Tom Mahoney wrote:
> Since the paper describing a genetic component to telomeric maintenance
> was not published until July, 1998 then many researchers are still under
> the mistaken impression that all the telomeres were being depleted in
> Greider's knock out mice. The scientists on Lifelines Scientific
> Advisory Board have all acknowledged that an alternative process of
> maintaining or restoring telomeric length, absent telomerase, would help
> explain many of the results seen in her work.
I would welcome seeing their comments on this thread but, I stress, I have
agreed with you that this alternative process lets us reconcile Greider's
results with the idea that telomere shortening/loss determines the rate of
aging. I'm just pointing out that that reconciliation also lets us quite
rapidly eliminate a lot of options for the mechanism of such a process --
specifically, it lets us identify cell types that cannot be ultimately
> Telomeres are not known to affect the "rate" of aging and apparently
> only come into the aging picture at the "end game" where the cells
> enter senescence and stop replacing cells lost for whatever reason.
> When the cells no longer replicate and start expressing the negative
> genes associated with senescence, the system they belong to begins to
> deteriorate and will, eventually, fail, causing the death of the
> organism, (this latter is, of course only a hypothesis that needs to be
> tested but the evidence is mounting).
Understood. I never meant to suggest that you were saying that the early
stages of telomere shortening were damaging. Let me rephrase my original
statement: "if the time taken for telomere *loss* determines the rate of
aging, then logically it must do so by eventually (when some telomeres are
lost) affecting the health of cells whose telomeres DO shorten during life
(so that some can be eventually lost)". Does that resolve this point?
> Since each cell is
> regenerated during embryonic development their shortened telomeres are
> most likely the result of the shortened telomeres in the germ cells as
> opposed to the absence of telomerase.
Clearly any cell's telomere length is by definition due to the combination
of (a) the telomere length in the original gametes and (b) any telomere
lengthening process that may have been available to the intervening cell
lineage (and (c) the number of cell generations in that lineage, of course).
> This shortened period of telomeric addition could possibly cause the
> longer telomeres not to be completely replaced but may provide sufficient
> time for a shorter telomere to be fully restored. Thus to address your
> question, the individual cells could very well die as a result of
> telomeric shortening on a single, short telomeric, chromosome but it
> would be at the same rate as wild type mice.
The period of addition is no shorter: the difference is that the starting
length (in the gametes of the later generations) is less, so more needs
to be added, which may take longer. But I don't think that alters your
argument, which is (if I understand it) that, in these later generations,
all the telomeres in the lifespan-determining cell types are restored by
non-telomerase means to a sufficient length to sustain normal lifespan,
just as in wild-type mice, but that the wild-type mice also extend some
(but not all) telomeres a lot more than that. Since the shortest ones
are the ones that matter for lifespan, these unnecessarily lengthened
telomeres in wild-type make no difference. That's logically sound, but
in the figure I cited (Cell 91:25-32, fig 5) it is quite clear that the
*minimum* telomere length *also* diminishes relative to wild-type. Any
cell type in which that decrease of *minimum* telomere length occurs is
excluded (by my original argument) from driving aging by telomere loss,
even if we allow for the possibility you have now introduced.
> Quite the contrary! His use of "IF" makes it clear that Greider's
> results did not show any results contrary to the position that a single
> short telomeric chromosome could be the cause of cellular senescence.
> What he is saying is that IF that is the case then these telomeres must
> be maintained in the absence of telomerase since Greider's mice had
> telomerase activity inhibited
I can do no more than to ask you to read the paragraph more carefully.
Sedivy begins it by noting that the average telomere length declines with
each generation, agreed? He then notes that the number of doublings before
senescence is unaltered. He finishes by saying that, if telomere loss is
the senescence signal, but yet the number of doublings is unaltered, then
the frequency distribution of telomere length must NOT be affected. He
could, if he'd felt it was necessary, have gone on: "Since this frequency
distribution *is* affected (see above), therefore, we can conclude that a
minority population of chromosomes with short telomeres is *not* responsible
for generating the senescence signal." The logic here is much simpler than
for the organismal lifespan question, since it discusses two properties of
just one cell type (embryonic fibroblasts). In particular, the mechanism
of telomere length maintenance doesn't come into it.
Aubrey de Grey