Thanks to John for cross-posting his article to bionet.molbio.ageing.
I have been through the rest of the thread on misc.health.alternative
(which I don't usually read) and Doug Skrecky's article, and there are
quite a lot of factual errors about mitochondria and free radicals which
I will try to clear up here. I'll leave the telomere/telomerase stuff
to someone else.
----------
In response to Doug's article:
1) The anti-aging effects of growth hormone still require a great deal
more evaluation. The study Doug cites, Mech Ageing Dev 57(1): 87-100,
was very encouraging; a couple of years later another study, Mech Ageing
Dev 68(1-3): 71-87, rendered the picture altogether more complex. A
review from a few months ago, Endocrine 8(2):103-108, indicates that
the field is still wide open. (Abstracts of the above are in Medline.)
2) While it is true that hydroxyl radical is enormously more reactive
than superoxide radical, it must be borne in mind that the only way we
know of in which much hydroxyl radical can be produced in the body is by
starting from superoxide. The reaction which Doug mentions involves the
reaction of a molecule of hydrogen peroxide (which is produced mainly as
an intermediate in the detoxification of superoxide) with a molecule of
superoxide, using iron (or copper) as a catalyst. (The Fenton reaction
is half of this.) Thus, if we could avoid making any superoxide (or if
we could mop it up more assiduously) then we would also make no hydroxyl
radical. Moreover, there are some other highly reactive derivatives of
superoxide which do not require the prior creation of hydrogen peroxide
or hydroxyl; the worst is probably perhydroxyl radical.
3) The above might appear to be contradicted by Doug's ref. 8 (Proc
Natl Acad Sci 87: 4270-4274), but in fact it is supported by subsequent
work (Science 1994; 263:1128-1130) showing that SOD overexpression IS
effective if one simultaneously overexpresses an enzyme that finishes the
job of detoxifying the superoxide (by destroying hydrogen peroxide).
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Steve Harris wrote:
> There isn't any reason to think that "aging" is caused by entirely
> or mostly by free radicals from the mitochondria. Many organisms have
> mitochondria, but don't age-- therefore the free radical made by
> mitochondria are obviously fully containable by a healthy organism
Convincing though this may sound on the surface, it is completely wrong.
The cells in the human body which appear to suffer mitochondrial damage
are the non-dividing (or rarely-dividing) ones; the rapidly dividing
ones remain mitochondrially healthy. Our possession of (and reliance on)
cell types which do not divide is, according to the mitochondrial theory
of aging, the thing that renders us vulnerable.
> If they do damage in aging, that may be because aging screws up the
> repair systems. But that doesn't mean the mitochondria are the cause of
> aging-- in that case they would simply be one more system that causes
> problems as aging takes out the control and repair systems.
This is quite true, but it also doesn't mean that mitochondria are not the
cause of aging. It is very well established that, in non-dividing cells,
mitochondria which suffer spontaneous mutations are not destroyed and
replaced by non-mutant ones, but instead the mutant ones are replicated
at the expense of the non-mutant ones, so that entire cells become unable
to use oxygen. The initial damage (to one molecule of mitochondrial DNA)
is thus amplified out of all proportion. That is, in turn, proposed to
accelerate subsequent damage (and retard its repair) in other cells. So,
since the initial damage to the mitochondrial DNA is thought to result
largely from free radicals, of which mitochondria are the main producers,
the theory that mitochondria are the main cause of aging (strictly: the
main determinant of the rate of aging) in humans is entirely consistent
with the evidence.
> Attempts
> to influence rate of aging in cells by fooling with mitochondria
> haven't been sucessful.
This is quite true (at least in regard to retardation, as opposed to
acceleration, of aging), but tells us only that IF mitochondrial damage
is important then we don't yet know how to retard it. My view is that
the mitochondrial DNA is not significantly accessible to pharmacological
agents, and that therefore the only approach likely to be effective is
gene therapy to render the mitochondrial DNA superfluous to us.
> The Hayflick limit, for example, is not
> influencable by damping out oxidative metabolism in mitochondria.
This is quite true, but it applies to dividing cells and is therefore not
in conflict with the idea that mitochondrial damage in non-dividing cells
drives aging.
> As organisms that do age get older, their mitochondria take a
> beating. But so does the rest of them. That's not good evidence.
With this I can agree! Other evidence is needed.
> Red blood cells age in many interesting ways, without mitochrondria.
Indeed, but since they contain no genetic material at all one might say
that their aging is more like the aging of a car than of an organism.
> And you can culture cells without oxygen, which stops mitochondrial
> free radical production. This has no effect on Hayflick limit
I believe it has a small effect, in fact; but this observation (again,
in dividing cells) can equally be taken to indicate that the Hayflick
limit is peripheral to organismal aging.
> and not
> that much effect on lipofuscin and membrane changes and anything else
> you can reasonably call aging in vitro.
This is not my understanding (see eg Free Radic Biol Med 6(1):23-30).
Please give references.
> Nor does it stop mitochondria from degenerating.
Nor is this. Please give references.
> I personally think it's because we have CNS systems, and
> nature just hasn't ever figured out how to repair non-dividing cells
> from free radicals. But don't blame mitochondria for that. They make
> the nasty things, but the nasty things are perfectly easy to deal with,
> if nature just would. She doesn't because she's lazy and or simply
> hasn't happened onto a scheme for animals with[out ?] non-dividing cells.
Aha - we agree after all :-) However I think it is very dubious to say
that it's nature's fault, not mitochondria's fault: the question is what
we might do to fix it. We could wait for nature to happen onto a scheme
for animals without non-dividing cells, but there may be quicker ways.
The interspecies evidence that Doug cites is very persuasive that we'll
be more successful if we diminish the production of free radicals than
if we rely on improving their mopping-up.
> I'll look, but the entire series of Tappel's vitamin E
> supplementation experiments on mammals pretty much lays the issue to
> rest. Mitochondria are protected, but aging isn't slowed.
No, Tappel's (excellent) work shows nothing of the kind. The crucial
distinction one must always make is between the rate of damage to the
mitochondrial DNA (which, so far as we know, is not slowed by vitamin
E or any other dietary supplement) and the rate of damage to the rest of
the mitochondrion (which probably is). The reson this distinction is so
vital is that the mitochondrial DNA cannot be built from scratch, only by
copying an existing one (complete with any mutations it may have). The
mitochondrial membranes also can't be built from scratch, only by adding
new membrane material to an existing membrane, but that added material
is not copied from the old membrane, it really is made from scratch,
so it's undamaged, so mitochondrial division dilutes out any existing
damage and thereby keeps it under control long-term.
> > Empirically, Strecky suggests that substances
> > which inhibit hydroxyl radicals in the mitochondria make test subjects
> > live longer, more youthful lives.
>> What, fruit flys?
Here we again agree: fruit fly (and nematode) aging is very probably
driven by free radical damage, but probably not by free radical damage
to mitochondria. That's because they don't live long enough for damage
to the mitochondrial DNA to be amplified by mitochondrial division.
Aubrey de Grey
