Tom Mahoney wrote:
> While much additional research does need to be completed the basic
> questions have, finally, been answered.
You simply cannot say this. It is emphatically not the view of the
research community; thus you must explain what we are all missing
before you can make such an assertion. You acknowledge later that:
> how we get from telomeres determining cellular reproductive
> capacity in replicative cells to their being a determinant
> of life span in any organism is the biggest question ahead of us.
I think that is a rather basic question! As yet, one plausible answer
to it -- made much more testable, if not more plausible, by Greider's
work -- is that that they are not a determinant of lifespan at all.
> I don't think there is any
> theoretical basis for telomeric shortening to cause damage to cellular
> In crisis stage, where the telomeres are completely depleted, the
> chromosomes fall apart or fuse inappropriately resulting in cellular
> apoptosis or death but up until that point there is no apparent
> detrimental effects known to be a direct result of telomeric shortening.
Ah - I see, you distinguish between (a) effects due to shortening but
not total loss and (b) effects due to total loss (of only some telomeres,
in both cases). I'm not making that distinction -- the argument I gave
in the previous post applies whether or not telomere loss must be total
before there is an effect.
> >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 ... the
> >whole edifice relies on the existence of those cell types.
> Those "type" of cells constitute the majority of somatic cells. The
> only exceptions being those cells, like T cells that normally require
> telomerase for their normal functioning
This is wrong. In their first paper on the knockout mice (Blasco et
al, Cell 91:25-32), Greider's lab examined fibroblasts from successive
generations and found that the telomeres shortened (Fig 5). Thus, these
fibroblasts or their progenitors did not have their telomeres restored
to wild-type length during embryogenesis. Such cells are excluded, by
the argument I gave in the previous post, from being causative in any
mechanism whereby telomere shortening determines lifespan.
> that is exactly what J. Sedivy in Proc Natl Acad Sci U S A 1998 Aug
> 4;95(16):9078-9081 was referring to when he said "...their frequency
> distribution, would not be affected by the absence of telomerase activity
> for several generations."
No, Sedivy argues the exact opposite of what you say. That paragraph
begins by noting that the average telomere length declines with each
generation -- that is, that the lengths do NOT have the same frequency
distribution as in wild-type mice. The sentence whose second half you
quote then begins: "If a minority population of chromosomes with short
telomeres is responsible for generating the senescence signal, one
would have to assume that these chromosomes, and their frequency ...".
In other words, Sedivy says that Greider has shown that the senescence
signal is NOT generated by short telomeres. (That says nothing about
organismal lifespan, though -- only the lifespan results do.)
Aubrey de Grey