Major Criticisms of The Telomeric Theory

Tom Matthews tmatth at netcom.ca
Sun Sep 13 22:35:56 EST 1998


Excelife wrote:
> 
> In article <35FB0E52.5331 at netcom.ca>, tmatth at netcom.ca says...
> >
> >Excelife wrote:
> >
> >> Most unicellular species
> >> like Budding yeast (S. cerevisea), and most mammals, (in their germ >>
> cells), utilize the enzyme telomerase to maintain their telomeres.  This >>
> enzyme adds telomeres to the ends of the chromosome but if the cell in   >>
> which it is active replicates too fast the telomeres can be shortened    >>
> faster than telomerase can  replace them and the cell may eventually enter >>
> senescence, (see I. Theory E. Telomeres and Senescence).
> >
> >I should have asked about this before, but can you provide us data about
> >the *amounts* of telomere length which is lost during cellular division,
> >and also data about typical *rates* at which telomerase can relengthen
> >telomeres. It appears more and more that major portions of the Telomeric
> >Theory of Aging highly depend on this data. I don't think "hand-waving"
> >about these amounts and rates is sufficient any longer.
> 
> This data is readily available but it does differ between different types of
> cells and between species. Human telomeres are around 18-25 kbp in length
> when young. A rough estimate is that human telomeres shorten around 50-100 bp
> per division.  At senescence the telomeres can still have 8-10 kbp remaining
> of their telomeric repeats but are in the 3-4 kbp or absent altogether when
> the cell enters crisis stage.  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 occuring too quickly (as in immune system diseases),
data about telomerase's mechanisms of operation is critical to
validation of your argument.
  
> >> Other organisms like the mosquito (Anopheles
> >> gambiae), utilize DNA recombination to maintain telomeric length
> >
> >Please describe in more detail. How does this differ from the DNA
> >recombinations in meiosis? And why can't meiosis maintain telomere
> >length (without telomerase) by the same process?
> 
> It is similar but the mechanics of the replication of the chromosome are
> unable to reproduce the last part of the telomere so it shortens at one end
> when replicated.  I believe Aubrey gave us a detailed analysis of this
> procedure some time ago.

Again, this is not the level of detail which I need to understand and be
convinced of anything. Meiosis does not simply refer to chromosome
replication, but refers also to the shuffling of genes between the two
separate nuclear chromosomes which have the same genes, before these
newly created chromsomes each quite distint from either parent
chromosome are passed on to the gamete. What I would like to know is
what happens to the telomeric chromosome end during such shuffling
processes. And furthermore, why and how does such shuffling not maintain
telomer length in knockout mice without telomerase, but still some
undefined process which you refer to as "DNA recombination" can do so in
mosquitos.
  
> >> But what does this have to do with aging and the criticisms of the
> >> telomeric theory?  Well, each of these processes determines how the >>
> organism "ages".
> >
> >I don't understand want you are saying here. Each of these process has
> >"something to do with telomeres", but that is *not* equivalent to "how
> >the organism 'ages'"
> 
> I should have been clearer here.  I wasn't saying telomeres were causing
> aging just that the method utilized, ie;telomerase, not replicating at all
> etc.., to maintain the telomeres dictated the path it took to aging.

I think it is better to say that telomeres and telomerase is
"irrelevant" to the way such organisms age.

> >> For most unicellular organisms, utilizing telomeres to maintain telomeric
> >> length, their telomeres are fully maintained during mitotic division and
> >> theses organisms are essentially immortal.
> >
> >Question: Have any experiments been done on any such organisms to
> >attempt to "speed-up" mitosis so that the rate of telomerase activity
> >might not be sufficient for full telomeric length maintenance?
> 
> Some experiments mimic the results which this would achieve by actually
> shortening the telomeres or knocking out telomerase altogether and the
> results were that the organisms could not replicate and died.

This answer doesn't help me, but I will leave it for now.
I simply will have to read the full papers sometime.
 
> >> Budding yeast (S. cerevisea), are an exception to this in that they go
> >> through assymetric mitotic division.  The mother cell of the yeast then
> >> age much in the same manner as most other eukaryote cells. Austriaco NR
> >> Jr, at The Massachusetts Institute of Technology has demonstrated how the
> >> telomeres in the mother cell regulate the silencing machinery of the genes
> >> to control aging in these cells.
> >
> >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 daugther 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 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.

> >> Other research has shown that the loss of telomeres can result in the loss
> >> of cellular mass in organ systems of the body but this could be an
> >> aberration and not applicable to aging.
> >
> >Or it could simply be a correlation with aging (passage of time)
> >phenotype.
> 
> 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!

> >> Still other research has shown telomeric length to be a controlling factor
> >> in the senescence of cells in the human body but this too may not be >>
> related to aging.
> >
> >Because it may not even be related to these cells accumulating an aging
> >phenotype.
> 
> 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). 

> >> Cells cannot survive without maintaining telomeric length but they can't
> >> survive without cell walls either so this may not relate to aging.
> >>
> >> Maintaining or adding telomeric length allows replicating cell lines to
> >> become immortal but that could lead to cancer and probably has no relation
> >> to aging.
> 
> >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.
 
> >> And the fact that telomeric length may be involved in age related genetic
> >> expression probably has little to do with organismic aging.
> >
> >I would certainly not agree with this logic, but we first must show that
> >telomeric length *is* "involved in age related genetic expression".
> 
> 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.

> 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.

> >> So maybe I do agree with the critics, that telomeric loss over age is
> >> unrelated to aging.
> >
> >Maybe we will make a "non-telomerist" out of you yet! (Sorry, I just
> >couldn't resist :-(

Oops, I had meant a :-) in that place.

> >Thomas, I don't think that anyone here or anywhere else is trying to say
> >the telomeric loss it not relevant to aging, *in general*. The important
> >and contentious question is whether it is the relevant to any current
> >causes of human mortality, especially those taking place in old age.
> 
> 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.

--Tom 
Tom Matthews
 
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