IUBio

about the nature article: apotosis

Dr. Sydney Shall sydney.shall at kcl.ac.uk
Sun Dec 19 12:23:18 EST 1999



Aubrey de Grey wrote:

> 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).
>

I have two comments about these comments. Firstly, some years ago Paolo
Giacomoni suggested that ageing was due to the excessive response of
macrophages to the inevitable traumas of all kinds that tissue would suffer.
In the present context his idea supplies a possible origin for the trauma
that might lead to apoptosis.

Secondly, I would point out that while telomere shortening does not seem to
be a good candidate for the cellular ageing clock, because without
telomerase activity mouse cells still apparently show the usual cellular
ageing, still many people believe that telomeres ARE the cellular ageing
clock.  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. Although this is random and unpredictable, on average it
will be rather stable. Thus, with a given lifestyle DNA damage may occur at
a relatively constant rate.  Thus either mitochondrial damage or nuclear DNA
damage could lead eventually to the senescence of the cell. 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.




>
> 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 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.

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.

>
>
> 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?
>

This raises an interesting point. Eventually the mice that lack telomerase
activity do get sick.  This demonstrates that without telomerase activity
organisms cannot survive.  The phenotype of these sick mice does not
resemble ageing very well.  It seems to me that homeostasis in an adult
requires lots of cell division. I believe that biologists have grossly
underestimated the extent of apoptosis and hence of cell replacement in
adult organisms. I think that the experiment that you would like to see done
is very simple and can be done. I will bet in public here that 5th
generation telomerase minus mice do not accumulate senescent cells
excessively!  My neck is now stuck out!


>
> Aubrey de Grey

A happy holiday to all, and a great New Year.

Sydney Shall

-- Dr. Sydney Shall, Department of Molecular Medicine, King's College School
of Medicine & Dentistry, The Rayne Institute, 123 Coldharbour Lane, LONDON,
SE5 9NU, TEL: 01 71 346 3126; FAX: 01 71 733 3877, E-Mail:
sydney.shall at kcl.ac.uk

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