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Lou Pagnucco wrote:

> Telomerase May Protect Nerve Cells from Brain Disorders

Very interesting, potentially.  The well-established acceleration of
telomere shortening by oxidative stress in vitro (von Zglinicki's
work, among others) certainly suggests that telomerase should slow
telomere shortening in highly-stressed postmitotic cells as well as
in rapidly-dividing ones.  Mattson's earlier work found an anti-
apoptotic role for telomerase in cancer cells (J. Biol. Chem. 274:
7264); similar reports exist from other groups.

However...

The thrust of this news report (though maybe not the actual article,
which I haven't seen) is that apoptosis of neurons is a causative
step in development of Alzheimer's pathology, such that inhibiting
apoptosis would be therapeutic.  This is an example of the general
assumption that apoptosis is bad for us, which is usually wrong --
in general, apoptosis SLOWS DOWN aging and age-related pathologies
by eliminating cells that are causing the pathologies.  Retarding
that sort of apoptosis would therefore exacerbate the pathology.

So, is neuronal apoptosis in AD good or bad?  In fact, does it
happen at all?  A very instructive letter to Science from George
Perry and colleagues (Science 282:1265) explains the problem.  Here
is the start of it:

  An article ... presents the case for apoptotic neuronal death in
  Alzheimer's disease (AD) based on culture studies and histological
  analyses.  We strongly disagree that this evidence supports
  widespread apoptosis in AD.  Apoptosis requires only 16 to 24 hours
  for completion and, therefore, in a chronic disease like AD with an
  average duration of almost 10 years, less than one in about 4000
  cells should be undergoing apoptosis at any given time (that is,
  observation of apoptotic events should be rare).  Indeed, if all the
  neurons reported with DNA cleavage were undergoing apoptosis, the
  brain would rapidly be stripped of neurons.  This is certainly not
  the case in AD.

The conclusion is that AD neurons may exhibit some of the hallmarks of
apoptosis because they initiate apoptosis but then arrest it.  Similar
features are seen in muscle fibre segments that have accumulated mtDNA
mutations (see e.g. Mirabella et al, Brain 123:93).

In conclusion: there is more to this topic than meets the eye.

Aubrey de Grey

Thanks for the thoughtful reply, Aubrey.

I have a few questions and comments below.
(By the way, I hope you Brits keep fighting MI5 on the email
 spying issue!)

Cheers,
Lou Pagnucco

Aubrey de Grey wrote in message <8i7utv$md1$1@pegasus.csx.cam.ac.uk>...
>
>Lou Pagnucco wrote:
>
>> Telomerase May Protect Nerve Cells from Brain Disorders
>
>Very interesting, potentially.  The well-established acceleration of
>telomere shortening by oxidative stress in vitro (von Zglinicki's
>work, among others) certainly suggests that telomerase should slow
>telomere shortening in highly-stressed postmitotic cells as well as
>in rapidly-dividing ones.  Mattson's earlier work found an anti-
>apoptotic role for telomerase in cancer cells (J. Biol. Chem. 274:
>7264); similar reports exist from other groups.
>
>However...
>
>The thrust of this news report (though maybe not the actual article,
>which I haven't seen) is that apoptosis of neurons is a causative
>step in development of Alzheimer's pathology, such that inhibiting
>apoptosis would be therapeutic.  This is an example of the general
>assumption that apoptosis is bad for us, which is usually wrong --
>in general, apoptosis SLOWS DOWN aging and age-related pathologies
>by eliminating cells that are causing the pathologies.  Retarding
>that sort of apoptosis would therefore exacerbate the pathology.

I agree that apoptosis is absolutely vital for optimal maintainance.
It certainly appears that apoptosis is upregulated during caloric
restriction.
However, the Milan group (I cannot remember the authors) that published
in Nature some months ago, seemed to show that mice genetically modified
to exhibit lower rates of apoptosis lived about 35% longer.

So it seems better to defer conclusions until definitive experiments are
performed (IMHO).

>
>So, is neuronal apoptosis in AD good or bad?  In fact, does it
>happen at all?  A very instructive letter to Science from George
>Perry and colleagues (Science 282:1265) explains the problem.  Here
>is the start of it:
>

Very, very interesting.

Is it possible, though, that the process of apoptosis might be only
partially
turned on?  -i.e., activated for just a while (and perhaps dithers, rather
than
latches into a terminal state) and then lapses?.  Could failed, transient,
apoptotic
episodes result in extensive cell/tissue damage instead of cell death?

