The Mitochondrial Free Radical Theory of Aging

michael mader ziggurat at sympatico.ca
Fri Nov 5 21:44:58 EST 1999


what methods do you propose to slow mitochondrial aging?
(i understand if you are reluctant to answer since it is probably
in your new book :))

Aubrey de Grey wrote:

> "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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