The Mitochondrial Free Radical Theory of Aging

Aubrey de Grey ag24 at
Sat Nov 6 07:33:15 EST 1999

"private" wrote:

> Is it possible to take a cell that does not divide (muscle or nerve,
> right?), then half-way through its normal life span, suck out all its
> mitochondria, then take some mitochondria from a newly made
> non-dividing cell of the same type, and put it into the middle-aged
> cell?

No, but also it would be ineffective anyway.  One of the most important
aspects of mitochondrial biology, which has actually been scandalously
overlooked by most specialists until very recently, is that they are not
static: even in non-dividing cells, they are recycled all the time.  Some
are destroyed (by being engulfed by another subcellular structure, the
lysosomes) and others are replicated, to keep the overall number stable.
This process is VERY poorly understood, but that doesn't mean we can't
infer anything from it; it turns out that we can infer a lot.  A crucial
consequence is that if we replace all of cell X's mitochondria with those
from cell Y, a year or so later cell X's mitochondria will be composed
entirely (except for their DNA) of material synthesised by cell X itself,
because all aspects of mitochondrial biogenesis (such as making the lipids
that form the membrane) are performed by nuclear-coded proteins.

This is why I first began to focus on the mtDNA as the weak link.  But
mitochondrial turnover actually tells us even more than that.  It is now
well established that mutant mtDNA is not spread uniformly across cells
of a given type: rather, a few cells become totally taken over by mutant
mtDNA while most cells have undetectable levels of mutant mtDNA.  This is
what led me to the "reductive hotspot hypothesis" which forms the core of
my present view of how mtDNA mutations may drive aging: basically that the
few (but accumulating) mitochondrially mutant cells are actively toxic,
and cause systemic trouble for the majority of mitochondrially healthy
cells.  (This was first published in J. Anti-Aging Med. 1(1):53-66; an
update incorporating much recent data will appear in the Dec. 1st issue
of Arch. Biochem. Biophys.)

So to come back to your question: if we could identify the cells in the
body which were mitochondrially mutant and replace their mitochondria
with healthy ones -- from other cells of the same individual, would be
enough -- then yes, we'd be improving the situation.  But such a
treatment is not presently feasible.

Conveniently, however, Michael Mader wrote:

> 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 :))

The intervention in which I have the most confidence in the long term is
the one I alluded to in a recent post: complementing the mtDNA by nuclear
versions of its 13 protein-coding genes.  The mitochondrion is made up of
around 1000 different proteins, of which only 13 are encoded in the mtDNA.
The rest are nuclear-coded and are synthesised in the cytosol (outside the
mitochondrion) and imported, using very sophisticated machinery known as
the TIM/TOM complex.  The idea, then, is to make versions of the 13 (the
"dirty baker's dozen", as I seem to be calling them these days) which we
could introduce into the nuclear DNA; they would be altered so as to be
imported into the mitochondria, where they would be incorporated as if
they had been synthesised inside the mitochondria.  The potential value
of this treatment is that whenever a cell's mtDNA starts to become mutant
it will still have working mitochondria because the nuclear-coded copy
will still be working.  (This is just the same as when a mutation occurs
in a nuclear-coded gene, of most of which we have two copies: the other
copy generally suffices.)  Making this work in humans obviously requires
very big advances in gene therapy, but I think those advances are likely,
since so many people are currently working on it; moreover, we can do
the same experiment in mice already (since we know how to get transgenes
into the mouse germ line).  There are other obstacles, however....

Aubrey de Grey

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