Cells and Aging

Thomas Mahoney excelife at earthlink.net
Thu Mar 4 08:24:09 EST 1999


In article <36DE1347.9B2BE53B at ryley.com>, james at ryley.com says...
>
>Tom Matthews wrote:
>> 
>> Thomas Mahoney wrote:


>> > The evidence that cellular loss or thinning of cell walls is conducive 
to
>> > artheriosclerosis, that the majority of cancerous cells have by-passed
>> > senescence and that much immunological deterioration is the result of 
T-cell
>> > senescence all suggest that it is late stage cellular development or 
lack
>> > thereof that contributes the most to systems failures.
>> 
>> IMO, all three of those premises go far beyond what is proven.
>> 1. There is no proof that any thinning of cell walls (I assume you mean
>> arterial walls here) even if conducive to artheriosclerosis is caused by
>> apoptosis generated by a reduction of telomere length of any cells.


You are correct that I was indeed referring to arterial and vein walls.  As 
to evidence of the apoptosis being the origin of this thinning I refer you 
to; Bennett MR et al, Circ Res 1998 Apr 6;82(6):704-712 "Cooperative 
interactions between RB and p53 regulate cell proliferation, cell senescence, 
and apoptosis in human vascular smooth muscle cells from atherosclerotic 
plaques."

If there is evidence of some other cause of this thinning I would be 
interested in seeing it. 


>> 2. The majority of cancer cells have bypassed senescence because all the
>> ones that did not are not detected because they have not caused the
>> symptoms of cancer. Furthermore, this likely has little relevance to
>> aging since the DNA in those cancer cells was mutated in such a way as
>> to make them divided more often than others of their kind or again they
>> would not have gotten to where they needed to by-pass senescence.

That sounds like a good hypothesis.  Unfortunately I know of no research that 
supports it.  I can, however, cite several studies like; Bryan TM, Reddel RR, 
Eur J Cancer 1997 Apr;33(5):767-73 "Telomere dynamics and telomerase activity 
in in vitro immortalised human cells.", that indicate the cells do not turn 
cancerous until after by-passing senescence and re-activating telomerase.


>> 3. Finally, there is only evidence that T-cell senescence *may* be the
>> cause of immune deterioration in *some* cases (perhaps even likely in
>> AIDS). To conclude that T-cell senescence many be the cause of *all* or
>> even *most* immunological deterioration goes far beyond reason.

Much is neither *all* nor *most*.  Once again, Dr Effros' work is merely 
evidence that senescence plays a role in "functional decrements of the immune 
system".  How great a role is yet to be determined.  However, I know of no 
other research that suggests that there is a gradual loss of T-cell 
functioning that would precipitate a decline in the immune system.
 
>> Since every one of your premises are so unproven, your conclusion that
>> "it is late stage cellular development or lack thereof that contributes
>> the most to systems failures" is wild conjecture in the extreme based on
>> current available evidence.

I have provided evidence supporting the positions I have taken and am willing 
to argue their validity and application but it would be nice to see any 
contradictory viewpoints back up with at least a little research.

>james at ryley.com says>

>I'd like to add one point to this discussion: Being more generous
>than Tom Matthews, I will allow that Tom (Mahoney) could be right
>-- FOR THE EXAMPLES THAT HE PICKS.  But, he is making broad
>generalizations that are inappropriate even if he had the
>evidence to support his specific examples.

Thank you for your courtesy.  I have tried to provide evidence supporting the 
examples I picked.  If you would like to pick some other systems to 
investigate I would be glad to oblige.

>You just can't say "This is what we see in T-cells (or
>fibroblasts, or anything), so this is how aging works."  We have
>over 200 different cell types in our bodies.  They all have
>different metabolisms, evolved for different purposes, and are
>subject to different stresses.  There is no reason to hypothesize
>that they all experience aging in the same fashion.

I agree with that statement entirely.  Different cellular systems have 
evolved different methods to cope with the stresses and environments to which 
they are exposed.  Some cell lines utilize telomerase to maintain their 
replicative capacity, others don't have active telomerase and "age" each time 
they divide, while still other cell systems don't replicate at all.  Throw in 
some stem and satellite cells and you have a pretty complex biological 
system.

That's one of the benefits of having a theory which can unify these various 
processes into a an understandable framework.  By knowing that shortened 
telomeres causes any particular cell to enter apoptosis or senescence then we 
can understand why T-cells with active telomerase can still lose telomeric 
length.  We can understand why telomerase can cause a cell to become 
immortalized.  We can understand why children with progeria look like 80 year 
old men.  And we can understand why cellular proliferation falls 
precipitously around age 80 in humans.

Additionally the recent findings for both muscle and nerve cells suggests 
that telomeric shortening is operational in those cells, (or at least their 
stem or precursor cells), as well.  The exact process by which this 
shortening occurs has yet to be elucidated but the research continues.


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






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