From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Sat Dec 07 2002 - 10:35:26 MST
Hi Joao,
On Sat, 7 Dec 2002, Joao Magalhaes wrote:
> By saying aging is programmed into the genes I don't wish to imply that
> aging evolved for a purpose. I don't see any evidence that aging in humans
> or even mammals evolved for a purpose--as I point out in my Exp Ger paper.
Ok, so we agree on that much.
> I do see great differences in rate of aging amongst genetically similar
> species, which makes me think rate of aging is a result of some small
> alterations in the genetic program.
I'd tend to agree with this as well, though it isn't clear the extent
to which small mutations can have a large effect. The very mixed p53
story in mice (both shortened and normal lifespans depending on the
mutations in and expression of p53) is just one case in point.
> I would say life had enough time to
> develop protections against these common sources of damage and, equally
> important, life had enough time to develop mechanisms to repair the
> damage--DNA repair mechanisms are the perfect example.
And in some cases it has, e.g. Deinococcus radiodurans. I believe that
D. radiodurans can repair up to 300 double strand breaks, most probably
through homologous recombination repair pathways (my speculation).
In contrast a human cell will commit apoptosis with only ~3-5
double strand breaks (mouse cells seem programmed to allow many
more which may be why they get cancer more frequently). In a
multicellular organism it becomes a very interesting question
as to when the needs of the many outweigh the needs of the few
or the one.
> In other words, if a
> yeast or a bacterial culture can divide eternally despite free radicals,
> UV-damage, DNA mutations, etc., why assume--and most gerontologists
> do--that our cells cannot cope with these processes?
It isn't that they can't cope -- its that they aren't tuned "just right".
If protein deamidation is functioning as a "molecular clock" that is
a signal as to when to recycle poorly functioning proteins, then
what is the probability that 30,000 proteins have the correct
molecular structure that signals cells to recycle a protein
just at the time it becomes dysfunctional?
> I think they do cope
> and I think aging is caused by something else. One good evidence of this is
> the huge amount of anti-oxidant protection in ALL--not just the ones that
> live longer--but ALL mammals [See the papers by Sohal].
I know. We have great anti-oxidant defenses. But they cannot protect
against a X/gamma ray going through the nucleus (producing DSB). They also
don't seem to protect against the accumulation of undigestable cellular
metabolites (e.g. lipofuscin).
> Now, if damage does not cause aging, then what does? Well, something goes
> wrong in the genetic program. Hence aging is programmed into the genome,
> though not intentionally.
I can completely agree with "something goes wrong in the genetic program"
and "aging is programmed into the genome, though not intentionally".
(with the emphasis on the "not intentionally" part).
> And I also don't think the program gets
> corrupted. Why not? I've told you--Robert--before: clones. If there were a
> widespread accumulation of somatic mutations in cells, we wouldn't be able
> to clones so many animals--namely mice who have lots of cancer.
Ah, but we know how difficult it is to produce clones. What is the
success rate: 1 in 50? 1 in 100? One could have mutations accumulating
in developmental genes that have no impact on the viability of adult
cells that could easily explain why cloning is so difficult. The
"abnormalities" that one finds in clones would be explained if they
were derived from cells with a non-fatal accumulation of mutations.
> That's why
> I think the accumulation of damage as we grow older is epigenetic; I think
> aging results from some sort of misregulation of the genetic program; the
> expression of genes goes wrong with time. Since we're both programers, I'll
> put my arguments in a programer's way: I don't think the program itself
> changes much during aging; I think the program is bugged in some way that
> the procedures and functions get out of control with time.
This is the dysdifferentiation theory of aging. I'm not opposed to
this being part of the process. If one gets double strand breaks
in the ribosomal DNA, then the homologous repair pathway may well
delete segments (due to the large number of repeats) resulting in
a decrease in the cellular protein production capacity. I strongly
suspect that if you alter the total protein production capacity
of cells then the regulation of normal cellular functions will
begin change.
> Finally, you can argue that the soma of multicellular organisms lost some
> protection against damaging agents and this causes aging.
They didn't "lose" it -- they had to make a choice between tolerating self-repair
(that might cause cancer due to mis-joining double strand breaks) and removing
heavily damaged cells (hoping that stem cells may replace them).
> I mean, there are papers correlating the resistance to stress with longevity in
> mammals--though I don't think yeast H2O2 resistance is superior to that of
> a human cell. It could be and I keep my mind open to such possibility, but
> when I work with cells taken from a patient with Werner's syndrome, I see
> that these cells are less resistant to stress than normal cells.
You need to keep in mind however, that the yeast cell is out for
its own survival. The cells in mammals however are out for the
survival of the organism. They must have a program that says
to not kill the collective to benefit themselves.
The things to consider are that the Werner's syndrome protein is an
exonuclease (i.e. it chews up DNA) and the fact that p53 modulates
its activity.
> What this
> tells me is that one gene involved in DNA metabolism can make cells and
> organisms less resistant to several forms of stress and thus shows how
> multiple stress resistance might be a consequence, not a cause of longevity.
I'd tend to disagree. Stress leads to DNA damage, DNA damage results
in a corrupted code, a corrupted code results in cells that function poorly,
poorly functioning cells leads to aging.
It seems quite logical to me. Proving it is the hard part -- though Jan Vijg's
work on the accumulation of mutations in transgenic mice seems to be providing
some supporting data.
Robert
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