DNA from chromosomes in immortal human cells lacking telomerase 
activity."

Utilization of these procedures in mammals that age more like humans may 
answer the question of whether extending telomeric length in vivo will also 
extend the life span of the organism.



>As I understand it, this isn't necessary -- mice die of natural causes way
>before there telomeres have shortened significantly.  So the experiment you
>describe has basically already been done, by Nature.


Possibly, but no definitive study has been done to determine whether 
telomeric shortening is a causative factor in the death of mice.  The long 
telomeres of of mus musculus, the telomerase knock-out mice studied by Dr. C. 
Greider and the fact that mouse cells do not experience telomeric related 
senescence do suggest a different progression of cellular development but do 
not described any alternative cause of aging in mice.  In fact one study of 
mouse telomeres shows that some chromosomes have significantly shorter 
telomeres than the other chromosomes, (Proc Natl Acad Sci U S A 1997 Jul 8 
94:14 7423-8 "Telomeres in the mouse have large inter-chromosomal variations 
in the number of T2AG3 repeats").  Yeast studies have shown that the "loss of 
a single telomere results in cell-cycle arrest and chromosome loss", (Nat 
Genet 1998 Jan 18:1 76-80).  

Without further research we cannot rule out telomeric loss as being a 
causative factor in the aging of mice.



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





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