Re: AGING: Accumulation of DNA damage

From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Sun Jul 09 2000 - 05:05:53 MDT


On Tue, 27 Jun 2000, Joao Pedro de Magalhaes wrote:

> The question is whether this affects or not the aging process
> (upstream or downstream?). Studies done in the 60's and 70's
> using ionizing radiation, UV, chemical mutagens, etc. in mice and flies
> showed that the mutations caused by these agents are not a part of the
> aging process.

It would be interesting to go back and look at these in detail.
We know now that high doses of radiation are going to cause extensive
apoptosis due to the number of double strand breaks they cause.
That would presumably not be the same as "aging". You also
need to carefully differentiate between the mouse and fly studies
because the adult flies are all post-mitotic tissue. It is
also questionable whether you could use mice, because many lab mice
die from cancer (not "aging"), and all the mutagens are going to
do is increase the cancer rate.

What would be interesting is to study the effects of long-term low-dose
exposure to mutagens/radiation. Also interesting would be using
mutagens/radiation to attempt to induce aging in non-aging organisms.

> I asked this in a previous post, I ask it again, why then do clones made
> from young cells (taken from foetus, not young adults) show the exact same
> problems? Until you can answer me this I will not be convinced.
>

Do you have studies that cite the clone failure rate and developmental
abnormalities are the same with foetal cells *and* adults?

I would not have expected that people would have done these studies yet,
certainly not in replicated work that you can make strong claims about.

>
> I never liked Kirkwood's disposable soma theory and this reminds me of it.
> Here's my problem: if you overexpress telomerase in mitotic cells they will
> overcome aging without any noticeable loss of resources. So, even assuming
> the telomeres as an anti-cancer mechanisms, cells can very cheaply overcome
> senescence, contradicting Kirkwood's theory.

It sounds like you are mixing apples and oranges. Mitotic cells in
my mind cannot be classed as "soma". My brain cells typically don't
divide and that is the "soma" that when disposed of causes the problems.
While the "perfect" cells can overcome senescence, cells that have
fatal mutations in essential genes (from mutagens, cosmic rays or
simply even error in copying from DNA polymersase) certainly cannot.
The thing that always gets left out of cell scenescence studies is
the discussion of what fraction of cells you "lose" because they have
accumulated fatal mutations.

> Many species showing vegetative reproduction are other examples refuting
> these theories.
In the long run even the bodies of Sequoia trees are disposable!
Certainly in bacteria or endlessly self-cloning plants there is
no "soma" to dispose of. The entire organism is "reproductive".
There *is* aging however in that some fraction of those reproductive
cells are likely to be sterile. Guarante's work in budding yeast
shows that cellular aging does occur and it is caused by what is
effectively DNA damage.

> In addition, studies done in biotechnology show that cells can overexpress
> large amounts of trangenic genes without any noticeable deleterious effect
> (unless a toxic product is involved, of course).

I'm not sure that I see how this applies. You have machines that are
designed to produce proteins. They do that. However there is a
great deal of work that shows these cells have limits and you can
overengineer them to an extent that they cease functioning. If
you want to harvest a nonsecretable protein, you don't much care
whether the cell is sterile, you simply care what its yield was.

> I must say that although your ideas are logical I'm not convinced. For
> instance, wouldn't it be cheaper to just repair everything instead of
> creating and powering a whole mechanism just to determine what is useful
> and what isn't.

Yes, we can say that, but in the beginning nature *had* to go the mutation
and selection route to get something that could organize itself and
catalyze the production of more similar copies.

In fact, it is probably only when you get to the stage where you have
a significant information content in a non-copyable form (e.g brains)
that it makes sense to switch from a reproductive process to a
preservation process. In the beginning, the environmental niches
were completely unoccupied, so making copies as a way of preserving
the developed code was an important survival strategy.

> Besides, I am not aware of any experimental evidence
> supporting these ideas (unless you know something I don't; for example, has
> DNA repair the same efficiency in introns and exons?).

I'm fairly sure there is a difference in repair rates between transcribed and
untranscribed genes. Think about it for a minute -- how do you even *do*
repair for the genes that are switched "off" in cells? Shouldn't those
genes be wrapped up in condensed DNA and unavailable to the repair enzymes?
If so (or if the repair simply proceeds at a rate below the damage
accumulation rate), then you are going to get an accumulation of defective
DNA.

The genes that are "forever" turned off are only needed if you want to
make a clone from the cell and so only show up as defective if you
try to do that. I have a hard time linking DNA damage with aging
in active cells, where, in theory, the active genes should be repaired.
But I could see something like a slow accumulation of iron or copper
in the nucleus accelerating the rates at which DNA damage occurs
such that the cell can't maintain a functional set of undamaged
genes, leading to an eventual decline in cell function (e.g. aging).
Note that I'm primarily discussing post-mitotic cells here, though
this could be applied to some degree in infrequently dividing
stem cells.

Robert



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