IUBio

about the nature article: apotosis

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Thu Dec 23 12:33:22 EST 1999


Lou Pagnucco wrote:

> (1) Apoptosis appears to be upregulated in CR lab animals
> (as discussed in J. of Gerontology last year).  So a natural
> (speculative) deduction is that apoptosis may be responsible
> for the life extending effects of CR.  However, it has been
> (supposedly) demonstrated in some papers that I sent Aubrey
> last year that CR also greatly reduces cellular turnover, and hence
> the mitotic rates in many tissues.  This seems to suggest that
> apoptosis in CR animals is far more selective than in AL animals.

Maybe.  Another interpretation is that apoptosis is up-regulated only
in rather unusual tissues in which cell attrition is very high anyway,
i.e. it's up-regulated in order to keep these short-lived cells in the
best of shape on average by not letting them deteriorate too far.  (I
know only of reports of CR up-regulating apoptosis in liver and gut.) In
that model, apoptosis in most cell types (those with slow cell turnover)
would be reduced simply because of the well-known lowering of oxidant
production.  I think that model is more economical (but I don't claim
to have an objective measure of a theory's economy!)  I recall your
suggesting last year that one might be able to have high apoptosis
and low mitosis in all tissues, but I don't think that situation can
be sustained long-term: CR mice are small, sure, but their body size
is pretty constant during adulthood and so is that of AL mice, so in
both cases cell division must match cell death.

> Could this be a factor in the results reported by the Milan lab?
> (i.e., could they be inhibiting the less discriminating apoptosis in
> AL animals that lead to proliferative exhaustion in certain tissues?)

I don't think so.  In the model I just outlined, there's no proliferative
exhaustion in the AL animals: the low apoptosis is due to low collateral
damage to tissues which normally maintain homeostasis by getting rid of
damaged cells and thus don't drive aging.  However, in view of Sydney's
comment that rates of cell turnover may be much higher than most of us
believe, I will be very interested in his answer to this.

> (2) It seems to me questionable to assert that post-mitotic cells are
> too sparsely distributed to cause any real damage.

I infer from what you say later that you mean replicative-senescent, as
opposed to intrinsically post-mitotic like muscle.  It is best to avoid
using "post-mitotic" for senescent cells -- even though it's logically
impeccable, the term is usually reserved for muscle etc. so readers will
be confused.

> The recent results reported on gene upregulation/suppression in aged
> tissues (using micro-arrays) appear to show a profound difference
> between tissues derived from young and old animals.  Specifically, a
> diffuse inflammatory condition appears to pervade old tissues.  Might
> one reason be that post-mitotic fibroblasts generate approximately 40
> times the collagenases (and possibly other extra-cellular matrix
> destroying enzymes) as juvenile fibroblast do?

I think some people think this is so, but I don't think it stands up to
quantitative scrutiny.  Cristofalo says that only one dermal fibroblast
per 10,000 shows senescent gene expression (such as high collagenase) in
aged tissue.  That means collagenase is only 0.4% higher in bulk tissue
as a result of the 40-fold overproduction you cite.  One could say that
the overproduction affects only the region quite near the senescent cell,
but then it would only affect a small proportion of the tissue.  The big
difference with the mitochondrial theory, in which again only one cell
in 1000 or more is affected, is that those cells may generate reactive
oxygen species at their surface that can initiate peroxidation chain
reactions, which would amplify and spread the damage enormously.  No
analogous scenario has been proposed (yet!) for anything that senescent
cells have yet been found to secrete.

> (3) If it has not been ruled out that cell division itself may ratchet
> cells further down the developmental pathways that lead to terminal
> differentiated, post-mitotic states, shouldn't we be investigating
> mitosis inhibitors as life extending agents?  (Hasn't the Russian
> gerontologist Frolkis published some encouraging results about anti-
> mitotic drugs, e.g. olivomycins, on life extension?)

Even though I'm doubtful about your premise, I think mitosis inhibitors
might conceivably have effects similar to p66, if they were similarly
specific (i.e. to mitosis induced by cell death induced by oxidative
damage).  I don't think non-specific mitosis inhibitors would be good,
for the same reason that I don't think non-specific apoptosis inhibitors
would be good -- namely, mitosis and apoptosis are usually good things.

Aubrey de Grey





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