decreasing proliferative capacity theory

Aubrey de Grey ag24 at
Fri Feb 9 10:15:15 EST 2001

Iuval Clejan wrote:

> Does anyone know any arguments against the theory stating that the main
> cause of aging is the decreasing proliferative capacity of most cells as
> they differentiate away from stem cells. I think this theory is a
> generalized telomere shortening one, saying that telomere shortening is
> not necessarily the cause of decreased proliferative capacity, but is
> correlated with this unidirectional differentiation, and the decrease in
> stem cells (?) may be due to changes in e.g. extracelllular matrix. (Is
> it true that it is not the case that stem cells have a decreased
> proliferative capacity with time, but that there are less stem cells and
> more differentiated cells, and the more differentiated a cell is, the
> less its proliferative capacity?)

I don't know of evidence that stem cell numbers diminish in most tissues,
no (and I agree that your model depends on this).  There are exceptions:
see for example Potten's work on intestinal crypts).  Stem cells tend to
express telomerase anyway (though apparently not quite enough to avoid
any telomere shortening).  Degree of differentiation doesn't entirely
correlate with proliferative capacity either, but that's a side issue.

> I suppose this is coupled with the idea that there is a constant
> fraction of damage that escapes repair, and that while there is a good
> supply of stem cells (and perhaps descendants which still have some
> proliferative capacity), cells escaping damage repair are replaced, but
> when proliferative cells run out, damage accumulates.

Not really.  Since the stem cells are a dividing population, so long as
they keep their rate of accumulation of damage down to a low enough (but
not infinitesimal) level and can detect that damage reliably and quickly,
they can indefinitely maintain a constant population of cells with no
increase in damage whatsoever.  The only time that this would fail is if
ALL the stem cells in a given population suffered damage simultaneously
(strictly, within the time frame of detection and selection based on the
damage) so that there was no way to recover -- "Muller's ratchet".  This
can happen if the stem cell population is really really small, as in an
intestinal crypt, but when there are hundreds (let alone more) of cells
each of which contributes to the same tissue, the chance of this is too
small to matter even in a human lifetime.

> The only thing I can think of is that by birth there are no cardiac stem
> cells left, and there are very few in the neuron population, but maybe
> these cell types are pretty efficient at damage repair and other organs
> are going to accumulate more damage first.

Indeed, that is what your model requires, but in fact problems due to
cell loss appear to affect the brain and the heart quite a lot.  There is
less neuron loss in the brain than was traditionally believed, but some
regions undoubtedly lose a lot -- 20% in the substantia nigra even in
the absence of Parkinson's disease, for example.  In the heart there is
also cell loss, much of which is compensated by growth (without division)
of the remaining cells, but there is also increased fibrosis.

Aubrey de Grey

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