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Telomeric Theory of Aging IV

Excelife excelife at earthlink.net
Fri Sep 11 19:06:24 EST 1998


E. Telomeres and Senescence

Besides limiting cellular replicative capacity, telomeric shortening has been 
experimentally linked with cellular senescence.  A process has been proposed 
whereby the shortening of the telomeres is surveyed and recognized by the 
genes the ataxia-telangiectasia (ATM) and p53 and once a critical length, 
(not crisis), of telomeric DNA is reached.  ATM and p53 relay a signal that 
causes the induction of a family of inhibitors of cyclin dependent kinases 
(including p21 and p16) and the eventual G1 block of senescence. 

In most instances, in human cells, once this point is reached the cell, 
apparently, recognizes this state as an aberration and initiates apoptosis.  
This can lead to the cellular loss and aging as described earlier.  However, 
a small subset of cells avoid apoptosis and these cells can survive in this 
non-replicative senescent state for a significant period of time.

Senescent cells beside being blocked from replicating also adhere less 
rigorously to their differentiated phenotype, produce more free radicals than 
non senescent cells and show signs of inappropriate genetic expression.  An 
example of the latter is in senescent fibroblast that produce many times the 
amount of collagenases than non-senescent fibroblasts.

Each of these processes are detrimental to the cellular tissues involved and 
likely to the functioning of the organ system in which they are located.  By 
avoiding apoptosis these senescent cells may block the production of more 
functional cells as has been proposed for T cells in the immune system.  By 
expressing a more embryonic phenotype the cells may not function properly for 
the organ system in which they are located and the increased production of 
free radicals may damage the cell, causing further deterioration of its 

Finally inappropriate genetic expressions can disrupt the production of 
necessary bio-chemicals like cd 28 required for telomerase activity in T 
cells or the production of inappropriate bio-chemicals like collagenase in 
fibroblasts, that can not only damage the cell itself but also the matrix 
surrounding it and nearby cells.

Telomeric shortening leading to cellular senescence may be the primary factor 
in how replicative cellular systems deteriorate over time and lead to 
organismic death.

Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.


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