Telomeric Theory - Those Damn Mice

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Tue Sep 8 17:35:56 EST 1998

With regard to Sedivy's passage: OK, I grant that it can be read that way.

With regard to the reconciliation of the telomere theory with the lifespan
of knockout mice, I think we agree on the logic.  I think your proposal --
that only some chromosomes are responsible for triggering senescence when
their telomeres are lost, and that these chromosomes are singled out for
special extension by non-telomerase means -- is highly implausible, but I
accept that, if we allow the possibility that such a system is present, the
data we have so far do not settle the question (since no analysis of any
specific chromosomes has been done).  Moreover, I think we are agreed that
it is both possible and valuable to gather this specific data, in many
different cell types, since that will potentially eliminate those cell
types from being ultimately responsible for a telomere-based determination
of lifespan.  I think we thirdly agree that a knockout of both telomerase
and this gene (or genes) on chromosome 2 would be even more valuable,
though until we also look at specific chromosomes one will always be able
to postulate yet another (uncharacterised) telomere maintenance mechanism.

In conclusion, I stand by (and I think you agree with) my earlier statement
that Greider's work constitutes enormous progress with regard to testing
the telomere theory of aging, since it tells us that, if that theory is
correct, aging must be driven by those particular chromosomes in those
particular cell types, so all we need do is look for them.  I must also
repeat, however, that your invokation of two crucial, untested postulates
-- that the senescence signal is associated with specific chromosomes, and
that the non-telomerase mechanisms of telomere maintenance are adequate
to maintain telomere length over six generations (on those chromosomes,
in the lifespan-determining cell types) -- is not accurately summarised
by your original assertion that "these legitimate questions have been
substantially answered in favor of the telomeric theory of aging".  The
answering has hardly begun, and the final answer shows no sign whatever,
as yet, of being in favour of that theory.

Time, and experiment, will tell!

Aubrey de Grey

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