From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Thu Jul 25 2002 - 23:47:24 MDT
On Thu, 25 Jul 2002, Joao Magalhaes wrote:
> Did you read my paper:
> de Magalhaes, J.P. and Toussaint, O. (2002) "The evolution of mammalian
> aging." Exp Gerontol 37(6):769-75
Haven't read it, if you send me a copy offlist, I'd be happy to do so.
> It's just an hypothesis on how mammals evolved from small animals.
Interesting, we may be thinking along the same lines. When I ran across
a Science article on the first proto-mammal fossil for an animal weighing
a few oz a year or so ago, I sent the reference off to George Martin
and Steve Austad (if I recall) to get them thinking along these lines.
> [snip] 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.
I guess I'm almost at the other end of the spectrum. I'll advocate
most or all of them. IMO, as animals evolve from r-selection to
K-selection (generally becoming larger) one is going to have to
apply "patches" to the genome to increase longevity. That has
probably happened multiple times. In reptiles (tortises), in
birds (parrots, etc.), in mammals (whales, elephants, humans,
large bats?). So aging is a failure of specific programs to
deal with specific detrimental effects associated with the
processes of life itself. These can range from failure to
evolve a robust mitochondrial DNA repair system, to failure
to evolve a robust DNA DSB repair system, to failure to
eliminate lipofuscin, to failure to maintain proper histone
acetylation, etc.
It is going to take "a thousand cuts" to solve aging. The
trick is to determine which cuts buy us the most and how
do we develop solutions to them sooner rather than later.
> Oh yes, but there are still a lot of pieces missing in the puzzle. It's
> just an hypothesis I've been thinking about.
Fine. Perhaps a different way to think about it is that
you may have many puzzles. If you have a piece that doesn't
appear to fit in the puzzle you are working on, it may be that
it actually belongs to a different puzzle.
> 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.
I need to go back and review this work in detail to see what the
precise details of the experiments were. But from my perspective
it is unlikely that one would see an increase in defective proteins.
Proteins that do not fold properly get degraded. What one would see
is an decrease in "effective" protein synthesis per unit of energy
consumed.
> 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?
There is a lot of work with the HPRT locus finding both micro and macro
deletions. There is also a lot of work with transgenic mice with the
lacZ and similar reporter genes finding that deletion type and frequency
have organ specificity (suggesting that the puzzle for aging in one
organ may not be the same as the puzzle for aging in a different organ).
I've got a large number of references organized and am trying to turn
it into something coherent that people can discuss. We are quite a
bit further down the road than we were a decade ago when I first
studied this. Now we have almost all of the DNA repair and cell cycle
control genes. We just aren't completely sure what they all do.
Robert
This archive was generated by hypermail 2.1.5 : Sat Nov 02 2002 - 09:15:40 MST