In article <35FB0E52.5331 at netcom.ca>, tmatth at netcom.ca says...
>>> 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.
>> 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.
>> But what does this have to do with aging and the criticisms of the
>> telomeric theory? Well, each of these processes determines how the >>
>>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.
>> 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.
>> 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 two 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. 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.
>> So if worms and flys age and die without losing telomeric length and the
>> post mitotic cells in humans don't have shortened telomeres just how can
>> telomeric shortening be a cause, let alone the controlling factor, of >>
aging in humans?
>>>> Some research has shown that extending telomeric length by introducing
>> h-TERT, the catalytic protein subunit of the enzyme telomerase can cause
>> human replicating cells to survive well beyond their expected Hayflick
>> limit, in a phenotypically youthful state. But this may be a fluke and
>> not applicable to aging.
>>And these cells are not undergoing the *passage of time* and other
>extracellular influences which ages cells in vivo.
I haven't seen any follow up to the cells in this study except that they are
>> 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)
And exactly what biological mechanism(s) is driving this passage of time
>> 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
Citations on this aging phenotype unrelated to telomeric length?
>> 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 morality 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!
>> 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 and generating the
senescence signal among numerous other studies, is suggesting that they are a
>> 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 :-(
>>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.
Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.