Cells and Aging

James james at ryley.com
Wed Mar 3 23:51:11 EST 1999

> >Just so that there is no future confusion, there is an incorrect
> >use of the word "heterochromatin" going on here.  While the
> >telomeres of chromosomes may be largely composed of
> >heterochromatin, the two are not even close to synonymous.
> >Heterochromatin exists throughout each chromosome, and is a
> >compacted form of DNA (with associated proteins) that normally
> >inhibits gene expression.  There are some genes that work just
> >the opposite -- they must be in heterochromatin to be expressed.
> I believe you mis-read the implications in Williams statement.  What he was
> saying is that the heterochromatin structure is changed by the shortening of
> the telomeres and that previously silenced genes are therefor allowed to be
> expressed. You are quite correct that telomeres and the heterochromatin are
> distinctly different structures but they are inter-related to some degree
> particularly in the sub-telomeric regions.

After reading it again, I don't concur.  Maybe that's what he
meant, but that's not what he said.  See below.

> >> > ufotruth at ix.netcom.com wrote:
> >>
> >> > We were discussing the different processes which causes the aging of
> >> > human cells. It was my opinion that telomere shortening does not just
> >> > result in human aging by causing an increase in the number of senescent
> >> > cells, but also by causing the heterochromatin or "hood" of chromosomes

This sentence implies that "heterochromatin" and "hood" (by which
I assume he means telomere) are the same thing.  I don't think
I'm misreading, I think that it is incorrect to talk about
telomeres as the "heterochromatin... of chromosomes", at least
without substantial qualification.

> to
> >> > shrink and cause altered and incorrect gene expression. This incorrect
> gene
> >> > expression would gradually cause protein production to be reduced, DNA >
> >> > repair to be slowed, more free radicals, and fewer defences against free
> >> > radicals.
> >
> >Altered gene expression does not necessarily equate to reduced
> >protein expression.  In fact, in this case, because most
> >heterochromatin is tanscriptionally inactive, loss of telomeres
> >would be more likely to caused increased gene (protein)
> >expression.  Saying that this would impact DNA repair is making
> >quite a leap of faith.  Is there evidence that the altered genes
> >are involved in DNA repair?
> I quite agree that a shrinking heterochromatin structure would result in
> more, not less, genetic production of proteins.  The hypothesis, that this is
> the triggering event for initiation of p-16/p-53 senescence block, needs to
> be explored but it does seem to be a logical inference.

Why is this a logical inference?  Would excess DNA production
cause DNA damage?  Would it effect P53 levels?  RB levels?  Sure,
it's a possibility.  One of a thousand.  I don't see that that
makes it a logical inference.

> >> While this may indeed be the case, you still have to look at the full
> system
> >> to see the effects of theses accumulating processes.  Cells in a system
> >> differentially reproduce with those at the periphery reproducing more
> often
> >> than those in the "center" with more contact inhibition.
> >>
> >> The redundancy inherent in evolutionary perfected biological systems is
> >> profound. Even if some of the cells have decreased capacity due to
> telomeric
> >> shortening the entire system remains functional.
> >
> >Sometimes yes, sometimes no.  The amount of perturbation that a
> >biological system can take and still function greatly depends on
> >the particular system and the particular insult.  Without
> >specifics this is just a hand-waiving argument.
> Yes, this was a generalization and in some systems even a small disturbance
> could result in a catastrophic event.
> >> It is my contention that "aging" is the result of the senescence or
> apoptosis
> >> of a significant number of cells in the system and that the "gradual"
> >> approach to these states by individual cells does not play a large role in
> >> the process.
> >
> >Aubrey might agree ;)  I find it unlikely.
> 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.

No, one does not logically follow from the other.  You have
specifically chosen system failures that necessarily involve
many, many divisions, and systems where senescence is a relevant
concept.  How about muscle weakness in the elderly?  Senility? 
Brittle bones?  There are plenty of examples of problems that
occur during aging that, as far as we know at this point, have
nothing to do with cellular replication.  Muscle cells are
terminally differentiated and non-dividing from before birth (I
think - I could be wrong about the timeframe but it's of little
consequence).  So senescence certainly doesn't have much to do
with them.

Seeing problems mainly during "late stage cellular development"
as you put it (Don't you just mean old age?  Late stage cellular
development could be taken to mean terminal differentiation, but
I don't think that's what you mean) doesn't prove anything.  It
is only logical under just about ANY theory of aging, since the
insults a cell suffers, whatever they may be, are going to be
additive, and this is going to make it exponentially more likely
to have problems as time goes by.

My guess is that we will find out that some cell types experience
the type of aging that you describe:  They are fine until they
hit some "wall", at which point there is a problem, and that we
will find that other cell types experience a gradual decline in
function from the day you are born (probably before birth


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