IUBio

about the nature article: apotosis

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Sun Dec 19 09:56:50 EST 1999


Sydney Shall wrote:

> Perhaps, just perhaps apoptosis is important because it would require
> replacement of cells.  Perhaps, when cell replacement becomes deficient
> we realise that we have "aged"??  Just perhaps!

I feel that this very interesting possibility can be evaluated quite
powerfully by considering a few of its unavoidable implications.  In
the context of the Nature article on p66shc, it suggests that the
apoptotic response to oxidative damage is unnecessarily trigger-happy,
so that hindering that response allows cells that would have apoptosed
to recover under their own steam without significant deleterious side-
effects.  I see no difficulty with that, since if the only drawback of
this trigger-happiness is aging then there may be no selection against
it.  However, if aging is substantially driven by defective replacement
of cells, something must be changing in those cells with time: usually
this is of course proposed to be a change that is a direct result of
their prior divisions.  The traditional candidate, telomere shortening,
appears to have been decisively eliminated from consideration by the
mTR knockout mice (though if you disagree I would welcome your views).

It must also be emphasised, however, that there is another option which
does indeed allow compromised cell division to play a role in aging --
and which was perhaps what you were getting at.  It seems that very few
cells in vivo exhibit detectable senescent gene expression (SGE), so a
role for them in aging usually involves the idea that they secrete stuff
that is damaging to the surrounding tissue (e.g. too much collagenase).
My favoured elaboration of the mitochondrial theory of aging involves
the same idea -- that the evidently very few cells which are taken over
by mutant mitochondria generate extracellular free radicals which cause
oxidation of circulating material and thence stress to mitochondrially
healthy cells.  But of course this means that the two theories converge:
whether the primary culprits are telomeres or mitochondria (or both),
the victims that matter may likewise be either mitotic or postmitotic
cells (or both).  I find it wholly plausible that highly mitotic cells
which suffer stress, from whatever source, would become less proficient
at cell division as a result - i.e. NOT as a result of having undergone
a lot of prior cell division themselves.  The key question is whether
that decline in mitotic capacity matters for the organism; I agree with
you that this possibility remains open.

I would be interested in your view on a related point, which may be a
route towards distinguishing between the suspected primary culprits. 
The idea of systemic decline driven by SGE requires that the critical
tissue(s) in mice, i.e. those whose SGE drives aging, do not exhibit
any greater SGE in fifth-generation mTR knockouts than in age-matched
controls.  I appreciate that assays for SGE are less well developed in
mice than in human cells, but with luck that will change.  I recently
suggested to Campisi that, if such assays in mice could be improved,
an efficient approach to designing her favoured intervention (namely,
the selective ablation of senescent gene-expressing cells) would be to
compare the levels of SGE in fifth-generation mTR-/- knockouts versus
controls in various cell types: any in which SGE is much higher in the
knockouts can than be ignored, since they are evidently irrelevant to
lifespan, and efforts at selective ablation can focus on the others.
What do you think of this approach?

Aubrey de Grey





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