Aubrey de Grey wrote:
> Lou Pagnucco wrote:
>> > My (possibly naive) speculation is that apoptosis commands are received
> > by wayward pre-cancerous cells from their neighbours through gap
> > junctions. Perhaps when these deviant clusters grow too fast they lose
> > contact with adjacent cells so quickly that the apoptotic agents do not
> > have time to initiate cell death (at which point the mass becomes an
> > overt cancer.) After all, gap junction inhibitors are cancer promoters.
> >
> > Wouldn't this explain both the reduction in the mitotic rate and
> > increase in the mitotic rate effected by CR?
>> This sounds very plausible to me, but I have rather paltry knowledge of
> how the apoptotic signal is transmitted and would welcome comments from
> anyone who knows more.
>> > ageing tissues are subject to what Floyd refers to as "smouldering
> > inflammation"
>> Yes -- one of the most succinct characterisations I've come across.
> But I feel that doesn't distinguish between the competing hypotheses
> for what is/are the main originating cause(s) of that inflammation.
>> > I believe that your 0.4% figure is much too conservative, but do not
> > have figures to contest it.
>> My figure of one dermal fibroblast per 10,000 comes from a note in PNAS
> 95:10614-10619:
>> reports of donor age-dependent increases in beta-galactosidase
> staining really reflect less than 1 in 10^4 cells stained even in the
> oldest individuals and are of questionable significance in vivo
> (V.J.C., unpublished work).
>> (VJC is Cristofalo.) Campisi and others who have reported senescent
> gene expression in vivo have been coy about providing this important
> number. On the other hand, since this 10^-4 result is unpublished we
> don't know important details such as whether the donors and/or biopsy
> positions were plausibly representative of typical mitotic tissues.
In addition, a similar non-quantitative observation can be made by examining
the photographs in the published papers from the Campisi Laboratory. I can
confirm that this discussion has been widespread. The manner in which Campisi
explains the effect of these aged cells also confirms the notion that there
are relatively few of them. Judy Campisi then undertakes to explain how
relatively few senescent cells may alter the properties of the bulk of the
tissue. She agrees, I think, that that there are not enough senescent cells
[according to current observations] to explain the diminished function as due
to a deficiency in cell number.
>>> > is it certain that only Hayflick-limited post-motitic fibroblasts are
> > responsible for excess production of the matrix degrading enzymes? Is
> > it not more likely, that fibroblasts approaching the Hayflick limit
> > are already expressing some of these senescent traits?
>> Sure, but senescent gene expression was assayed above, not mitosis.
>> > if my speculation above is correct, then reducing the mitotic rate
> > would make escaping apoptosis more difficult for wayward cells by
> > keeping them in contact with their normal neighbours who would have
> > more time to eliminate their deviant siblings.
>> Yes. I think this idea fits well with the various other theories of
> how CR retards cancer (see Warner et al, J Gerontol 50(3):B107-B109).
>> Aubrey de Grey
Cheers,
Sydney
-- 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
---
