Tom Mahoney wrote:
> Well, I'm happy to report that these legitimate questions have been
> substantially answered in favor of the telomeric theory of aging!
I think this is substantially overstated....
It indeed seems likely that mechanisms other than telomerase contribute,
in some tissues more than others, to telomere maintenance. Moreover, we
cannot yet exclude the possibility that, in some such tissues, these other
mechanisms are sufficient to maintain telomeres indefinitely, without the
help of telomerase. But, if telomere shortening determines the rate of
aging, then logically it must do so by affecting the health of cells which
are NOT in that category -- ones whose telomeres DO shorten during life.
Now, it is possible (and I think this is what you're suggesting) that the
non-telomerase mechanisms of telomere length maintenance are incompetent
(in those cells) during most of life, but are so good during embryogenesis
that they restored everything that was lost in the germ line of the earlier
telomerase knockout generations. This would give the observed result, i.e.
that lifespan was not affected. But if that is the only way to reconcile
Greider's results with the idea that telomere shortening determines the
rate of aging (and I believe that it is indeed the only way, other than to
argue that it determines it in humans but not in Mus musculus), then the
whole edifice relies on the existence of those cell types.
Therefore I would argue that Greider's work constitutes enormous progress
with regard to testing the "telomere theory of aging". It means that we
should work to identify all cell types (if there are any) whose telomere
length is maintained through multiple generations of the knockout mice --
this is not trivial, principally because of the heterogeneity of telomere
length that you note -- and then we can narrow the search for a detailed
mechanism of how (if at all) telomere shortening determines the rate of
aging to ones that start from those cell types. Furthermore, those cell
types would be likely to be the ones expressing (in embryogenesis) the
highest levels of the non-telomerase telomere maintenance proteins, so
they may be the cells in which those genes are easiest to characterise.
Once characterised they could be knocked out; in mice which were negative
for them as well as for telomerase, if telomere shortening determines the
rate of aging there should indeed be lifespan effects. (Of course there
might be yet a third maintenance mechanism, etc, but one could repeat the
Aubrey de Grey