[extropy-chat] AGING: New Theory

[Robert J. Bradbury]

I've been working on this theory for the past year or so and
thought I would present it to the list so it gets into general
circulation.

You could call this either:
  A Grand Unified Theory of Aging
or
  The Mutation-Energy Catastrophe Theory of Aging

I try to bring together a number of elements from a number of other
aging theories to see if we can begin to reach a greater understanding.

First, lets assume the Free Radical theory of Aging which involves
various aspects of Mitochondrial damage and aging are correct.
[This explains why caloric restriction works.]

Second, lets assume you can't do too much about them because
radicals and/or other pro-oxidants (e.g. nitric oxide) are being
used as signal molecules (this may be somewhat controversial).

Third, lets assume that the free radicals lead to DNA mutations
(which is one way cancer develops) or worse leads to DNA double
strand breaks.  (Radiation and perhaps toxic substances in
food or the environment might contribute to this as well).

DNA double strand breaks are bad.  There are 3 possible
results:
 (a) Repair the break via the homologus recombination pathway.
 This can lead to "gene conversion" where a masked
 defective gene gets copied such that it becomes dominant.
 (so for example you may have a cell that can function well
  with one good and one bad p53 gene, if the bad p53 gene
  gets copied to where the good p53 gene once was you are
  in big trouble).  Net result: increased risk of cancer.

 (b) Repair the break via the non-homologus end-joining pathway.
 This appears to involve perhaps the Artemis protein and/or the
 Werner's Syndrome protein both of which seem to be exonucleases.
 Bottom line your DNA gets chewed up and you get a microdeletion
 during the repair.  Alternatively if you happen to have two
 double strand breaks at the same time the two chromosomes
 can get mispaired with the wrong chromosome.  This leads
 to several types of cancer.

 (a) and (b) are aspects of various "mutation" theories of aging.

 (c) Avoid repair by the cell committing apoptosis.
 In this case you lose cells and if the cells are not replaced
 by stem cells [which may themselves have damage from (a) or (b)]
 then you suffer a gradual loss of function.

The above seems to explain much of aging and cancer.

Now the problem gets worse.

If (b) goes on for long enough you will gradually accumulate
mutations in various (most probably different) genes in *ALL*
cells.  I.e. the genomic "program" that the cells require
to operate properly is gradually corrupted in random ways.

So gene expression may become defective in many various ways
in many cells (this incorporates the dysdifferentiation theory
of aging and perhaps aspects of the neuroendocrine theory of aging).

However if the mutations occur within genes rather than say
regulatory regions now you will probably have a protein
that will not fold properly.  This will probably be detected
and the protein will be degraded.  But the lack of a sufficient
quantity of these proteins will probably result in cellular
signals to make more of them.  But they or at least half of
them will not fold properly either.  Now both protein manufacture
and many types of protein degradation require energy (ATP).
So when the cells detect a decline in ATP (due to futile
synthesis and degradation of proteins) they may attempt to
increase energy production.  This might be through making the
mitochondria work harder or making more mitochondria.  In
either case the result of this will most probably be more
free radicals which feeds back into the start of this whole
process.  So over time cells will "age" increasingly faster.

Net result -- you get an exponential decline in function (i.e. aging).

So far I've only managed to imagine two solutions for this.
1. Develop better DNA repair processes that do not allow the genome
   to become corrupted.
2. Shift things to allow more apoptosis when DNA double strand breaks
   are detected but also increase the replacement rate by stem cells.

(1) is a reason to support the sequencing of the genomes of other
long lived species -- to see if they have figured out better
solutions to the problems outlined.  (For example we know that
Deinococcus radiodurans has better double strand break repair
but we do not fully understand this yet or know if it can be
applied to humans.

(2) is a reason to be very supportive of stem cell research.

Robert