Telomeric Theory of Aging IV

Excelife excelife at earthlink.net
Mon Sep 14 02:23:47 EST 1998


In article <35FC6851.381E at netcom.ca>, tmatth at netcom.ca says...
>
>Excelife wrote:
>
>> 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.
>
>I think that we need to distinguish quite carefully here. While the
>behavior that you have described above is *correlated* with
>non-replicative cell capacity, ie senescence, it may not at all be
>*caused* by senescence.

This is more a description of what occurs in senescent cells without 
attribution as to cause so correlation is an acceptable term to apply here.


> In my view it is more likely, that both
>senescence and the various behaviors which you have described (and many
>more possibilites) are both simply caused by the *aging* (time passage)
>of cells.

Some of the processes mentioned above, like the phenotype expression, appear 
to be gradual and are not directly related to the telomeric induction of 
senescence.  However most of the genetic changes like the expression of ATM, 
p53, P21 and P16 as well as other biochemicals like collagenases an cd28 have 
been directly related to the cells entrance into the G1 block of senescence.

>It would be an interesting experiment to see whether slow
>dividing cells which have reached senescence because of telomere
>reduction, display more of these aging attributes that do fast dividing
>cells.

While some genetic expression or lack thereof in senescence are dependant on 
the type of cell involved, ie; cd28 in T cells and collagenase in 
fibroblasts, these effects would be seen only when the shortened telomeres 
generated the signal for senescence regardless of its rate of replication.


>> 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 functioning.
>
>Two things here.
>1. In this case apoptosis would be beneficial whereas above you talked
>about it being part of the problems of aging. Thus, you need to be very
>careful about the "place" and relevance of apoptosis to the Telomeric
>theory of aging.

As I understand the role of apoptosis, so long as there is sufficient 
replicative capacity in surrounding cells to replace cells lost to apoptosis 
then it is beneficial.  Where cells lost to apoptosis are not capable of 
being replaces then we see the cellular mass loss normally associated with 
aging.  Where senescent cells avoid apoptosis cellular mass is retained but 
with cells that may be injurious to the organism as described above.

>2. While senescent cells are, in general, less differentiated, I think
>this is simple related to changes which have taken place during the time
>of aging

Yes as mentioned above this does appear to be a gradual development.


>(reversal of inhibited gene expression). I believe it is quite
>wrong to refer to this in any manner as a kind of reversion to
>"embryonic phenotype". It is more of a pure and simple, uncontrolled
>*distortion* of their natural differentiated phenotype. Still, as you
>say, the result is that they contribute inefficiently or even harmfully
>to their parent tissue.

There is specific research that shows some cells revert to an 
undifferentiated state as seen in embryonic phenotypes and these cells are 
considered by some to be pre-cancerous.

>> 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.
>
>I think you conclusion is inappropriate unless/until you show that
>telomeric shortening *causes* the inefficient and destructive aging
>attributes of cells, rather then simply being correlated with them.

As I described in my last post, 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.

That most of the negative effects of senescent cells are not present until 
and unless this state is reached then avoiding this senescent signal by 
maintaining telomeric length would likely also avoid these damaging effects. 
That was demonstrated in Gerons experiment published in Science in January.  
 

>This is seen by simply imagining that telomeres do not shorten and cells do
>not senesce, but simply accumulate all the other aging attributes over
>time.

Imagination is a wonderful thing but I prefer science:-)



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






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