From: Joao Magalhaes (joao.magalhaes@fundp.ac.be)
Date: Thu Dec 12 2002 - 14:16:42 MST
Hi!
At 11:02 10-12-2002 -0500, Rafal wrote:
>### Since toothy predators have been around for hundreds of millions of
>years, one might expect that life should have found a way of protecting
>itself from their depredations. The conclusion is that tigers do not cause
>death.
That is a ridiculous argument and it's easily disproved: tigers, unlike
free radicals or UV, evolve. So when preys find a way to protect themselves
against a predator, the predator also evolves. As far as I know,
ultraviolet radiation, except perhaps now due to the Ozone problem, has
remained constant for millions of years. Curiously, I remember reading
about teeth evolution and how the teeth and jaws of modern animals have
evolved so much since, say, the dinosaurs. So unlike the assumption in your
argument, toothy predators have evolved a lot in the past hundreds of
millions of years.
> 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? 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].
>
>### This is not correct. If you take a single bacterial cell and let it
>divide, randomly removing one of the daughter cells after each division,
>sooner or later the bacterium will suffer a mutation (as a result of free
>radical damage, most likely) and die without offspring. The "eternal"
>division is only a feature of colonies where the occasional mutated cell
>dies but the rest keeps going. As an analogy, a human society does not age
>(at least not biologically), even though its constituent parts do.
If you read my original message, I mentioned "bacterial culture", not
"bacterial cell". Sure, individual cells are not immortal. Yet a bacterial
culture, even when some cells suffer DNA mutations, survives. The question
I ask is: why do we assume a multicellular organism can't cope with DNA
damage? Why do we assume that DNA mutations accumulate in human cells when
they don't in a bacterial culture? You can argue that non-dividing human
cells can accumulate damage, but most cells in the body can be replenished
by stem cells--even neurons.
>There is no doubt that DNA damage contributes to aging.
I have doubts about everything we think we know about aging.
>### Isn't "damage" the same as "something going wrong with"?
No. Although when a system is "damaged", there's "something wrong with it",
there could be "something wrong" with a system without it being "damaged".
If a car runs out of fuel, there's something wrong with it, but it doesn't
mean it's damaged. In the same way, if a cell, for example, overexpresses
p21waf, the cell cycle is blocked but it doesn't mean the cell is damaged.
>### The low success rate with cloning explains the problem - you need to go
>through hundreds of cells from an adult animal to find a single undamaged
>one.
True, but--as I pointed to Robert, though probably off-list--you also need
to go through hundreds of fetal cells to clone animals. Yet according to
the theory, fetal cells should not have DNA mutations. My conclusion when
both controls (i.e. fetal cells) and adult cells have a low chance of
yielding viable cloned animals is that something is wrong in the process of
cloning and not with the cells themselves. See the papers by Michael West
and there's a few papers by a Korean team too.
> > Finally, you can argue that the soma of multicellular organisms lost
> > some protection against damaging agents and this causes aging. 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. 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.
> >
>### What types of stress are you referring to?
Oxidative stress of many kinds, UV, even other cytotoxic compounds such as
ethanol.
> Do you mean an increased
>tendency for apoptotis?
No, I mean the concentration of, say, H2O2 necessary to kill 50% of a
culture of WRN cells is much lower than the H2O2 necessary to kill 50% of
normal cells human.
>Is there any accumulation of mutations in the
>Werner's cells?
Yes, there is an increase in chromosomal abnormalities, though I'm not sure
about somatic mutations.
>If so, then this would be a prefect example in favor of the
>DNA-damage hypothesis - a pleiotropic effect of mutations on energy
>production, reduced antioxidant defenses, and a proapoptotic state of the
>cells.
Indeed, Werner's syndrome is probably the best evidence in favor of
DNA-damage as a cause of aging.
All the best.
--- Joao Pedro de Magalhaes The University of Namur (FUNDP) Research Unit on Cellular Biology (URBC) Rue de Bruxelles, 61. B-5000 Namur. Belgium. Fax: + 32 81 724135 Phone: + 32 81 724133 Website on Aging: http://www.senescence.info Reason's Triumph: http://www.jpreason.com
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