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 at 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
