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Are AGEs and Lipofuscin related? Could ALT-711 eliminate lipofuscin?

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Fri Jan 8 17:35:14 EST 1999


William wrote:

> I have read that on several sites on the internet. I do not
> specifically remember which ones, because I do a lot of surfing and
> reading on the net and don't keep track of the URLs.

I think it's likely that the people who wrote that were confusing
age spots with another aspect of skin aging, one which certainly
is thought to be largely due to AGE accumulation, namely wrinkles.
They arise from loss of elasticity of the skin, due to excessive
linking of the network of collagen fibres in the lower layer (the
dermis).

Anyway, if you surf a lot then you've probably learnt not to believe
everything you read on the net, especially in medical matters!  If
you can't confirm an assertion by searching Medline, the chances that
it's wrong are pretty high.  Nevertheless I recommend that you start
to make a habit of recording how you found things out -- scientists
do that religiously, for the very same reason, ie that when they get
conflicting information later on they can weigh up the strength of
evidence on either side.

> what causes all of these
> different aspects of aging to occur in the first place? And why do
> they occur only slowly during the first part of life and then so
> rapidly near the end?

You're absolutely right to focus on those questions.  The "generic"
answer is that some things DO happen just as fast early on as late (or
nearly as fast, anyway), but they don't have any serious effects until
they have progressed quite a long way; at that time they start to have
many other effects on systems that were hitherto working fine; as soon
as that happens everything starts to accelerate rapidly, just as you
describe.  So, any theory of aging involves identifying some damage
that accumulates throughout life and then exploring how it could have
the late-onset effects.  This doesn't rule out any of the suspects,
unfortunately: chromosomal mutations, telomere shortening, mitochondrial
DNA mutations, lipofuscin accumulation, extracellular AGE accumulation,
shrinking heterochromatin...  In other words, this:

> in my opinion it is the only theory, that I have read about at
> least, that can "link" together even a few of the different aspects of
> the aging process

is definitely wrong.  Any of the above can, in theory, get cells into
stress once they get far enough.

The problem with blaming telomere shortening (as you know unless you
have a very short memory!) is that the cells whose telomeres shorten
during aging are ones that don't actually appear to suffer any decline
in function even in very old age -- with the possible exception of the
immune system, whose decline may indeed be largely due to telomere
shortening (see recent papers by Rita Effros).  Then there are "those
damn mice", as Tom Mahoney calls them, whose lifespan is unaffected
by their telomere length at birth; Tom has noted that this isn't a
totally conclusive proof that telomere shortening is irrelevant to
mammalian aging, but it certainly doesn't give the theory any support.
I don't see much point in regurgitating this any further: see DejaNews.

> In your current
> opinion, if you do not mind me asking, what do you believe is the
> cause of the human aging process (or at least most of it)?  

Personally I think that the theory with the most plausibility on
current evidence is that mitochondrial DNA mutations are the main
driving force.  But I must stress that that theory has an unfair
advantage over a lot of others at the moment, namely that we don't
yet have good tools for doing a proper test of it -- interventions
that greatly retard or accelerate the rate of accumulation of those
mutations, and which are therefore predicted (if this theory is right)
to make a big difference to lifespan.  If someone develops a way to
make mutations arise a lot faster in the mitochondria, and the mice
(or whatever) that get this treatment live as long as ever, then this
theory will be in the same amount of trouble as the telomere theory.

Aubrey de Grey




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