From: Rafal Smigrodzki (rms2g@virginia.edu)
Date: Tue Dec 10 2002 - 09:02:29 MST
Joao wrote:
>
> I've read your NHEJ-based theory before. I'll tell why I'm not
> convinced by your theory and I'll tell you why I don't think free
> radicals cause aging either. Life has billions of years on earth,
> having to face UV, background nuclear radiation, free radicals, etc.
> 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.
### 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.
-----------
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.
No cell can truly cope with the processes you mention - they can only reduce
the probability of failure, but not the eventual outcome. The only way of
escaping biological death is through copying faster than the damage
accumulates, and removing the damaged copies by a selection process. The
same logic applies to multicellular organisms.
There is no doubt that DNA damage contributes to aging.
-------
>
> Now, if damage does not cause aging, then what does? Well, something
> goes wrong in the genetic program.
### Isn't "damage" the same as "something going wrong with"?
------
Hence aging is programmed into the
> genome, though not intentionally. 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.
### 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.
-------
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. Now, I have no
> idea what genes might be involved, apart from perhaps the Werner
> protein. Yet I think the key to understanding aging will be to
> understand the transcriptional regulation of mammals.
### It is quite possible that transcriptional misregulation does influence
aging, but ascribing to it an exclusive role is IMO missing the point
entirely.
------
>
> 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? Do you mean an increased
tendency for apoptotis? Is there any accumulation of mutations in the
Werner's cells? 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.
Rafal
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