Mitochondria oxidative damage?

MFossel mfossel at aol.com
Sun Jul 28 11:49:49 EST 1996


David:

Thanks for your comments on aging. Regarding telomeres and non-dividing
cells
such as neurons and muscle cells (unless we include the exceptions in the
olfactory bulb and satellite cells respectively), please remember that
none
of these cells function in isolation.  In the case of the nervous system,
for
example, only 10% of the cells are neural, whereas 90% are glial.  Glial
cells (especially microglia, which are implicated in the early
inflammation
which is part of the poorly understood etiology of Alzheimer's dementia)
do
divide.  Their telomeres may therefore play a prominent role in this
common
form of dementia.  The (unproven) model would go something like this.  The
glia divide, their telomeres shorten, their gene expression alters during
the
gradual loss of the last few thousand DNA bases, glial function alters and
they no longer provide neurotropic factors in the abundance (or pattern)
sufficient for normal neuron function, and some neurons show typical
changes
consistant with Alzheimer's dementia.  In this model, telomeres do NOT
cause
aging (nor do they in any model), rather they time its onset and
progression.
The causes are more ill-defined and numerous, including anything that
promotes excessive glial cell division, incites local inflammation, or
interferes with normal neuron function.  Nevertheless, telomere shortening
theoretically would play a pivotal role in the etiology and (far more to
the
point) treatment:  if we can extend telomere lengths in glial cells, could
be
halt the pathology.  If we do so early enough, could we prevent dementia? 
Of
course, once neurons are lost, they are lost:  a "humpty-dumpty effect".  

By the way, the same model has considerable data to support in the onset
of
atherosclerosis:  muscle cells may not divide (satellite cells aside), but
their normal function is dependent upon endothelial cells (which do
divide)
in the case of vessels, and the vessels themselves (hence again
endothelial
cells) in the case of myocardial tissue.  See for example Cooper, Cooke,
and
Dzau's article and the work on telomere shortening in vessels which came
out
last year.

Incidentally, I agree vis a vis mitochondria:  they are the major (95%)
source of intracellular free radicals and therefore one of the major
sources
of entropic damage within cells.  The question is begged however (if we
call
them the only "cause" of aging) why have they been inherited flawlessly
(for
an estimate 1-2 billion years since they first took up residence in
eukaryotic cells) and yet "age" within a matter of decades within your
somatic cells?  What times (or switches on) this sudden degradation in
function.  It clearly occurs in somatic cells (you are correct) and yet it
clearly has not occurred within the inherited maternal germ cell line of
mitochondria for an astounding timespan.  It is as though mitochondria are
biologically immortal (and homeostatically flawless) for billions of years
until you and I inherit them, and then go downhill almost instantly (in
comparison).  This demands an explanation:  telomere theory, senescent
gene
expression, and cell senescence offers one that is consistant, elegant,
and
predictive.  So far (we'll see), this prediction has been borne out in the
laboratory...

Anything that improves our homeostatic defences should extend lifespan,
but
these effects (whether Coenzyme Q, DHEA, more efficient SOD, or vitamin E)
can scarcely be expected to result in the biological "immortality" already
inherant in germ cell line mitochondria.  The secret is far more likely to
lie within altered gene expression (and hence the telomere) than with
dietary
alteration or supplementation.

Glad to see someone else who trains as a neuroscientist is also interested
in
aging.  The nervous system was my first love as well.

Best Wishes, 
Michael Fossel, MD, PhD
Author, Reversing Human Aging




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