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Major Criticisms of The Telomeric Theory

Tom Matthews tmatth at netcom.ca
Mon Sep 14 21:19:24 EST 1998


Excelife wrote:
> 
> In article <35FC8F1C.30E6 at netcom.ca>, tmatth at netcom.ca says...
> >> >
> 
> >> I haven't seen estimates of how much telomeric
> >> length is replaced by telomerase.  This data may be available but
> >> depending on cellular replication rate the telomeres can either be
> >> lengthened,shortened or remain the same.  Telomerase is upregulated when
> >> required for cellular differentiation or replication but may not be active
> >> at all when the cell is not in these or related states.
> >
> >Thanks for reviewing what you have reported before, but since many of
> >the arguments you have proposed for the relevance of the telomere
> >shortening to certain disease processes make reference to existing
> >telomerase perhaps not having sufficient time to extend the telomeres
> >when divisions are occurring too quickly (as in immune system diseases),
> >data about telomerase's mechanisms of operation is critical to
> >validation of your argument.
> 
> Quite so and it has been described in various experiments but since
> telomerase is only active during specific periods of the cell cycle and
> varies according to species and cell type, there is no "average" amount of
> length added.

I had really meant something typical or a specific example which I could
"get my hands on" instead of simply generalized hand-waving.
 
> In cancer cells it appears that as soon as sufficient telomeric
> length is added to allow for mitosis the cell does replicate. Thus the
> measurements in these cells almost always show short telomeres.  There are
> descriptions of how much telomeric length is necessary for this replication
> but again it varies between the different type of cells studied.

That is interesting information. As a former engineer, physicist,
mathematician and computer scientist this whole business of cell
telomere length stopping and starting cell division is looking to me
more and more like an extremely concrete, well defined and describable
mechanistic process, rather than like the "misty", extremely variable,
ill-defined, influenced by 1000s of variables process that so many
biological events are. Now *that* would be a refreshing change.
 
>  >> >So could it be, in essense, that rate of division is too fast for the
> >> >telomerase to act on *both* sets of chromosomes, therefore the mother
> >> >cell has decided (by evolution) to sacrifice the chromosome set which
> >> >she retains in favor of the chromosomes set which she gives to the
> >> >daughter cell. Again the idea of an experiment to speed up the process
> >> >so that even the daughter cells do not have fully lengthed telomeres,
> >> >comes to mind.
> >>
> >> I see your reasoning but in S. cerevisea there is only a single division
> >> when the "daughter" cell is produced.
> >
> >Don't mother cells have successive daughter cells?
> 
> Yes but there is more than sufficient time between replications for the
> telomerase to restore what little telomeric shortening did occur in both the
> mother and the daughter cells.

I am confused. I thought you were attempting before to argue that
telomere shortening *did* have some relevance to aging in budding yeast.
That is why I typed in my big explanation below.

> >> Aging in both mother and daughter is unrelated to replicative telomeric
> >> shortening but is regulated by telomeric length. Interestingly it is just
> >> opposite of what one would suspect.  Long telomeres apparently shorten
> >> life span but shorter telomeres lengthen it.  It seems to depend on the >>
> transcriptional silencing effects of the genes SIR2&3.
> >
> >According to a report by Greg Fahy on the "Conference on Age-Related
> >Disease" of Dec 11-12, 1997 which is in the October LE magazine but
> >which I had not read when I made the last post, aging in budding yeast
> >(exact name not given) appears to have little to do with telomeres (he
> >does not mention them), but is cause by increasing amounts of useless
> >rDNA loops. The report states (my comments in []):
> >
> >        "Young yeast have no rDNA loops. The parent cell from which other
> yeast
> >cells arise, the mother cell, keeps all the loops to itself, thus
> >sacrificing itself for the continuation of the species. Each new
> >daughter cell, however, eventually develops a loop [which is a type of
> >accumulated damage thing] after dividing many times. Once this happens,
> >deterioration becomes inevitableas the loops accumulate."
> >        "To find out if the loops are sufficient to cause aging all by
> >themselves, Guarente introduced loops into young cells. The result was
> >that aging was induced at a younger yeast age, resulting in a 40%
> >shortening of replicative life span. Thus, loop formation is a
> >sufficient cause of aging in yeast."
> >
> >Thus, this appear to me to show that, at least in this type of budding
> >yeast, telomeres are quite irrelevant.
> 
> Not at all.  If they had included the telomeric transcriptional silencing
> effects in their experiment they might have seen the rDNA loops being a
> result of their inability to transcribe the DNA, or not. In other words,
> they're not mutually exclusive events so until we do the research we just
> don't know.

