Telomeric Theory of Aging IV

Tom Matthews tmatth at netcom.ca
Mon Sep 14 04:20:08 EST 1998


Excelife wrote:
> 
> 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.

I am afraid that I am not going to be convinced of the cause/effect
relationship here until:
1. a plausible mechanism is shown for these cell changes to occur
exactly with senescence, and
2. is it proven that none of these changes are extant in cells which are
just pre-senescent (say, 5-10 doublings short of scenescence).

> >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 than 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.

But WHY?? What possible relevance has the specialized behavior of
disabled division got to do with these other attributes which you say
are related? What is the common mechanism to cause all these things
together? And please don't say "shortened telomeres". The question is
HOW DO SHORTENED TELOMERES DO ALL THESE SEEMINGLY DISPARATE THINGS TO
THE CELL??
 
> >> 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.

Unless it happens at too high a rate which then may lead to the
incapacity for replacement.

> Where cells lost to apoptosis are not capable of
> being replaced then we see the cellular mass loss normally associated with
> aging.

This would certainly lead to loss of cellular mass and may even be the
major contributor to cellular mass loss in normal aging, even though the
major cause of this apoptosis in normal aging may not be telomere
shortening.
 
> Where senescent cells avoid apoptosis cellular mass is retained but
> with cells that may be injurious to the organism as described above.

Cells can also be injurious to the organism long before, and quite
independent of senescence.

With the addition of my comments above, I agree with your comments on
apoptosis.
 
> >2. While senescent cells are, in general, less differentiated, I think
> >this is simply 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.

Again, this is something of which I cannot be convinced without having a
mechanism for it.

After some thought, I can now see the relationship of embryonic with
pre-cancerous (which at first seemed strange because embryonics cells
are 'good' and cause directed and productive growth, whereas cancerous
cells are 'bad' because their growth is parasitic and uncontrolled)
because there are no positive and productive developmental directives to
guide these embryonic cells. If only we could somehow harness their
"embryonic" state to produce tissue rejuvenation 'in situ'. 

> >> 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 your 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.

Okay! This is the putative mechanism that I stated above that I needed.
You can now ignore some of my previous comments about such a mechanism
until I study the relevant papers (if I ever get time :)
 
> 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.

If this is fully demonstrated and explained (and I will temporarily
except that), then what we need to do is assess separately the
importance for various aging pathologies of the various cellular changes
which occur with aging prior to senescence, compared to those which
occur at senescence. The difficulty which I see in this is that
senescence does not occur until cells have also accumulated many other
aging changes. What we need to do is find a method of making telomeres
shorten faster, so that senescence is reached before aging changes which
might not depends on telomere shortening have accumulated. It just
occurs to me, is this not the exact case for some of the premature aging
pathologies such as Werner's and progeria? 
 
> >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:-)

I don't know if you are being facetious or really missed my point. The
"imagination" was a thought experiment to prove the logic of my previous
statement.


--Tom 
Tom Matthews
 
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