feedback requested on ideas(modified)

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Mon Feb 19 12:20:08 EST 2001


Iuval Clejan wrote:

> Differential expression of a particular protein between young and old
> cells occurs as a result of :
> 
> 1 a mutation to some genes (not necessarily the one coding for that
> protein)
> 
> 2 decrease (or halting of) replicative capacity or stoping replication
> due to e.g.  telomere shortening and lack of telomerase, and/or
> commitment away from stem cells to a more differentiated form.
> 
> 3 the cell's environment of nutrients and hormones is changed, perhaps
> due to other cells (which produce hormones or metabolize nutrients that
> go to this cell and the extracellular matrix) experiencing 1 or 2
> above.
...
> For the reasons above I will focus on mechanism (1) in this essay.

This is a fair start, but has several problems.  First, your category (2)
should be extended to include any cumulative change that occurs as a side-
effect of normal metabolism, not just the two that you mention (replicative
senescence and differentiation).  One that may be very important is the
buildup of undegradable junk in lysosmes.  In nerves and muscle this is
lipofuscin and its causal role in aging is still controversial, but in
some other cell types it is definitely very bad for us: a major example
is the oxidised cholesterol that accumulates in arterial macrophages and
turns them into foam cells initiating atherosclerosis.

Second, mechanism (3) can occur due to something much more dramatic than
mechanisms (1) and (2) happening to other cells, namely other cells
dying and not being replaced.  It is certain that a lot of aging is of
this type.  The decline of the immune system is due in large part to 
loss of cells in the thymus, for example.

Third, your mechanism (3) can occur due to changes in the extracellular
environment, not driven by other cells at all.  This is why AGE-breakers
are so exciting: AGEs probably accumulate intracellularly too, but in the
extracellular matrix they seem to play a much more major role in making
tissues less elastic.  This makes the heart work less well, for example,
which clearly has rather widespread potential consequences.

Fourth, when you dismiss decreased replicative capacity as having much
to do with aging you do so on the basis of replicative senescence, i.e.
you essentially ignore the other cause (differentiation), which is not
studied in typical in vitro cell senescence experiments.  Cell loss in
muscle is a good example of something that should be (indeed, is) very
largely reversible by stimulating cell division: in that case by the
very low-tech method of appropriate exercise.

> If hormones/nutrients/extracellular matrix change due to decreased
> replicative capacity of some cells (3), then the change should be
> artificially induced in vitro to see if other cell types (e.g. heart
> or brain) react to that change by aging more quickly.

You seem to imply that this is an easy experiment....

> I think there are
> very few mutations that can cause a continuous change in protein
> expression per cell. These include (correct me if I'm wrong) mutations
> to:

Hang on.  This list covers only the simple case of mutations that cause
modulation of expression of the same protein, in the same cell, that
the mutation is in the gene of.  What about mutations in other genes in
the same cell, quite apart from your mechanism (3) dealing with other
cells?  Also, mutations may have nothing to do with these changes --
gene expression is modulated by cellular state in terms of degree of
oxidative stress, for example.  At any particular moment a particular
gene may be being expressed or not being, but over a long period it
will alternate between on and off and the proportion of time it spends
in either state can vary continuously during aging due to arbitrarily
complex interactions of other changes.

> In a non replicating
> cell, the only way to knock out a gene with random damage (due to toxic
> environmental or metabolic oxidant species) is if there is only 1 (or
> no) repair pathway for that type of damage (or one enzyme shared
> between two or more pathways), and if a gene coding for an enzyme in
> that pathway (or the shared enzyme)also gets the same type of damage.

Wrong: you're forgetting that these repair processes are imperfect.
Suppose that a methylcytosine is deaminated and so becomes thymine,
paired to guanine.  There's an enzyme that spots these and replaces
the thymine with cytosine.  But since that doesn't happen absolutely
instantly, and there is also other damage going on at the same time,
there's a chance that the other strand (the one with the guanine)
will suffer damage that requires bulky lesion repair, for example,
where a chunk of strand is just excised and rewritten using the
other strand.  If that happens while the methylcytosine is still a
thymine, you've got a fixed base pair substitution.

> Now the mtDNA may be the only DNA in mammals for which there is only
> one repair mechanism for some some types of oxidative damage.

Here your argument breaks down not only for the above reason but also
because mitochondria continue to divide even in non-dividing cells.
Replication can make mutations out of thin air, with no intermediate
oddity that can be recognised as damage by some repair enzyme.  Once
the mutation has happened, it may take over the cell by virtue of
having some sort of selective advantage -- see, for example, the model
I proposed in BioEssays 19:161.

Aubrey de Grey







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