>  An article ... presents the case for apoptotic neuronal death in
>  Alzheimer's disease (AD) based on culture studies and histological
>  analyses.  We strongly disagree that this evidence supports
>  widespread apoptosis in AD.  Apoptosis requires only 16 to 24 hours
>  for completion and, therefore, in a chronic disease like AD with an
>  average duration of almost 10 years, less than one in about 4000
>  cells should be undergoing apoptosis at any given time (that is,
>  observation of apoptotic events should be rare).  Indeed, if all the
>  neurons reported with DNA cleavage were undergoing apoptosis, the
>  brain would rapidly be stripped of neurons.  This is certainly not
>  the case in AD.
>
>The conclusion is that AD neurons may exhibit some of the hallmarks of
>apoptosis because they initiate apoptosis but then arrest it.  Similar
>features are seen in muscle fibre segments that have accumulated mtDNA
>mutations (see e.g. Mirabella et al, Brain 123:93).
>

This appears to answer the question I posed above.

Is it also possible that these failed cellular suicide attempts are due to
mitochodrial oxidative bursts that manage to leave behind the biomarkers
of cellular ageing?
i.e., Is it possible that normal mitochondrial respiration has gotten a "bum
rap" and unfairly indicted for the cellular "damage" seen in senescent
cells?
(whereas these intentional but abortive suicide attempts are actually
 responsible?)


>In conclusion: there is more to this topic than meets the eye.
>
Amen.
Too bad this area doesn't attract the research funding it deserves!

>Aubrey de Grey

Aubrey de Grey wrote in message <8i7utv$md1$1@pegasus.csx.cam.ac.uk>...
>
>Lou Pagnucco wrote:
>
>> Telomerase May Protect Nerve Cells from Brain Disorders
>
>Very interesting, potentially.  The well-established acceleration of
>telomere shortening by oxidative stress in vitro (von Zglinicki's
>work, among others) certainly suggests that telomerase should slow
>telomere shortening in highly-stressed postmitotic cells as well as
>in rapidly-dividing ones.  Mattson's earlier work found an anti-
>apoptotic role for telomerase in cancer cells (J. Biol. Chem. 274:
>7264); similar reports exist from other groups.
>
>However...
>


Another thought just struck me, Aubrey.

Shouldn't this paper's hypothesis be easily testable with the
new cloned sheep/goats which have long telomeres?

Wouldn't it be relatively easy to extract some neural or muscle
cells from them and challenge them (in vitro) with apoptosis
inducing stimuli?  If they proved to be resistant to these insults,
then we would have some very interesting results, no?

Cheers,
Lou Pagnucco

Lou Pagnucco wrote:

> the Milan group (I cannot remember the authors) that published
> in Nature some months ago, seemed to show that mice genetically
> modified to exhibit lower rates of apoptosis lived about 35% longer.

Miglaccio et al, Nature 402(6759):309-313.  True, but it is crucial
to remember that the reduction of apoptosis was not indiscriminate:
it was specifically a reduction in oxidative stress-induced apoptosis
due to knockout of one isoform of a protein.  However, I still agree
strongly with you that more experiments are needed.

> Could failed, transient, apoptotic episodes result in extensive
> cell/tissue damage instead of cell death? ...  Is it also possible
> that these failed cellular suicide attempts are due to mitochodrial
> oxidative bursts that manage to leave behind the biomarkers of cellular
> ageing?  i.e., Is it possible that normal mitochondrial respiration has
> gotten a "bum rap" and unfairly indicted for the cellular "damage" seen
> in senescent cells?  (whereas these intentional but abortive suicide
> attempts are actually responsible?)

I don't think this is very likely.  We must ask what initiated the
failed apoptosis in the first place: something must have been pretty
wrong with the cell or it would not have begun the program.

Aubrey de Grey

Lou Pagnucco wrote:

> Shouldn't this paper's hypothesis be easily testable with the
> new cloned sheep/goats which have long telomeres?
> 
> Wouldn't it be relatively easy to extract some neural or muscle
> cells from them and challenge them (in vitro) with apoptosis
> inducing stimuli?  If they proved to be resistant to these insults,
> then we would have some very interesting results, no?

Not particularly interesting, I would say: the existing data already
indicate quite strongly that telomere stabilisation is anti-apoptotic,
so such resistance would be no surprise.  That's no reason not to do
the experiment, though -- after all, the result might be the reverse.

I should have mentioned another recent article that is relevant to the
topic.  Henle et al, J Biol Chem 274:962-971 showed that telomeric
sequences are preferential targets for iron-mediated DNA damage, and
they hypothesise that this might be used as a sensor for oxidative
damage.

Aubrey de Grey