Mitochondrial competition and its effects

Aubrey de Grey Genetics ag24 at mole.bio.cam.ac.uk
Sun Feb 25 11:55:10 EST 1996


To to all of you out there who know a bit about mitochondria:  I would
be grateful for a succinct demolition of the following line of thought,
which came to me while browsing Medline.  Which of my statements about
the known facts are wrong, and/or which of my inferences are logically
unsound?  It all seems a bit too obvious to be really true.


The relevant known facts (as I understand them):

0) Aging in non-dividing tissues is associated with (can I go so far as
   to say "defined as"?) overall slowdown of cellular function, as
   measured by, eg, rate of protein synthesis.

1) Mitochondrion (mt) function is one of the really fundamental parts
   of an animal cell's machinery; if the overall respiratory performance
   of a cell's mta declines, everything slows down, and there is only one
   thing the cell can do about this: replicate some mta.  If that tactic
   is ineffective for any reason, aging will occur in that tissue.

2) Mta are always exposed to the mutagenic potential of the free radicals
   that they themselves make during the respiratory cycle.

3) In a non-dividing tissue, each cell's mta are an isolated population
   whose size remains roughly constant over time.

4) Mta do not live for ever; they are (at some rate that I could not find
   a number for) broken down, and replaced by replication of others.

5) Mta are chosen at random for replication, irrespective of utility;
   even mta whose DNA comprises entirely A's and T's still get replicated.


My inferences:

1) Fact (4) is a consequence of fact (2); free radical damage to a mt
   (not necessarily to its DNA) will sometimes sicken it enough that it
   gets degraded.

2) Damage to a mt's DNA that diminishes its respiratory performance is
   not alone enough to get it degraded, as that would preclude fact (5).

3) The mutagenic potential of free radicals must be very local.  Thus, a
   mt which is functioning poorly, so has a lower concentration of free
   radicals around it (perhaps that "so" depends on which gene is mutant),
   will be less prone to subsequent damage that would get it degraded.

4) In a non-dividing tissue, therefore, there is a selective advantage
   afforded those mta that have suffered some functionally debilitating
   muation.  This selective advantage is not countered by the replication
   machinery (see fact 5).

5) Therefore, aging of all non-dividing tissues will be an inevitable
   consequence of the failure of the replication machinery to target
   preferentially those mta that are pulling their weight.


My predictions:

1) Mta from a single old cell will mainly share one debilitating mutation
   not found in most other cells.

2) Aging would be stopped/reversed by nuclear cleverness that selects
   for replication only those mta that are pulling their weight.  Not
   that I have a suggestion for how to achieve this!

Cheers, Aubrey




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