Cause of aging
Aubrey de Grey
ag24 at mole.bio.cam.ac.uk
Mon Aug 17 07:50:50 EST 1998
Steve Harris wrote:
> Then all I can say is that it's a really stupidly named "theory."
> If failure of cells to divide led to non-repair of membranes (which
> otherwise happens in dividing cells), would you call this the
> "membrane" theory of aging? If failure of cells to divide led to non
> repair of of DNA, would you call this the "DNA theory of aging?" If
> non division let to protein turnover problems and clinker enzymes,
> would you refer to this as the error catastrophe theory of aging?
> If your gardener doesn't spray for bugs and the bugs eat
> your garden, you don't say you have a bug problem. If you're
> intelligent you realize that you have a gardener problem. Go to
> primary sources.
I have plenty of sympathy with the above, but not with this:
> in all cases it's clear that the
> damage problem is secondary to the failure of repair
This is not the case with the "mitochondrial theory of aging", at least
not any more. Formally, it's of course correct that if repair kept up
with damage then we'd be OK, but the question (as James stresses) is
whether that's achievable. To adapt your analogy: if your gardener DOES
spray for bugs and the bugs eat your garden anyway (because the spray is
the best available but is nonetheless insufficiently insecticidal), you
do indeed say you have a bug problem. The interspecies work that I keep
going on about (because it still gets less attention than it deserves)
shows us that this is the correct analogy: the only way that homeotherms
appear to have found to retard aging is to reduce the production of free
radicals, not to improve their destruction, nor to improve or the repair
of the damage they do. If nature had found a way to improve either of
these enough, then logically the effects (notably the anti-aging efects)
would be the same as reducing production; but it has not found such a way.
It is therefore reasonable to infer that we, too, will find it easier to
reduce free radical production than to make correspondingly effective
improvements to free radical destruction or repair of free radical damage.
Of course this may be wrong, since evolution and biotechnology have such
different tools (see my last paragraph below), but it's a starting point.
That being so, I would say that it IS reasonable to call this theory the
"mitochondrial theory of aging", since mitochondria are far and away the
major sources of free radicals in vivo. The fact that, theoretically,
the effects of these free radicals could be retarded further down the
causal road (by better free radical mopping-up or by better repair) is
made less relevant by the empirical evidence that that's not practical.
Steve also wrote:
> I would argue that if all cells
> make free radicals and only some cells, tissues, and organisms
> age, then the idea that free radicals "cause" aging in any kind
> of final sense, is at the very least grossly incomplete, and at
> worse, silly and wrong. And no, it doesn't help to qualify it
> and back down and claim you're only talking about some tissues
> and some cells and some part of aging
I fully agree with the second sentence, but not at all with the first.
I must reiterate something I said recently: "no cell is an island", i.e.
that it is quite possible for rapidly dividing cells in the body to age
(read: become less functional) SOLELY because of their proximity to non-
dividing or rarely-dividing cells. Moreover, I contend that this is not
only formally possible: it's fully consistent with the available evidence.
To complicate the issue a little more: as I've mentioned in the past, I
think that the intervention most likely to retard aging a lot is to put
copies of the mitochondrial DNA into the nucleus. This would not lower
free radical production, nor improve free radical destruction, nor improve
repair of free radical damage! Rather, it would remove the downstream
effects of a particular category of free radical damage (namely, damage
to the mitochondrial DNA) which I think is likely to be the category that
most strongly determines the rate of aging in homeotherms. But this also
does not militate against calling the theory the "mitochondrial theory of
aging". I think, however, that this serves to underscore your pivotal
point that we must keep an open mind with regard to both mechanisms and
Aubrey de Grey
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