From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Thu Nov 28 2002 - 15:25:29 MST
On Thu, 28 Nov 2002, Ramez Naam wrote:
> Richard Weindruch and Tomas Prolla (Science: August 27, 1999)
> - only about 1% of genese profiled in mouse skeletal tissue changed
> their expression as mice aged
I've been told by my former CSO that the Weindruch/Prolla
results were consistent with the results that ASG had in 1997.
We weren't at the point of counting genes, but the genes identified
were the same as those found in later studies.
Here is the bottom line (the programmers will understand this
though the biologists may argue) --
"The code becomes corrupted".
As you live, cells experience DNA double strand breaks (DSB), in
part from endo- and exo-radiation but probably mostly from free radical
damage. There are two pathways to repair this, one involving
homologous recombination (copying DNA from the sister chromosome)
and Non-Homologous End Joining (NHEJ) (where you simply stick the ends
of the DNA back together in a process that involves deletions
or additions to the genetic sequence).
The problem with the homologous recombination (HR) pathway is that
it leads to what is known as "gene conversion" where what was
a mutant recessive gene (previously masked by a dominant gene) becomes
dominant. So say you have a partially damaged cell containing
one good p53 gene and one damaged p53 (mp53) gene. If the HR pathway
replaces a DSB in the good p53 gene with a mp53 gene you now
have two copies of the dysfunctional mp53 gene and the cell
is on a downhill slide towards developing cancer.
The problem with the NHEJ pathway is that it corrupts the code!
Genes with corrupted code produces proteins that either function
poorly or do not fold properly at all. Proteins that do not fold
properly get recycled. But this is an endless loop of producing
a dysfunctional protein, then recycling it which uses up the
energy resources in the cell causing the cell to have to generate
more energy resources, producing more free radical damage, that
causes more DSB. I call this the "energy catastrophe hypothesis
of aging".
This is why the expression of heat shock proteins/chaperones
goes up with age -- the cells know they've got an increasing
amount of proteins that don't fold properly and are trying
to compensate -- but they can't do that because they can't
do anything to fix the corrupted code.
There are some other related aspects of aging that include the
fact that the genome isn't designed to deal with the fact that
protein turnover slows down with age -- (the decrease in "productive"
energy resources probably slows down the production and recycling
of proteins). The "clocks" that are built into the code that dictate
when proteins should be recycled are designed for when the copies of
your genome are "perfect" -- but when you get older and the code
becomes corrupted and recycling slows down it produces an accumulation
of proteins that are damaged -- in effect the recycling lines get longer.
This produces cells that function less efficiently.
What we need to find is an organism that executes the NHEJ DNA
DSB repair pathway *without* inserting or deleting any of the
genetic code and then replace that pathway in humans with that code.
Then we need to disable the HR DSB repair pathway.
That isn't a simple thing to do but it isn't "impossible" either.
For the programmers on the list you can think of aging as a combination
of two processes. The first is a process whereby one accumulates
random hits (remember when DRAM had the problem with radiation
flipping bits? If you are < 30 y.o. you may not). That gradually
leads to an accumulation of dominant mutations that produce cancer.
The second is a process where you get insertions or deletions in your
binary image. In the case of deletions all of the following code gets
shuffled down in memory. In the case of insertions all of the code gets
shuffled up in memory and some random stuff gets inserted. The cell
essentially traps the "bus errors" and "segmentation violations" that
result from these changes to the code -- but becomes increasingly
dysfunctional as the changes accumulate and the traps occur
more and more frequently.
It seems that longer lived organisms tend to compensate for this
by retaining a stem cell pool to replace the cells that have
kicked the bucket. I think Rafal may have pointed out that
stem cells may be operating in a very quiesent state so they
may accumulate much less free radical damage (causing DSB) over
the years (though they can't escape the radiation damage). The
best way (to me) to provide lifespan extension with existing
technologies would be to get fetal cord blood stem cells
and store them in in liquid nitrogen in the lowest radiation
environment you can identify. Then you can amplify this
population and "renew" oneself in the future. Alternatively
if you are an adult, you have to find the most genomically
"perfect" circulating stem cells currently in your body.
There are near term technologies that should be able to
determine the degree of "perfection" and we currently seem
to have the technology now to amplify the numbers of these
cells [1].
Robert
1. I. D. Bernstein at the Fred Hutchinson Cancer Research
Center, article in Oct 15 2002 Journal of Clinical Investigation.
Subject: Use of the Delta-1 protein to amplify CD34+CD38-
"blank slate" stem cells. [From Science News 10/26/2002]
[I'm not looking it up in PubMed because this is already a
too long of a commentary...]
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