Sydney Shall wrote:
> while telomere shortening does not seem to be a good candidate for the
> cellular ageing clock, ... still many people believe that telomeres ARE
> the cellular ageing clock.
I couldn't have put it better myself :-) On this topic I recommend all
here to peruse a quite glorious running battle between Harry Rubin and
the rest of the world in four issues of Nature Biotechnology, 16(5) and
(8) and 17(1) and (4), which I fear may have been terminated by Rubin's
invocation of Whitehead; I congratulate Sydney on his contribution to
it (such as it may have been) and intend in a later post to follow up a
couple of the points raised there.
> I would suggest that an alternative for the cellular ageing clock could
> be either DNA damage (or damage to any essential cellular organelle) or
> general damage. ... Thus since cells are essentially sensitive to DNA
> damage only during S-phase and during cell division, it will appear
> that it is the number of prior cell divisions that determine ageing,
> while in fact it may be the accumulated DNA damage that is significant.
I'm not sure that we can go that far. Of the three categories of damage
to dividing cells that you enumerate -- to nuclear DNA, to mitochondrial
DNA and to material other than DNA -- this logic only applies to nuclear
DNA, because mitochondria perpetually divide even in non-dividing cells
and non-DNA damage is diluted, rather than fixed, by cell division. But
yes, nuclear DNA damage could determine replicative capacity. Of course
von Zglinicki combines the two ideas (and I think he could be right), by
saying that it might be damage to telomeric sequences which matters most.
> I agree of course that it is possible that cells senesce because they
> are damaged; that is to say thaey stop dividing because of damage.
> However, in my opinion senescent cells do not look like arrested
> damaged cells; the phenotype is different.
Sure. I propose only that in vivo there is a continuous onslaught of
extracellular stressors (maybe originating from rare OXPHOS-less cells,
maybe from rare near-senescent cells) and that this slows them down,
but when liberated from that environment and subject only to internal
stresses (in vitro) they recover.
> I also have difficulty with the proposal of Judy Campisi that ageing is
> due to the presence of a small number of senescent cells. I would like
> to add that this proposal is exactly what Leonard Hayflick suggested in
> his early papers. But there seem too few cells to be such a problem;
> and the senescent products do not seem (so far) so very deleterious.
Absolutely -- in fact, this is a large part of why I prefer the rare
OXPHOS-less (mitochondrially mutant) cells as the culprit, since they're
likely to generate extracellular products that are quite respectably
deleterious.
> I believe that biologists have grossly underestimated the extent of
> apoptosis and hence of cell replacement in adult organisms.
That is a refreshingly provocative assertion -- could you summarise what
you see as the best evidence for it?
> I will bet in public here that 5th generation telomerase minus mice do
> not accumulate senescent cells excessively! My neck is now stuck out!
Good for you!
> A happy holiday to all, and a great New Year.
Seconded.
Aubrey de Grey