Now I am even more confused. You said above that there was plenty of
time for the telomerase to length the telomeres in both mother and
daughter cells, meaning to me that you were now saying that in budding
yeast telomeres do not shorten with aging at all. *Now* you are saying
that they still cause some "transcriptional silencing". Huh? How? Why?
Please explain what is going on here. Maybe I am just too dense.
[Afterthought: this was resolved below.]

> >> And exactly what biological mechanism(s) is driving this passage of time
> >> phenomena?
> >
> >Oxidative damage, glycosylation, damage to mtDNA, reactivation of turned
> >off genes, etc. That is the whole point of all the *other* theories of
> >aging!
> 
> O.K., I thought your were referring to just "passage of time".

Come'on Tom, why would I do that? We all know that the passage of time
per se means nothing. It is only the *events* which take place during
this passage of time which count! This reminds me of the silly people
who think that cryonics patients will still age somehow, when all of
their biochemical processes are stopped dead by solidification and a
temperature of -196'C.
 
> >> Citations on this aging phenotype unrelated to telomeric length?
> >
> >I did not say uncorrelated, I said unrelated in the sense of not being
> >*caused by*. The aging phenotype can be caused by any or all of the
> >other primary degradations of aging, just as easily as by telomeric
> >shortening (most researchers would say *more* easily, I think).
> 
> Sorry, same explanation as above.

So therefore. "Come'on Tom" again (said with a kind of whiny voice :-)
 
> >> >Ultimately, it certainly is relevant to aging, but perhaps not until we
> >> >first correct other more direct causes of essential human mortality and
> >> >current maximum lifespan.
> >>
> >> Of course if it is the essential factor in human mortality and longevity
> >> then we won't have to look any further!
> >
> >Quite true, but I think that is hardly even plausible from the current
> >evidence.
> 
> We are being quite pessimistic aren't we:-)

Just telling it like I see it :)
And only pessimistic with respect to the importance of the Telomeric
Theory of Aging.
Or, if you like, pessimistic from the point of view of those who hope
that the Telomeric theory and its research results will save their
lives.

> >> Yes, much research needs to be done here.  However, the evidence, of
> >> telomeric involvement in transcriptional silencing
> >
> >Please explain precisely what you mean here and give examples of such
> >evidence.
> 
> See my response to James where I provided the abstract on this phenomena in
> S. cerevisea, (Proc Natl Acad Sci U S A 1997 Sep 2;94(18):9768-9772).

Okay, I have reread that and now have it integrated into my limited
little brain. Sorry, I was not at the right point in my
thinking/learning to "take that in" before. However, my view of the
abstract and its explanation is that while this lifespan extension in
yeast does appear to relate to telomeres and their length, the
relationship and the mechanism is so foreign and different (let alone
opposite) from the effect of telomeres in cellular senescence and
possibly in human aging, that it too is irrelevant to the Telomeric
Theory of Aging which you have been attempting to "sell" to us. (sorry
to phrase it that way, no smear or insult is intended). 

> >> and generating the senescence signal among numerous other studies, is
> >> suggesting that they are a significant factor.
> >
> >Again, the generation of the "senescence signal" (cessation of ability
> >of the cell to divide) caused by shortened telomeres has not been shown
> >to be relevant to major human disease and mortality.
> 
> Yes, we all await the research results but on the plus side there is nothing
> showing that it isn't relevant!

Except all the other reasonable things which we *know* cause diseases,
and moreso in old age.
Revolutionary theories wishing to overthrow established knowledge
require extreme proof!

> >> Without going into detail I think that telomeric involvement in vascular
> >> disease, immune system decline, cancer and aging in general may have a
> >> large influence on mortality rates as we know them today.
> >
> >Maybe we are not as perceptive as you, but I think the rest of us need a
> >lot more evidence before we would conclude any such thing. However, if
> >telomere research continues to receive as much research interest,
> >funding and public adulation as it has, then I hope you are right.
> 
> That is what we are all hoping for and the exciting thing about the telomeric
> theory of aging is that it won't be too long till we will know for sure!

What you seem to totally ignore though is that there will have been an
enormous waste of resources which *should* have been spent on other
antiaging research, if you are wrong. *That* is the main reason that I
said (given the condition that I made) that "I hope you are right"!
*You* seems to have this mental vested interest in the correctness of
the Telomeric Theory, whereas *I* simply wish to live forever :) and
thus, want resources spent in the most efficient manner possible.
"Frankly, my dear, I don't give a damn" which antiaging theory is most
important for saving my life. 

--Tom 
Tom Matthews
 
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