From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Mon Apr 21 2003 - 16:00:39 MDT
On Mon, 21 Apr 2003, Rafal Smigrodzki wrote:
> ### Do you think that protein aggregation is causative in sporadic AD or PD,
> or that it is involved in the pathomechanism at some later stage, perhaps
> amplifying the damage caused by other factors?
Hard to say -- I'm not that familiar with either the AD or PD literature
(once I knew a bit more but that has long since fallen out of my brain).
> Recently it turned out that APP has a direct toxic effect on mitochondria,
> and mutant alpha-synuclein has also been implicated in diminished mito function.
I could see some strange protein aggregation function clogging up the
mitochondrial transport proteins -- APP is only a few dozen amino acids
I think. The mitochondrial transport proteins have to have pretty darn
large pore sizes to get all of the mito proteins inside.
If that is the case -- or some other process degrades mitochondrial
function then it seems likely that one will get either a shortage
of ATP (that's bad for protein synthesis *and* breakdown) or perhaps
the production of more free radicals (though improper protein function)
producing more double strand breaks leading to the production of
nuclear proteins that will not fold properly leading to the "wasteful"
use of ATP (I call this the "Energy Catastrophe Theory of Aging".
> Also, are protein aggregates in AD and PD really lysosomal, or cytoplasmic
> (or even extracellular)?
A think APP starts out cytoplasmic but is supposed to get exported to to
the cell membrane or even outside the cell but a lot can happen to mutant
proteins on the way to the forum. E.g. if the mutation is in part of the
signal sequence controlling transport and ultimate destination things
could get really screwed up. [I think I've heard George Martin state that
there is a polymorphism in the signal sequence (not perhaps a "mutation"
per se) of the Werner's Syndrome protein -- that might have a very
interesting effects by impacting the rate of transport of the newly
synthesized protein into the nucleus and therefore the quantity available
impacting the rates of DNA copying, transcription, etc. (it isn't fully
clear I think exactly when and where the WS protein is functioning) and
further downstream the overall "rate" of aging.]
> Atheromas are not aggregates of lysosomally indigestible material, so
> improving cellular digestion is not likely to be of help.
I did not mean to imply that it would help in *all* situations. I believe
that "aging" is only going to fall by "divide and conquer".
What is an Atheroma?
> Is there any indication that lipofuscin is indeed causally involved in cell
> death?
I'm not so sure it is "cell death" -- sufficient #'s of double strand breaks
will activate the apoptosis progam (and human cells are a lot less tolerant
of double strand breaks than mouse cells -- perhaps a major reason they
get cancer sooner even though they have many fewer cells).
Cell death *is* part of the process -- those cells that decide to undergo
apoptosis had better be replaced by stem cells -- otherwise you are just
going to fade away. I suspect there is a delicate balance between
underactive stem cells -- so you don't heal as fast, gradually lose
functional capacity, etc. and overactive stem cells -- potentially
posed to turn into various forms of cancer.
The data, for at least many cell types, I believe suggests that lipofuscin
accumulates with age -- thus the recycling ability of lysosomes containing
lipofuscin (or perhaps cytoplasmic lipofuscin) presumably declines and the
cells may compensate by making more lysosomes -- thus the cells fill up
with lysosomes containing lipofuscin (or perhaps merely lipofuscin
itself). This is supported by the fact that the cells effectively lose
water content with age (more lipofuscin, more lysosomes = less water).
So if the cells are filling up with lipofuscin/lysosomes there is less and
less space for the mitochondria that you need to generate the energy the
cell requires -- thus "Energy Catastrophe". The increasing density of the
cell probably also slows down transport processes to the cell surface
and/or protein export. That certainly has to have some negative
consequences.
> BTW, I agree that the best way of fighting aging is reversing it by genetic
> engineering (once you get it to work). I like your idea of transferring
> mtDNA-encoded function to the nucleus. Any more information on this project?
First you have to get genetic engineering *cheap* and *fast) (that I'm
reasonably sure I know how to do) -- *then* everyone can easily tinker
with various genomes to get it to "work".
I had the mtDNA-transfer to the nucleus idea probably 7-8 years ago. I
don't remember whether I came up with it. It may have come from a
theoretical paper that I read. Aubrey de Grey I think figured it out
independently and has worked on it a bit more and I think he thinks its a
bit tricky because the human mtDNA proteins that are currently still in
the mtDNA are a bit hydrophobic and so transport and getting them across
the membranes may be difficult.
I think he has some possible work-arounds -- do a PubMed search for his
papers over the last 3-4 years or send him an email.
But the nucleus being a safer place than the mitochondria may be why
humans such a small mt Genome -- someone (perhaps *you*?) needs to write a
paper comparing the human, elephant and whale (bowhead or blue) mtDNA to
each other to see if they "solved" this problem the same way. If we all
have small mtDNA then one could make a strong assertion that this is one
of the problems that has to be solved for a long lifespan! The divergence
of humans from elephants and whales were something like 100+ and perhaps
80 million years ago respectively. It seems likely the longevity
problem has been solved multiple times independently. [If you need the
refs on this I just semi-finished organizing them yesterday. I'm trying
to see if I can push Steve Austad and Maynard Olsen into preparing a white
paper for sequencing these genomes so we can do comparative genomic
analysis -- but the sequencing of mtDNA genomes (if they aren't already
done as part of the phylogenetic work) would be much easier than a $50
million "sell" for elephants and whales (each). $50 mil seems to be the
going price for the cow genome.]
Alternate ideas I've thought of is intracellular bacteria engineered
to produce the modified mtProteins or even souped up to produce and
export ATP in high volumes (essentially recreating the mitochondria
with lesser free radical generation properties). An alternate
process might be more robust mtDNA repair -- right now its pretty
minimal compared to the nucleus (something like 120+ nuclear DNA
repair proteins).
The short summary is that there are a number of ways to tackle
this problem. The pain in the rear end problem that we really
need to solve is what the heck in the mitochondrial transport
chain is generating the free radicals in the first place.
Every time I hear a talk on this topic it gives me a headache
due to the complexity.
Robert
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