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Major Criticisms of The Telomeric Theory

Excelife excelife at earthlink.net
Mon Sep 14 03:25:40 EST 1998

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. 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.
 >> >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.

>> 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 
>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.

>> 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

O.K., I thought your were referring to just "passage of time".

>> 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. 

>> >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

We are being quite pessimistic aren't we:-)

>> 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

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).

>> 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!

>> 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!

Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.

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