From: Joao Magalhaes (jpnitya@skynet.be)
Date: Thu Jul 25 2002 - 07:56:18 MDT
Hi!
At 17:40 24-07-2002 -0700, you wrote:
> > Why do humans age so slower than mice?
>
>Because all mammals evolved from creatures much smaller than mice
>and at every step of evolution where one selected for greater size
>(increasing survival odds) one had to also select for genetic programs
>that decreased the odds of single cells becoming cancerous.
Did you read my paper:
de Magalhaes, J.P. and Toussaint, O. (2002) "The evolution of mammalian
aging." Exp Gerontol 37(6):769-75
It's just an hypothesis on how mammals evolved from small animals.
> > Lately, I've been moving toward the DNA damage theory. Yet I'm not sure
as
> > to how it can work. I mean, somatic mutations don't appear to be the
cause
> > of aging -- take Dolly as a proof.
>
>You can't use that as an example. In any collection of cells you will
>always have some that have a less critical mutational load than others
>(say all of the mutations ended up in junk DNA). I posted a reference
>a few months ago citing failures in human conceptions in something like
>70-80% of the cases. Pointing to the surviving case is merely pointing
>at a source of genomic material that was relatively undamaged. We know
>from the conception and cloning odds that relatively undamaged genomes
>may be the exception rather than the norm.
True, you can always say that clones are an exception -- i.e. the mother
cell is an exception. Yet it doesn't satisfy my skepticism. I read many
theories of aging. All of them claim to be the ultimate truth. All of them
fail to explain certain observations. All of them call the observations
they can't explain "exceptions". My point is: when we have a theory of
aging that explains the observations without exceptions, we know it's the
right theory of aging. Until then, I don't advocate any theory of aging.
>Agreed, but the gene silencing approach may be one to simply reduce
>the metabolic rate, reducing the production of free radicals, fitting
>nicely into the nematode dauer and CR paradigms.
Oh yes, but there are still a lot of pieces missing in the puzzle. It's
just an hypothesis I've been thinking about.
>This ties in nicely with the free radical theory, since many of
>the DSB are probably due to oxidative DNA damage. Furthermore,
>as the frameshift mutations accumulate, one will have increased
>production of proteins that will not fold correctly and need to
>be degraded. This increases the metabolic requirements of the
>cell, increasing the activity of the mitochondria, probably leading
>to a downward spiral of increased ATP production, increased
>free radical production, increased genomic damage, increased
>demands for more energy, etc.
This sounds like Orgel's catastrophe-theory of aging. The papers that
initially disproved Orgel can be cited here again: for example, from memory
I remember an experiment where they fed mice with defective amino-acids.
They found an increase in defective proteins but the animals did not age
more quickly.
>If there happens to be a genome that selects the optimal balance
>between the NHEJ and HR pathways, then the animals with that
>genome will live longer.
Overall, I think your theory makes sense but there are a lot of theories of
aging that make sense and yet I doubt most will be right. Do you have any
experimental evidence supporting your views?
Best wishes from a skeptic.
--- Joao Magalhaes (joao.magalhaes@fundp.ac.be) Website on Aging: http://www.senescence.info Reason's Triumph: http://www.jpreason.com
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