The Mitochondrial Free Radical Theory of Aging

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Fri Nov 5 15:39:43 EST 1999


"private" wrote:

> This is sort of a general, non-scientific question.  When I think of
> all that goes on in aging, the wrinkly skin, the cancer, the shrinking
> muscles, the eye problems, the ear hair, increasing body fat.....it
> seems so diverse.  Does anyone else wonder at how just the
> mitochondria can be responsible?  Or...I guess the claim is not just
> the mitochondria are the cause, but they are one of several causes?
> How "important" are mitochondria  in the big picture?

This is a crucial issue, which I address at some length in the book.
It is pretty clear that many changes contribute to mammalian aging at
the molecular level, and it's also (as you say) very clear that huge
numbers of changes occur at the macroscopic level.  What is not clear
is what causes what.  There are essentially three extreme positions:

A) Many molecular changes proceed autonomously and independently of one
   another, each of them causing (or contributing to causing) a subset
   of the macroscopic features of aging, but each being dominant in at
   least one major facet of aging (by "major", for this purpose, I mean
   something that limits our life expectancy).
B) One of the molecular changes proceeds autonomously, and the rest are
   all contingent on tht one, such that if it were totally eliminated
   then so would all the rest be (thus also stopping the macroscopic
   changes).
C) Many molecular changes proceed autonomously, but *synergistically*
   rather than independently, such that totally stopping ANY one would
   somewhat retard all of the others.

Before looking at which of these scenarios (or which middle ground) is
the most likely, it is worth examining what they predict regarding the
feasibility of dramatic life extension in the foreseeable future.  The
first scenario is pessimistic, since it predicts that we will not make
much difference to maximum lifespan until we've developed rather a lot
of diverse interventions.  Scenario (B) sounds optimistic, because it
suggests that only one process need be tackled in order to extend our
maximum lifespan quite a lot.  But scenario (C) is the most optimistic
of all, because it suggests that we have a choice of which process to
tackle, whereas in scenario (B) we have to go for the one at the top
of the pile.

As I perhaps hinted by the use of "extreme", I believe that the truth
is between these three.  There is definitely a lot of synergy between
several of the molecular processes that underlie aging (oxidation and
glycation, for example).  The accumulation of nuclear DNA mutations
and lipofuscin are two examples of events which probably happen both
autonomously and independently, but whose rate of accumulation may
(but we don't know for sure) be related to the rate of other molecular
aspects of aging; moreover, we don't yet know whether lipofuscin has
any deleterious effects in a normal lifetime.  However, mitochondrial
DNA damage can (in my view) be considered a prime suspect for the most
influential determinant of the rate of most or all other processes,
and perhaps of its own rate (by positive feedback).  I argue in the
book that there is a good chance that eliminating the direct effects
of mtDNA decline (by, for example, complementing the mtDNA by nuclear
versions of its 13 protein-coding genes) would slow down all the other
molecular processes that contribute to mammalian aging -- and, hence,
aging at the macroscopic level -- by a factor of at least two.

A topical example is perhaps helpful.  It's well known that some of
our cells divide rather often, some hardly ever and some never.  One
school of thought is that rapidly-dividing cells and non-dividing
cells age by completely different mechanisms: in particular, that
rapidly-dividing cells age by telomere shortening and non-dividing
cells age by mitochondrial decline (maybe mitochondrial DNA, maybe
not).  But it is also possible that non-dividing cells age as stated
but that rapidly-dividing (and indeed rarely-dividing) cells don't
age autonomously AT ALL, or at least only negligibly: i.e. that the
functional decline which they exhibit during aging is purely due to
the misfortune of having to inhabit the same body as all those aging
non-dividing cells.  This scenario is absolutely consistent with the
available data and is even actively supported by certain indirect
lines of evidence.  Again, though, I suspect that the truth is an
intermediate between these extremes.

Aubrey de Grey





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