about the nature article: apotosis

Lou Pagnucco pagnucco at oeonline.com
Thu Dec 23 01:07:45 EST 1999

Hello Aubrey and Sydney,

A couple questions from a layman trying to follow your very
interesting discussion:

(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.
      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?)

(2) It seems to me questionable to assert that post-mitotic cells are too
      sparsely distributed to cause any real damage.   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
      condition appears to pervade old tissues.  Might one reason be that
      post-mitotic fibroblasts generate approximately 40 times the
      (and possibly other extra-cellular matrix destroying enzymes) as
      fibroblast do?

(3) If it has not been ruled out that cell division itself may ratchet cells
      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
      encouraging results about anti-mitotic drugs, e.g. olivomycins, on

Cheers & Happy Holidays,
Lou Pagnucco

Aubrey de Grey wrote in message <83li10$hq3$1 at pegasus.csx.cam.ac.uk>...
>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
>> 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.
>Aubrey de Grey

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